97
Pain, -1 (1977) 97-132 @ Elsevier/North-Holland
Review Article
Biomedical
______
PAIN-SIGNALLING SPINAL CORD
STEPHEN Department
(Accepted
G. DENNIS
SYSTEMS IN THE DORSAL AND VENTRAL
and
of Psychology,
June
Press
Bnd,
RONALD .llcGill
MELZACK University,
;2lontreal,
Que.
(Canada)
1977)
SUMMARY
A review of the literature on pain-signalling systems in the spinal cord provides convincing evidence that nociceptive information is transmitted by multiple ascending systems. These systems include: (1) the postsynaptic fibers of the dorsal columns which relay in the rostral dorsal column nuclei; (2) the spinocervical tract which relays in the lateral cervical nucleus; (3) the neo-spinothalamic tract which ascends directly from cord to thalamus; (4) the paleo-spinothalamic tract which projects to the midline-intralaminar thalamic regions; and (5) the spinoreticular system which sends fibers throughout the brain stem reticular formation. In addition, the diffuse, polysynaptic, propriospinal systems may also carry pain-related information. The data indicate that the first 3 systems, which comprise the “lateral” group, are generally similar to each other on at least 4 dimensions: modalities represented, conduction velocities, loci of origin, and areas of termination. However, despite their overall similarities, there are clear differences, particularly in the precise modes of termination and routes of ascension. Moreover, they appear to be controlled differently by the inhibitory systems descending from the brain. The other 3 systems, which constitute the “medial” group, appear to have the same modality spectrum. However, they differ from the lateral group on other dimensions - they conduct more slowly; their cell bodies tend to be located more deeply in the spinal grey matter; and, most importantly, their patterns of termination are grossly different from those of the lateral group. Several speculative proposals are presented to explain the functions and possible interactions among the various systems. These proposals emphasize two main factors: (1) the possible influence of on-going behavioral sequences on the relative activity among the systems; and (2) the possible effects of existing tissue damage on the mediation of subsequent noxious stimuli. Although these proposals are speculative, they are amenable to experimental investigation. Implications for the treatment of pain are discussed.
Contemporary theories of pain maintain that the major spinal pain-signalling systems lie in the ventral half of the spinal cord. These projection systerns include the neo- and paleo-spinothalamic tracts, the multisynaptic propriospinal paths, as well as the spinoreticular fibers that course medially into the reticular formation and limbic systems. These systems, it is assumed, underlie the sensory-discriminative and affective-motivational dimensions of pain [156]. In contrast, the long ascending pathways in the dorsal half of the spinal cord, particularly the dorsal column and spinocervical tracts that project to the brain via the medial lemniscal system, are traditionally held to play no direct role in pain experience. Specificity theory maintains that the dorsal cord projection systems mediate fine tactual discrimination, spatial locahzation at the skin, and proprioceptive-kinesthetic functions. Pattern theory [173] proposes an additional function: the inhibition of pain signals transmitted from small peripheral fibers to dorsal horn cells that subsequently project through the ventral pathways. The gate control theory [156,157] agrees with this inhibitory property but proposes yet a further role for the dorsal cord pathways: that of a central control trigger that activates memories, pre-set response strategies, and other central neural processes that exert control, via descending pathways, over inputs ascending in the ventral pain pathways. Clearly, none of the contemporary theories proposes a direct role for the dorsal spinal pathways in pain perception and response. Several reviewers have recently reiterated these basic views [ 1,24,118,228, 2361. However, they also point out that an increasing amount of experimental evidence does not readily fit any of the contemporary theories. In particular, it is becoming apparent that the dorsal cord pathways may play a more direct role in pain perception than was previously thought. The evidence for this view comes from numerous physiological and behavioral experiments, no one of which constitutes conclusive proof, but all of which, taken together, present a consistent picture. The purpose of this review is to present the evidence in the context of a general summary of spinal pain-signalling pathways. The data, we believe, show that in addition to the major pain tracts in the ventral cord, there are small, functional pain-signalling pathways in the dorsal cord of all mammalian species, including the human. We cannot specify the precise role of these dorsal pathways, nor indeed of any ascending pathway, in pain perception and response; we shall only speculate on what they might be. While the inferential nature of this conclusion is fully recognized, as is the vulnerability of some of the evidence, we suggest that the importance of this hypothesis to the understanding of pain, and its therapeutic control, warrants its presentation. At the very least, it may stimulate research on hitherto unconsidered problems.
99 PHYSIOLOGICAL
EVIDENCE AND ANATOMICAL
CHARACTERISTICS
The presence of specific mechanical and thermal nociceptive neurons in peripheral nerves has been well documented [19,52,115]. Also well established is the representation of these neurons, either as specific relays or as convergent “multimodal” relays, throughout the spinal grey matter [61,93, 99,106,115,185,224,227,237]. How this nociceptive information is distributed from the spinal grey to the various long ascending pathways in the spinal white matter has been of concern to investigators for many years. The picture which is emerging is one of widespread distribution to all areas of the white matter [ 361, including the dorsai and dorsolateral areas. Dorsal column system Physiology. The dorsal columns (DC) are composed chiefly of primary and secondary afferent fibers ascending to the dorsal column nuclei (DCM) in the caudal medulla. For decades the dorsal columns have been viewed as carriers only of innocuous tactile or proprioceptive information. While this still appears to be the case for the DC primary afferent fibers, it can no longer be said of the secondary afferents. The first conclusive demonstration that dorsal column postsynaptic (DCPS) fibers carry pain-related information was made by Uddenberg [219, 2201, although others [ 39,233] had hinted at their existence. Of 295 axons recorded in the cat’s cervical dorsal columns, 79 (26.8%) were found to be transsynaptically activated from small to medium sized peripheral fields. All were found to give a rapidly adapting discharge to hair movement, but an unspecified number also exhibited a sustained, high-frequency discharge to noxious pinch. The peripheral fields for the nociceptive and light tactile responses were found to be co-extensive; no such fibers were found among the primary afferents sampled. Uddenberg’s results have recently received compelling confirmation by Angaut-Petit [8,9,182]. Also recording from the feline dorsal columns, she found that 92 units (9.3% of DC fibers) were DCPS axons. Of these, 77.2% responded differentially to both gentle and noxious stimuli, and 6.5% responded only to noxious mechanical stimuli, while the remainder were activated only by light mechanical stimuli. Moreover, an unspecified number were sensitive to noxious thermal stimuli, exhibiting a sustained, high-frequency discharge once the skin temperature exceeded 45°C. Some units were sensitive to cooling, as noted also by Uddenberg [ 2201. Cells exhibiting similar properties have also been observed by Angaut-Petit [9,182] in the rostra1 and ventral nucleus gracilis. Of 134 units recorded, 41.8% were hair- or touch-activated, and 26.9% responded only to tapping on the skin. The remainder (31.3%) were differentially sensitive to both gentle and noxious mechanical stimuli, and responded well to noxious heat. Transections of the spinal cord, sparing only the dorsal columns, did not greatly alter these cells’ responses to either noxious or gentle stimuli, indicating that they are activated by DCPS fibers. Dart and Gordon [ 711 have also observed pain-related units in the DCN; however, these cells were activated
100 L)y fibers in the dorsolateral funiculus. DCN cells which might have been nociceptive have been reported by others [96, 147 1. The above experiments clearly establish the presence of pain-signalling information in the DCPS-DCN system of the cat. Whether this is true for all mammals, or simply a peculiarity of the cat, cannot be said with certainty. There are as yet no comparable data for primate species. ,4natomical characteristics. One of the principal unanswered questions regarding the DCPS-DCN system is whether its information, particularly the nociceptive type, is transmitted rostrally, or whether it carries out its functions exclusively within the DCN. Present evidence is consistent with both possibilities. Fig. 1 summarizes the basic nruroanatomy of the DCPS-DCN system. In the spinal cord, the DCPS fibers lie deep within the dorsal columns, ventral to the bulk of cutaneous primary afferents [8,219]. They ascend the DC ipsilateral to their receptive fields, and synapse preferentially in the rostral and ventral portions of the DCN [9,200,201,219]. Primary afferents tend to terminate in the caudal and superficial areas of the DCN. The cytoarchitecture [ 130,200,201] and physiological characteristics [ 96, 98,147] of these DCN regions differ significantly. As indicated in Fig. 1, virtually all the DCN efferents cross the midline in
Nuclcur Nucleus
Cunsotur Grorilis
21,
21. 105,
SC/K
105,
MGm
26.
109, 105,
109. 130, 130,
136, 136, 136
(142).
206
141. 193
1225) 225
193
Fig. 1. Summary of the neuroanatomy of the dorsal column postsynaptic (DCPS) system. Postsynaptic fibers, many of which respond to noxious stimuli, ascend the dorsal columns to the rostra1 dorsal column nuclei (DCN), and are then relayed to various brain structures. Numbers are references to published articles reporting the terminations of the DCN. Numbers in parentheses are reports in which the evidence for terminations in a parbut in which the conclusion is not explicitly stated. Abbreviaticular region is suggestive, nucleus of thalamus; PO, posterior thalamic group; ZI, tions: VPL, ventroposterolateral zone incerta; SC/IC, superior and inferior colliculi or collicular plate; MGm, medial part reticular formation; PT, pretectal of medial geniculate body; MRF, mesencephalic regions; NR. red nucleus, (Note: Figs. l--3 are meant to neuroan;rtomy of the systems depicted. For this reason, been given detailed attention. In particular the problem identification of subnuclei within structures deserve a ran be given here. For a more precise understanding of tems. the reader is urged to consult the original articles.)
convey several
a general important
overview of the issues have not
of species differences and the more detailed presentation than the neuroanatomy of these sys-
101 the lower brain stem, and ascend to higher levels in the medial lemniscus (ML). There is no doubt that all regions of the DCN contribute axons to the ML [21,54,55,71,96,105,130,136,205]. However, the magnitude of the rostral DCN projection and the type of information it contains are not entirely clear. Kuypers and Tuerk [ 1301 found that a substantial number of rostral DCN cells do not show retrograde degeneration when the ML is cut. Similarly, Gordon and Jukes (96) estimate that only about one-third of the cells can be antidromically activated from the ML. However, these investigators raise two technical points regarding their studies: first, the rostral DCN projection is rather diffuse and is not confined to the main body of the ML; second, if the DCN cells have collaterals to other regions (e.g., within the DCN), in addition to their ML axons, a significant portion might escape retrograde degeneration following ML lesions. Both possibilities would tend to produce underestimates of the rostral DCN contributions to the ML. There is little evidence regarding the modality properties of the rostra1 DCN projections. Dart and Gordon [71] found that none of their 15 nociceptive cells projected past the DCN, while about 30% of other types did. However, their studies were concerned with DCN cells activated by the dorsolateral funiculus, not by the dorsal columns. Brown et al. [ 441 reported axons in the ML which apparently had nociceptive capabilities, but their origins were not traced. Kuypers and Tuerk [130] have offered the intriguing speculation that the rostral DCN cells which do project through the ML receive convergent inputs from many other rostral DCN cells, and as such may code stimulus intensity. However, this is speculative. Clearly, there is as yet no conclusive evidence for the rostral projection of nociceptive information from the DCN. But neither can the possibility be ruled out, since the appropriate experiments have yet to be reported. In view of the rather high proportion of rostral DCN cells which have a nociceptive component (e.g., 30% [9]), and the fact that at least one-third or more of all rostra1 DCN cells project rostrally, it is possible that at least part of the pain-related DCPS information is in fact relayed to higher brain structures. Fig. 1 lists the regions in which DCN axons have been found to terminate, and which may therefore be the recipients of the pain-signalling DCPS information. The main somatosensory nucleus of the thalamus (VPL) is the principal site of termination, although other areas clearly receive fibers. Not indicated in the figure is the suggestion by several workers [ 105,136] of differences between rostral and caudal DCN projections. They report that, in rats and cats, the caudal DCN projection is more restricted to the VPL and MGm, while the rostral DCN terminates in the other regions listed, in addition to the VPL and MGm. Boivie [ 211, however, saw little difference between the rostral and caudal DCN terminations. Of particular interest are the DCN projections to the posterior thalamic complex (PO), which has been found to contain nociceptive cells [68,183], and to the zona incerta (ZI), which is regarded as the rostral extension of the mid-brain reticular formation [217]. Projections to cortex from VPL [217], MGm [ 197, 2211, and PO [ 691 have been identified.
102 Sunzmry. A small system of secondary (and perhaps hight%r order) affertnts has been d~~nlonstrated in the feline dorsal columns. These ;t\;ons are capable of carrying ~~~~l-si~l~ii~lg i~lforl~~ation to the rostra1 parts of the dorsal column nuclei. Some appear to be rxclusively nociceptive. Projection of this information to various thalamic and collicular regions and to the zona incerta is possible, as is a subsequent relay to cortex. The primate homolog of this system has yet to be demonstrated; however, its existence is suggested hy indirect evidence t,o be presented in later sect,ions. Spinocervicothala~nic system Physiology. The spinocervical tract (SCT) [ 1631 ascends the dorsolateral spinal funiculus to the lateral cervical nucleus (LCN) [ 331. Neurons which respond to noxious mechanical and thermal stimuli have been amply demonstrated in the feline SCT-LCN system ~41,42,50,97,138,159,179,188]. A substantial portion of these fibers respond to stimulation of peripheral ,316 and C fibers [45,47,159], and some show the “wind-up” effect [159,160] characteristic of pain-signalling systems at the spinal and midbrain levels [ 151. The ease with which pain-signalling information can be demonstrated in the feline SCT-LCN, coupled with the difficulty in demonstrating the presence of a neo-spinoth~a~n~c tract in this species [ 5,165], has led some investigators to suggest that the feline SCT-LCN system is simply the homolog of the primate neo-spinothalamic tract [5,209,224]. However, as will be shown below, the cat does have a functional neo-spinothalamic tract, in addition to the well-developed SCT-LCN system, making the homology argument less attractive. More recently, records have been obtained of primate SCT-LCN units which respond to noxious stimulation [ 49,107,191], Bryan et al, [ 491 found that of 25 SCT cells activated by light tactile stimuli, 11 (43?) showed an increased discharge to intense mechanical stimulation. Six of 16 cells tested were sensitive to noxious heat (42°C). One cell responded exclusively to noxious stimL]lation, Thus, in primates as well as in cats, the SCT-LCN SYStern may be a pain-s&milling system. ilnatomical characteristics. Fig. 2 summarizes the neuroanat,omical characteristics of the SCT-LCN system. Although its existence was at one time denied in primates, the SCT-LCN system has now been identified in all higher species, including the human [ 100,101,125,161,172,218]. Truex et al. 12181 report that the size of the human LCN varies greatly among individuals. It was identified in 9 of 16 cords examined, and was well developed in two. In the remaining seven it could not be identified. This has led Kerr [ 1181 to conclude that the SCT-LCN system is “vestigial” in humans. However, while the SCT-LCN system in man is less well developed than that in carnivores [ 102,103,127,164,218], it does not rule out the possibility of a functional role for the SCT-LCN system in those people in whom it is present. As indicated in Fig. 2, the SCT axons ascend the dorsolateral funiculus ipsilateral to their receptive fields. Approximately 75% of the fibers termi-
103 Midline VPL:
6,
23,
137, Caudol Medulla
Dorsal
Lateral High
Cervical
Cord
(Cl -‘Xl
Column
100,
103,
131.
141, 165
PO:
23,
70
MGm:
23.
141
21:
137
CM-PI:
137
Cervical
I
Spinal
Cord
Fig. 2. Summary of the neuroanatomy of the spinocervicothalamic system. Postsynaptic fibers ascend the spinocervical tract (XT) and terminate mainly in the lateral cervical nucleus (LCN) although some also reach the rostra1 DCN. A subsequent relay through the medial lemniscus is shown. Numbers are references to articles reporting the terminations of fibers from the lateral cervical nucleus. CM-Pf, centrum medianum-parafascicularis complex; other abbreviations as in Fig. 1.
nate in the LCN [ 2111, the remainder probably going to the rostra1 DCN [ 71,95,172,201,202,212]. The latter includes a nociceptive component [ 711. Other sites in the medulla (e.g., the lateral reticular nucleus and medullary central grey) receive a few fibers from the dorsolateral funiculus, but it is uncertain whether these are SCT axons [ 1721. The LCN efferents cross the midline in the caudal medulla and ascend in the ML along with the DCN efferents [23,54,100,141,165]. Collaterals synapsing within the LCN have also been suggested [ 971. The LCN terminations are summarized in Fig. 2. Like the DCN projections, the main somatosensory thalamic nucleus (VPL) is the principal site of termination for the LCN fibers. In fact, some of the DCN and LCN projections to this region have been found to converge on a group of cells which surround the somatotopic (and presumably caudal) DCN projections [ 6,131]. The other terminal zones also appear to overlap with the DCN projections to some degree. A direct neuroanatomical route to the reticular formation has not been demonstrated, except perhaps for very small projections noted by Nijensohn and Kerr [ 1721 and Nauta and Mehler (cited in ref. 171). However, electrophysiological studies suggest an input to the reticular formation [ 1621 and subthalamic complex [76] from the dorsolateral funiculus. In addition, SCTLCN information is relayed to several areas of cortex [ 6,24,85,163,174]. Summary. The spinocervical tract is a somatosensory pathway that ascends in the dorsolateral funiculus of the spinal cord. It appears eminently capable of transmitting pain-signalling information to rostral levels of the cord in both primates and carnivores. After relaying in the lateral cervical nucleus, the information is projected to the somatosensory thalamus and adjacent areas, and may reach the reticular formation. The pathway is also represented at the cortex.
104
dledial lernniscus The DCN and LCN projections through the ML make the latter a key structure in the analysis of the nociceptive capabilities of the former. However, little is known about ML physiology. Brown et al. [44] report that 9 of 52 lemniscal units activated by hair follicle receptors also showed a sustained discharge of higher frequency to pressure on the skin. For some units, noxious pressure was required to evoke this slowly adapting discharge. Since the bulk of ML fibers come from the DCN, it is possible that these neurons are the rostral relays for the nociceptive DCPS-DCN cells, although some may be SCT-LCN axons.
Nco-spinothalamic tract Physiology. The neo-spinothalamic
tract (nSTT) ascends from the ventral and ventrolateral regions of the spinal cord to the thalamus. Its capacity for carrying both light tactile and pain-related information, especially in primates, is firmly established [ 4,11,88,190,191,214,215,232]. For example, Treviiio et al. [214] report that 30% of primate nSTT fibers require intense mechanical or thermal stimulation, while 38% respond to hair movement, 21% to light pressure, and 11% to stimuli affecting deep, subcutaneous structures. Price and Mayer [ 1901 estimate that 12.2% of ventrolateral cord units are exclusively nociceptive, 26.8% are sensitive only to gentle tactile stimuli, and 61.0% are multimodal (responding to both light and noxious stimuli). While primate nSTT units are easily studied, some difficulty has been reported in obtaining satisfactory recordings from comparable feline cells [ 51. However, the use of more sensitive signal-averaging techniques [ 148, 2161 and recordings from cervical cord regions, instead of the usual lumbar preparation [82], have clearly revealed the presence of the feline nSTT. Pomeranz [184] observed nociceptive units in the feline ventrolateral cord, some of which may have been nSTT fibers, and evoked potentials due to C fiber stimulation have been recorded in this region [ 1401. It is apparent then that the cat does indeed have an nSTT, as does the primate. In both, the systern clearly carries nociceptive information. Anatomical characteristics. The ascending route taken bv nSTT axons is distinctly different than in the dorsal cord pathways. As shown in Fig. 3, the fibers cross the midline in the spinal cord and ascend predominantly in the ventrolateral spinal quadrant. A ventral division is also present. No further synapses are intercalated between the cord and brain levels in the classical nSTT pathway. Fig. 3 also summarizes the brain regions in which ventral and ventrolateral cord fibers have been found to terminate. The segregation of these terminal zones into 3 separate groups illustrates the fact that several major systems ascend from the ventrolateral cord to the brain. Group A represents the terminations and includes the nSTT and spinotectal systems. “ML-like” Group B lists intralaminar and midline thalamic nuclei which are considered the terminal zones for the paleo-spinothalamic tract (pSTT). Group C corresponds to the spinoreticular tract (SRT) whose anatomical differentiation
105 Group A
,_-. ‘,. ’ \,..
.*,’ .
,_.\ ,l
I
VPL.
7, 27, 151-154,
TRN: PT:
27,
31, 90, 171
119.
122,
137,
31. 90
137
Group
C
7, 27, 31. 137, 151-154, 171 31, 119, 137, 151-154, 171
Fig. 3. Summary of the neuroanatomy of the ventral and ventrolateral cord pathways, including the neo- and paleo-spinothalamic tracts and the spinoreticular system. Postsynaptic fibers, including those which cross the midline in the spinal cord, ascend directly to brain structures. Three separate groups are shown. Numbers are references to published articles as in Fig. 1. Abbreviations: TRN, thalamic reticular nucleus; CL, centralis lateralis; \lD, medialis dorsalis; Pf, nucleus parafascicularis; CM, centrum medianum; RF, brain stem reticular formation; CG, brain stem central grey; others as in Fig. 1.
from the other ventral tracts has recently been made clear by the elegant studies of Kerr and Lippman [ 121,122]. The pSTT and SRT systems will be considered in a later section. The group A terminations are clearly similar to the areas listed in Figs. 1 and 2 for the DCPS-DCN and SCT-LCN systems. However, there are specific differences which will be discussed below. The VPL is considered a major terminal zone for nSTT fibers in the primate and has been frequently listed as such for the carnivore. However, Boivie [22,24 1, using a more rigorous definition of VPL, has found in cat that the nSTT terminates in a transitional zone between the VPL and the more rostral ventralis Iateralis. Whether this anatomical species difference underlies a functional difference remains to be determined. Te~inations in other thalamic and subth~amic areas in the vicinity of the ventrobasai thalamus have also been found as shown in Fig. 3. Tectal connections are present, as they are in the DCPS-DCN system, and their possible association with central grey projections has been noted [152]. In view of the extensive thalamoco~ic~ efferents from the group A nuclei (see above), the projection of nSTT information to the cortex is probable [ 241. Recently, Eidelberg et al. [84] reported the rather precise convergence of the nSTT and dorsal cord information onto cortical units. Similarly, Curry and Gordon [70] have found convergence of the 3 pathways on units
106 in the PO thalamic complex, somc~ of which may project to corks [ 69 1. The anatomical differences bet,ween the ventral and lateral nco-spinothalamic tracts are few but significant [ 1191. However, these may be related mainly to the mediation of subcutaneous, deep-field sensations since physiologically the ventral and Iat,eral components seem to differ only in this modality [ 111. Summary. The neo-spinothalamic tract transmits pain-signalling information from the ventral half of the spinal cord to the brain of primates and carnivores. Its terminations are generally similar to those of the dorsal cord projection pathways, although its axons are in close proximity to those of other spinal systems ascending to a variety of rostral areas. Cortical project,ion of the nSTT information occurs and is in part convergent with the cortical projections of the dorsal cord systems. Comparisons among the systems The preceding sections indicate the widespread distribution of nociceptive, thermal, and tactile information to three major ascending somatosensory systems in the dorsal and ventral spinal cord. The transmission to the brain of this information, including nociceptive signals, has been demonstrated for the nSTT and SCT-LCN systems. Furthermore, there is suggestive, though indirect, evidence for a rostra1 projection of the DCPS-DCN
TABLE
Light
I
DCPS-DCN
SCT-LCN
nSTT
SCT-LCN
9, (39),
12, 7.5, 97, (1 15) 138, 159, 166, l79,lHH
82, 118, (lHl), 216
19, (191)
12, 50, 97, 179.18H
(115). (1X-l)
118.
-19. (191)
12, 18X
(115).
(129).
-19, (191)
129, (181), (191), 232
(115), 148,
19, (107). (191)
4, 5, 11, 88, (190) (191) 232
220
tactile
Noxious tactile
9, (39)
Noxious thermal
9
Multim od al
82,
’
138, 12, (115) 159, 179,188
* Table entries are references tems. Numbers in parentheses modality type in a particular In some cases, the conclusion that of the present authors.
(181), 216
5, 11, 88, (181), (190), (191), 211.232
5. 11,58,
(lSl), (191).
(181) $33) 9 220
nSTT
(ISA),
to articles reporting the modality represent reports which imply the system, hut in which the conclusion is inferred hy the cited authors; in
129.
(199), 211,232 (190),
21-1.
types in the listed syspresence of a particular is not explicitly stated. others, the inference is
107 nociceptive information. It appears necessary, then, to re-examine present views of the neural basis of pain perception and response to account for the presence of multiple pain-signalling pathways from the spinal cord to the lateral thalamus. The present section compares these systems on several physiological dimensions. Table I presents a compilation of published reports on the representation of 4 basic modality types in the feline nSTT, DCPS-DCN, and SCT-LCN, and primate nSTT and SCT-LCN. Although different authors have used different classification schemes, the one shown in the table represents a convenient way to compare the reports. Table entries are references to articles which demonstrate the existence of the modality type in the system listed. The table reveals a clear similarity among the systems with regard to the qualitative modalities represented. No system can be claimed as having the exclusive ability to mediate either nociception or light touch. However, there may be some important differences superimposed on this pattern of general similarity. Brown [36], for example, has noted differences in the types of light tactile information carried in the feline dorsal cord systems. Neural activity from Pacinian corpuscles, slowly adapting types I and II touch receptors, and pad and claw receptors is projected through the DC, but not apparently through the SCT, while the SCT rather than the DC carries activity from the ubiquitous, highly sensitive down-hair receptors. Whether such differences are also present in the specific types of nociceptive information they carry has not been determined. There may also be quantitative differences among the systems that are not indicated in Table I. For example, cells that are exclusively nociceptive make up only 6.7% of the feline DCPS-DCN units [9], but possibly up to 20% of the SCT-LCN [42]. Bryan et al. [49] found only one nociceptor among 32 units sampled in the primate SCT, while Willis et al. [232] report some 30% in the nSTT. While it is difficult to assess the magnitude of quantitative differences due to procedural variations, particularly in the type or depth of anesthesia, the available data suggest different biases among the three systems in the mediation of particular somatosensory modalities. However, exclusivity in any one modality appears to be ruled out. A general similarity among the nSTT, SCT-LCN, and DCPS-DCN systems is also evident on two other physiological dimensions: conduction velocity (Fig. 4) and loci of origin (Table II). The entries in these tables are again references to articles reporting the particular conduction velocities and/or ranges and locations of cell bodies. Fig. 4 shows the axons of each system to be well myelinated and typically conduct impulses in the range of 30-60 m/set. This is substantially faster than the C and A6 fibers which carry nociceptive information from the periphery. It must be remembered, however, that larger axons and cells are more readily observed in single unit studies, and that larger axons conduct faster than smaller [ 113,114]. Thus, some conduction velocity estimates may be biased toward higher values. There is some indication from the table that the feline SCT-LCN may be faster than the DCPS-DCN or nSTT sys-
Feline
Primate
IOOL
80 -
I
: ;60 E
220
t” L 2 40
20
-’
1
11381 42
211 SO
I
II
82
216
49
-
A DCPSDCN
SCT~LCN
“STT
scr--LCN
terns, and this has direct support [56,174,211]. In the monkey, the nSTT appears to be faster than the SCT-LCN system [AS]. Table II lists results on the cells of origin of t.he t.hree systems. The only evidence on the origins of the DCPS-DCN axons comes from Rustioni and Dekker [203], who summarize dat,a showing DCPS cell bodies in the dorsal horn. The other systems have been more extensively studied. Again the table reveals no remarkable differences. Resed’s [196] laminae IVand V are most often reported as sources, and in many reports are ideIltified as the main sources. On the basis of electrophysiological studies on lumbar preparations, Trrvitio et al. [216] have suggested that the feline nSTT cell bodies are more concentrated in laminae VII and VIII than the SCT cell bodies [50,188]. However, the use of cervical preparations has revealed dorsal horn contributions to the feline nSTT, including a cell Iocalized in lamina I [SZ]. SIore recently, Treviiio and Carstens 12131, using the horseradish perosidase method, have essentially confirmed the electrophysiological results in monkey and cat, including the differences between feline lumbar and cervical dorsal horn contributions. The anatomical method also revealed a clear projection to lateral thalamic regions from lamina I ceils in the cervical and lumbar cord of both species. Lamina I contributions to the systems are of interest since this region of the dorsal horn has been shown to contain a high proportion of purely nociceptive cells [61,63,129]. The axons entering the spinal tracts from lamina I have been found to conduct at a significantly slower rate than projections from other laminae [49,189,215,232]. It has also been
109 TABLE
II
LOCATIONS
Lamina (Rexed)
OF CELLS
OF ORIGIN
OF FELINE
AND PRIMATE
SPINAL
TRACTS
Primate
Feline
SCT-LCN
nSTT
SCT-LCN
nSTT
(SO), (115)
82, (7 29), 213
49
11, 88, (129), (190), 213-215, 232
50, 83, 111, (115), 188
(115),
49, (191)
11, 88, (190), 213-215, 232
\’
50, 83, 111, 188
82, 213,
49, (191)
4, 11, 88, (190), 213-215, 232
VI
50, Ill, 188
82, 216
49
11, 88, (190), (191), 214, 215, 232
50,188
213, 216
49
(190), 232
50
82, 213, 216
49
213.-215,
DCPS-DCN I
IV
VII \‘I11
203
-
*
213 216
213-215, 232
* Table entries are references to published articles. Numbers in parentheses refer to articles in which the suggestion is made (or is inferred by the present authors) that the cells of origin of a particular system are found in a particular spinal lamina, but in which the identification is not explicitly stated.
suggested that cutaneous receptive fields tend to increase in size from lamina I to deeper laminae [ 111. Summary. Similarities among the nSTT, SCT-LCN, and DCPS-DCN systems are apparent on several dimensions. Each has been shown to carry nociceptive, thermal, and light tactile information. Each originates, in part, from the dorsal horn of the spinal grey, and projects predominantly to the nuclei of the lateral thalamus (ventrobasal, posterior, and subthalamic complexes). Each is rapidly conducting. However, although generally similar, the systems are not identical. Certain qualitative and quantitative differences have been identified, although their magnitude and importance are difficult to assess. Two additional differences are considered in the following section. Differences
among the systems
On the basis of the previous discussion, it is tempting to consider the nSTT, SCT-LCN, and DCPS-DCN pathways as equivalent systems in somatic sensation. Their similarities, at least in a broad sense, are clear. However, there are also several significant differences among them, suggesting that they may actually function in different ways or under different circumstances. Two key differences are discussed below. Anatomical differences. As shown in Figs. 1, 2 and 3, the DCPS-DCN,
110
XT-LCN and nSTT systems all terminate predominantly in the nuclei of the lateral diencephalot~~ However, within these nuclei, the 3 systems show differences in the reiative densities, locations, or modes of termination. Boivie [21-231 has studied the projections of all 3 systems in the cat. He found that nSTT terminations are more concentrated in the rostra1 ventrobasal thalamus in a zone of transition between the VPI, and the ventralis lateralis. The DCN and LCN projections were identified in the VPL proper, with the LCN terminals tending to be unevenly distributed while the DCN fibers were found relatively evenly throughout. All systems were found to terminate in the medial part of the PO complex (Porn). However, the densities and precise locations of termination differ somewhat. For example, overlap between the DCN and LCN fibers was found in the rostra1 POm, while the caudal regions receive only DCN fibers. More recently, Boivie [ 20,241 has summarized studies on the termillat.~ons of the DCN and nSTT in monkeys. As in the cat, the nSTT terminals tend to accumulate more rostrally in the ventrobasal thalamus, but do not obviously exceed the boundary of the VPL. In this species, the DCN and nSTT terminals clearly overlap in VPL. However, the nSTT fibers tend to terminate in “bursts” or clusters in the VPL [20,119,151], while the DCN terminals are more evenly distributed ]20,26]. Lund and Webster [136,137,229] have studied the terminations of the ascending somatosensory systems in the rat. They also found that the nSTT fibers tend to terminate rostral to the bulk of the DCN fibers, although the two systems overlap. In this species, ZI projections were attributed to the DCN, and by inference to the LCN, but not to the nSTT, unlike the pattern in cat 1221. While it is difficult to say precisely what these differences mean, their occurrence suggests that the DCPS-DCN, SCT-LCN, and nSTT, although generally similar, may not have identical functions. That all 3 systems reach overlapping regions of the lateral diencephalon is clear; however, it is equally clear that they do not terminate in precisely the same ways in these regions. Moreover, as shown in Figs. 1-3, their routes of ascension are obviously different. Inhibitory control, Recent evidence suggests that the descending inhibition exerted on the DCPS-DCN, SCT-LCN and nSTT systems may differ. Brown and co-workers [ 37,38,45,46,48] have demonstrated extensive descending control on the feline XT-LCN system. The inhibition can be triggered by stimulation of the contralateral dorsolateral and ventromedial cord and the dorsal columns. SCT inhibition has also been observed from stimulation of the mesencephalic tegmentum, central pontobulbar core and several cerebellar regions [ 2091. More recently, specific cortical regions have been found to exert strong inhibition on SCT cells 140,431, although LCN cells have been found to be unaffected by such stimulation [97]. Decerebration, however, does not abolish SCT inhibition, indicating both cortical and subcortical sources [ 371. of great interest is the modality specificity of descending control. The
111
inhibitory effects appear to be exerted predominantly on the nociceptiue signals in the SCT-LCN system, while the light tactile responses remain relatively unaffected during stimulation [ 37,38,237]. As might be expected, C fiber input is reduced preferentially over A fiber input [ 461. In contrast, no such differential inhibition has been reported by McCreery and Bloedel [ 1481 who studied the feline nSTT system. They found a general depression of unit activity when RF sites, particularly the caudal part of the nucleus gigantocellularis, were stimulated. Also unlike the SCT-LCN system, they found no inhibitory effect during cortical stimulation [ 1491, although this might have been due to the level of anesthesia [ 401. In primates, cortical stimulation has been found to inhibit nSTT unit activity [66,67]. Moreover, in this system, the cortical inhibitory control is directed predominantly at the light tactile inputs, leaving the nociceptive responses, particularly those from lamina I, generally intact. This is in clear contrast to the feline SCT-LCN inhibition pattern. However, the nociceptive responses of primate nSTT units, including those in lamina I, can be inhibited by stimulation of the nucleus raphe magnus [14]. Such stimulation is consistently more effective in inhibiting the A6 inputs than the larger A fiber inputs. This suggests a pattern just the reverse of that produced by cortical stimulation. That some form of inhibition can be exerted on all pain-signalling systems is strongly suggested by behavioral studies using focal brain stimulation to produce analgesia [ 134,144,146,204]. There is little direct information on inhibitory control of the DCPS-DCN system. A potentiation of both evoked and spontaneous discharge rates has been observed in spinal, as compared to intact, anesthetized cats [9] suggesting some form of descending control on DCPS fibers. The bulk of corticofugal fibers that terminate in the DCN do so in the rostra1 areas, where the majority of DCPS fibers also terminate [ 1301. There is indirect evidence that suggests differing inhibitory control on the DCPS-DCN and SCT-LCN systems. Carli et al. [56] recorded evoked potentials in the ML and found that REM bursts in sleeping cats produced phasic depressions of the ML response to peripheral nerve stimulation. The depression was 50% greater on the dorsal column component of the evoked potential than on the SCT-LCN component, suggesting differential inhibition on the two systems. However, it is not known whether the DCPS-DCN system in particular was affected. No differential inhibition was observed during other stages of sleep. Summary. Although further information is needed, particularly direct comparisons among the 3 systems under identical conditions, the present evidence suggests relative differences in the anatomy and inhibitory control of the DCPS-DCN, SCT-LCN and nSTT systems. The possibility that the transmission within the systems can be “switched” to carry selective information on one modality or another ~- pain or light touch - is highly intriguing. Contrasts with the pSTT and SRT systems Fig. 3 depicts 3 somatosensory systems
ascending
from the ventral spinal
112
cord. C)nt?, the nST’l’, has been discussed abovcl. Th!’ other two systems, the l)S’l’T (group B) and SRT (group C), are 1)riefly described in this schction, with particular reference to their possible involvement in nociception and their general characteristics. Although there has been much controversy over precise terminology [ 1511, the pSTT projections to the midline and intralaminar thalamic nuclei have been identified in virtually all mammalian species studied [ 151,1533. Mehler [ 1511 has indicated that the pSTT system differs little from species to species. The nSTT system, on the other hand, shows clear species differences in size and precise route of ascension. The pSTT is considered to cross the midline in the spinal cord [ 121,122], although some input may be homolateral. The fibers projecting directly from spinal cord to thalamus are few in number [25]. The projection of nociceptive signals to the midline-intralaminar nuclei has been demonstrated by several investigators [ 2,3,59,128,181]. However, the magnitude of the nociceptive contribution has been questioned [ 1761. Possibly the depth of anesthesia is a factor in this disagreement, since this has been shown to influence the observed properties of midline-intralaminar cells [ 591. The modality types reported for the midline nuclei are similar to those listed in Table I, although there is disagreement on the relative proportions of each. Receptive fields are generally very much larger than in the dorsal cord or nSTT systems. The spinoreticular system (SRT, group C in Fig. 3) is generally agreed to be substantially larger than the pSTT system, and has also been considered as phyletically constant [151,153]. The terminations of spinal fibers in the reticular formation form a complex pattern involving a variety of RF sites. The details are reviewed elsewhere [ 151,186]. Recently, Kerr and Lippman [121,122] have determined that the SRT projections do not entirely conform to the spinal cord diagram shown in Fig. 3. Using the technique of midline myelotomy - severing the axons crossing the spinal commissures by a longitudinal cut along the midline - they observed only sparse degeneration in the RF. Thus, most of the SRT axons apparently ascend the spinal cord ipsilateral to their cell bodies, instead of the contralateral scheme shown in Fig. 3. However, the possibility of bilateral, or even predominantly contralateral, receptive fields for these axons is not ruled out. By and large, the spinal input to the RF is diffuse, multisynaptic, poorly somatotopic if at all, and often highly convergent with other sensory modalities [ 161 and non-spinal RF connections [ 281. Physiologically, the units of the SRT have been shown to include the [ 12,15,17,53,57,58,60,87,139,186,223,2351, types listed in Table I although the relative proportion of each is debated [ 1751. The receptive fields of these cells are generally agreed to be larger than those of the dorsal cord or nSTT systems. The relay of SRT information to structures further rostral appears likely [ 251. While the modality types of the pSTT and SRT resemble those of the dorsal cord pathways and nSTT, they appear to differ somewhat on other phys-
113 iological dimensions. For example, the cells of origin, as determined by electrophysiological methods [ 5,25,87,132], appear to be concentrated exclusively in the deep spinal laminae (VI-IX). Both lumbar and cervical preparations have been studied. Treviiio and Carstens 12131, using the horseradish peroxidase method, found labeled cells only in lumbar laminae I, VII and VIII, even when the original injection included parts of the RF and midlineintralaminar nuclei. The pSTT and SRT may also conduct impulses more slowly than the dorsal cord pathways and nSTT [3,86,89,117,128,175,176, 1862231. When the evoked response latencies to a peripheral stimulus are recorded, it is generally found that those central structures receiving dorsal cord and nSTT input (VPL, PO, ZI) are activated prior to the RF or midlineintralaminar regions [ 86,89,128,176]. The difference is readily observed when comparing VPL responses against others, but PO and ZI responses also tend to occur sooner than RF or midline thalamic responses. Although the differences are not large and the distributions overlap, the direction of the difference seems clear and replicable. Summary. Two ventral cord systems, the pSTT and SRT, have been found to contain a proportion of cells that respond to noxious peripheral stimulation. Light tactile cells are also present in both. These systems appear to differ from those of the dorsal cord and nSTT with respect to loci of origin and conduction velocities. However, by far the greatest difference between the two groups is anatomical: the fibers of the pSTT and SRT turn medially to synapse in the reticular formation and midline-intralaminar thalamic nuclei, as opposed to the lateral course of the dorsal cord and nSTT systems. These contrasts suggest that the pSTT and SRT may be involved in aspects of pain fundamentally different than those of the nSTT, SCT-LCN, and DCPS-DCN. BEHAVIORAL
EVIDENCE
Although the physiological studies are highly suggestive, they do not necessarily establish the behavioral relevance of the dorsal cord pain-signalling pathways. That nociceptive information is carried by these systems seems undeniable; whether this information contributes to pain perception and behavior is not clear from the above data. However, research on the behavioral effects of spinal cord lesions and central electrical stimulation suggests that the dorsal cord projection pathways, in addition to the ventral pathways, can and do act as pain-signalling systems in the conscious, freely responding animal. Stimulation studies Medial lemniscus. Electrical stimulation of the medial lemniscus at pontine or midbrain levels is highly aversive. It motivates vigorous escape responding in rats and cats, and is described by human subjects as painful. In the rat, lemniscal stimulation provokes clear signs of distress: cringing, writhing, running, jumping, and some vocalizing [ 30,77,78,81,123,178]. Some rats show vigorous licking of contralateral fore- or hindpaws, or wiping of the ipsi- or contralateral muzzle, in a manner clearly suggestive of aversive
sensations referred to these regions. When trains of elcctrid pulses are delivered to the ML via chronically implanted electrodes, and the rats are allowed to turn off stimulation by pressing a lever, escape responding can be maintained at high rates, even after several months of daily sessions. Measurements of refractory period distributions [80,234] of the axons responsible for the aversive effects have indicated the presence of at least two functionally aversive axon populations in the rat ML [ 78,123]. Their sources, however, remain to he experime~ltall~7 determined. Electrode placements in the dorsolateral tegmentum, where presumably the rodent nSTT is located, are also highly aversive when st,imulated [ 1231. Studies in the cat also clearly demonstrate the aversive effects of ML stimulation [ 10,74,198,208]. Particularly convincing are the studies of Aoki and Nakao [ 101 who report that, of 310 electrode placements throughout the pontine brain stem, only those in or near the ML motivated reliable escape behavior (lever pressing). It seems unlikely that current spread to adjacent regions could account for these results since electrode tips actually located in these regions were often ineffective. Stimulation also produced pain-suggestive screeching and hissing, as well as a number of the stereotyped motor components reported in rats [ 771. Similarly, Spiegel et al. [ 2081, who make a clear distinction between nSTT and ML sites, report crying, hissing, struggling and flight reactions to ML stimulation. Stimulation of the ML also produces reports of pain or thermal sensations in man [ 104,167,168,170]. During stimulation of midbrain lemniscal sites, patients report distinctly aversive sensations once the stimulus frequency has reached a sufficiently high level. At frequencies below 60 Hz, only movement sensations or tremor are produced; at frequencies exceeding 120 Hz, the sensation is described as “hot and painful”. It is significant that the painful sensation is referred only t,o contralateral peripheral sites, indicating the activation of a predominantly crossed system. Nashold et al. [ 1701 also obtained reports of contraIateral pain from stimulation of the midbrain nSTT. However, nSTT pain is described as “brighter, sharper” than that evoked by ML stimulation, and appears at stimulus frequencies of about 60 Hz. Thus, stimulation of either the ML or nSTT can elicit sensations of distinctly negative effect, which are referred to contralateral peripheral sites, although the nSTT requires a lower stimulation frequency to produce this effect. The ML and nSTT sensations contrast sharply with the poorly localizable and highly intolerable sensations produced by stimulation of more medial midbrain sites where the SRT and pSTT fibers are located [ 1681. Other sites. At the spinal cord level, reports of sharp, burning pain are elicited during electrical stimulation of the ventrolateral cord [ 110,145], although this is by no means a universal observation [ 941 (LoeSer, PerSOnal communication). Electrical stimulation of the dorsal columns, by either surface [ 1691 or depth electrodes ]llO], has not been found to produce Pain, although distressingly unpleasant “shock-like” or “throbbing” sensations have been elicited. Mechanical stimulation of the dorsal columns, however, Morehas been reported to produce intense, localized pain [51,207,231].
115 over, Sourek 12071 has found that the peripheral sites to which patients refer the pain correlate precisely with the somatotopic organization of the dorsal columns. Thus, the insertion of a fine needle into the medial part of the fasciculus gracilis produces pain sensations in more distal dermatomes; stimulation of the lateral regions causes pain in higher dermatomes. When the midline is crossed, the pain shifts to the other side of the body. This curious effect may reasonably be attributed to axon injury discharges ascending in a dorsal column pain-signalling system. Such discharges would be expected to be of much higher frequency than those produced by electrical stimulation, Stimulation of the ventrobasal thalamic complex is also aversive to animal and human subjects [ 18,‘72,73,104,108,178,195,198]. Hassler [ 1081 elicited strong, localized pain from the basal parvocellular part of somatosensory thalamus, which contrasted with the somewhat more generalized contralatera1 pain produced by nSTT stimulation. Convergence of ML and nSTT fibers in this region is likely. Pain felt in the contralateral part of the body is also produced by stimulation of the tectum in humans [ 1971 and lower animals [ 2081. Summary. Direct electrical stimulation of CNS structures associated with either the dorsal cord projection pathways or the nSTT has been found to produce localized pain sensations which are capable of motivating escape behavior. It is therefore suggested that the dorsal cord pathways, like those in the ventral cord, are involved in the organism’s pain perception, motivation, and response mechanisms, and may thus be a natural part of the pain process. That pain can be elicited from the human ML suggests the presence of a functional DCPS-DCN and/or SCT-LCN system of the type found in lower species. Lesion studies Although behavioral studies employing spinal cord lesions have inherent difficulties in interpretation, they are useful as general indicators of function. This is especially true when the data are considered in the light of physiological studies, which establish the presence of particular cell types in a particular region, and stimulation studies, which suggest the behavioral relevance of impulse activity in a particular region. Dorsal spinal cord. Total dorsal cord hemisection, which interrupts the DC and SCT systems but spares the ventrolateral pathways, has been shown in cats to produce analgesia with a gradual postoperative recovery of pain perception [116]. Ventrolateral lesions were less effective in producing analgesia. Levitt and Levitt [ 1331 observed similar effects, reporting temporary impairments in pain reactions when the feline dorsolateral cord was sectioned. The impairment was more permanent when a dorsal cord hemisection was performed. However, isolated dorsal column lesions have been found to have little analgesic effect [ 1581. Levitt and Levitt [133] also noted that dorsal cord lesions did not completely abolish pain. Rather, the deficit was described as a failure to localize the source of the noxious pinch.
116 A response described as “general agitation” was still exhibited when the lcsioned animals were pinched. Christiansen [ 621 has noted similar effects in the macaque. Breazile and Kitchell [32] lesioned all but the dorsal columns and one dorsolateral funiculus of the pig’s spinal cord, and found that painsuggestive responses to noxious heat on either hindlimb could still be elicited, although the threshold was markedly raised. When the remaining dorsolateral region was sectioned, leaving only the dorsal columns intact, pain-suggestive reactions were strongly impaired. In this species it appears that the dorsolateral cord is capable of bilateral pain mediation. In monkeys, Vierck et al. [222] studied the effects of cord lesions on lever-pressing responses to escape electric shock to the flanks. Unilateral ablation of the dorsal columns reduced reactivity to shock on the ipsilateral side. Unilateral ablation of the dorsolateral funiculus tended to increase reactivity to ipsilateral shock. However, neither of these lesions significantly altered the threshold for responding. When the contralateral ventro- and dorsolateral regions were cut, a reduction of reactivity and an elevation of threshold were observed. These effects could be amplified by inclusion of the ipsilateral dorsal columns in the lesion. These data have been confirmed in part by Denny-Brown et al. [79]. Thus, in the monkey, the dorsal and ventrolateral columns could both be involved in pain signalling with the ventrolateral cord being the dominant substrate. The hyperreactivity produced by isolated dorsolateral lesions argues against a direct pain-signalling role for pathways in this region. However, it is possible that the interruption of descending pain-inhibitory systems may override the effects of SCT lesions in this species. In man, attempts have been made to relieve phantom limb pain by sectioning portions of the dorsal columns ipsilateral to the stump [ 34,35,187]. This operation generally produced relief of pain while sparing or only slightly impairing other tactile functions [ 64,192]. The best results occurred in patients whose pain had a “cramping” rather than sharp or burning quality. However, the pain often returned after several months. Although the operation is no longer recommended, the partial success of dorsal column section in relieving certain types of pain is consistent with a direct involvement of the dorsal columns in pain mediation. Similarly, Sourek [207] has attributed some of the therapeutic benefit of commissural myelotomy to incidental damage to midline dorsal column fibers. Ventral spinal cord. Surgical section of the ventrolateral spinal tracts is frequently performed to relieve chronic pain in man, although it is substantially less effective in lower animals. The therapeutic value of ventrolateral chordotomy has been extensively reviewed by White and Sweet [ 2311 who conclude that permanent pain relief can be expected in at least 50% of cases. Continuing improvements in techniques for precisely localizing the lesions [ 94,110,145] may increase the percentage of success. However, White and Sweet [ 2311 also document a distressing number of failures. In some cases, analgesia lasted only a few days or months; in others, pain returned after several years. It has been suggested [ 1501 that failures may be due to the spar-
117 ing of ventrolateral pain fibers. Others [ 120,231] argue against this, pointing out that no matter how complete the transection, pain can eventually return. Moreover, a second or third chordotomy, performed following failure of the first, seldom improves the long-term result [ 230,231]. It seems unlikely that ventrolaterai pain-signalling fibers would survive multiple lesions by competent surgeons. Extending the lesion to include the ventral tracts also does not substantially improve the result [ 2311, The failure of chordotomy to abolish chronic pain in all cases is consistent with the notion that spinal tracts, other than those in the ventrolateral cord, can carry pain-signalling information. Studies on the post-chordotomy pain threshold support this conclusion [ 124,180]. King [ 1241 found that chordotomy patients, including those who experienced prolonged pain relief, continued to report pricking pain in response to cutaneous or C fiber electrical stimulation. The threshold on the ~llordotomized side was approxima~Iy 50% higher, however. King also reported that 20% nitrous oxide was sufficient to restore the level of clinical analgesia in patients whose analgesic area had contracted in the months following the operation. On this basis, he suggested that a polysynaptic system, perhaps in the spinal grey, mediates pain following chordotomy. Interestingly, however, it has been reported that SCT-LCN cells are also highly sensitive to nitrous oxide [126,210]. It is apparent, then, that even in the absence of the ventrolateral tracts, peripheral noxious stimuli can still be perceived, although less readily than preceding chordotomy. That ventrolateral chordotomy works is evidence that this cord region is important in pain sensation. That it does not work all the time is evidence that these tracts are not the exclusive mediators of pain sensation. Summary. Surgical lesions in either the dorsal or ventral spinal cord have been found to decrease pain sensitivity in several species. However, no isolated neurosurgical lesion can be considered universally effective in abolishing pain. In primates, ventral cord lesions are most effective; yet some pain sense persists after such operations, and there is evidence that dorsal cord lesions may potentiate the effects of ventrolateral chordotomy. In sub-primates, dorsolateral cord lesions are temporarily effective, and can be potentiated by inclusion of the dorsal columns in the lesion. Thus, several spinal systems appear to participate in pain mediation, with no single one absolutely essential to it. IMPLICATIONS
The evidence reviewed above is consistent with the hypothesis that functional pain-signalling fibers are present in both the dorsal and ventral regions of the spinal cord. Three of these systems - the DCPS-DCN, SCT-LCN, and nSTT - are comparable on a number of physiological and anatomical dimensions. They all respond to mechanically produced skin damage, to heating the skin to painful levels, and to electrical stimulation of A6 and C fibers. Each conducts rapidly and is capable of sending its messages, via the lateral
118 thalamic nuclei, to the highest levels of the neuraxis with relatively few intercalated synapses. In other ways, however, the systems differ. Each is a distinct anatomical structure, which retains its own particular characteristics. Moreover, it is likely th::t ‘hey are controlled differently by the various inhibitory systems of the CNS. It is apparent, then, that the DCPS-DCN, SCT-LCN and nSTT are not merely redundant systems, each performing precisely the same function, but separate entities, each with its own particular role in the overall scheme of nociception. In addition to the above mentioned pathways, there appear to be at least two other spinal systems which could be involved in pain: the SRT and the pSTT. These pathways project medially to the reticular formation and paleothalamic regions, and thence to the limbic system. Compared to the dorsal cord pathways and nSTT, the medial ascending systems are relatively slow, indirect and highly convergent. Such properties are also shown by the multisynaptic propriospinal systems whose possible involvement in pain has been suggested [ 13,791. The emerging picture, then, is of two basic groups of pain-signalling systems, each group having several distinct components. For convenience we shall use the term “lateral” to refer to the dorsal cord and nSTT projection systems, and “medial” to refer to the SRT, pSTT, and propriospinal pathways [ 891. These two kinds of systems, often under different terminologies, have been proposed as playing distinctly different roles in pain [ 1,24,27,29, 156,236]. For example, under the Melzackxasey conceptualization, the fast, direct systems mediate sensory-discriminative and central control triggering functions, while the medial systems mediate the affective-motivational dimension of pain. While this model remains a current and useful description of pain mechanisms, the evidence reviewed above raises several new questions. For example, why do several individual systems appear to share the functions subserved by each general group? Is there a strict segregation of sensory-discriminative and motivational-affective fibers at the spinal levels, or are these dimensions “mixed” throughout the neuraxis? What are the exigencies governing the descending control of these various spinal pain-signalling systems? There are no simple answers to these questions. However, some speculations can be made. The role of the lateral projection systems The value of rapidly conducting, direct pain-signalling systems is obvious. Unless an organism reacts quickly, a stimulus which only threatens tissue damage may become overtly damaging. For example, if an animal steps on a thorn, the initial penetration may be minimally damaging. However, unless the animal immediately lifts the paw, the injury could become quite severe. Similarly, when an organism fights with another, or encounters objects which are injuriously hot or cold, appropriate response mechanisms must be rapidly activated if tissue damage is to be minimized. Obviously, spinal the reflexes play a role in this process. However, in many circumstances, appropriate action may require much more than simple reflex activity. It is
119
therefore essential to have a system which conveys the nociceptive message rapidly to the highest levels of the CNS. Its principal purpose is to trigger appropriate motor responses which minimize the damage done by any noxious stimulus. The dorsal cord systems - the DCPS-DCN and SCT-LCN and the nSTT appear to be well suited for such a role. Why three lateral projection systems? Injurious stimulation may occur under many circumstances. An animal may be attacked by another when it is awake or asleep. If asleep, the attack could occur during any of the various stages of sleep. If awake, the attack could come while it is food-gathering, drinking, nest-building, exploring a novel or familiar environment, grooming, copulating, and so forth. Similarly, objects which are sharp or at an extreme temperature may be accidentally encountered during any of the organism’s waking behavior patterns. The key to minimizing the damage done by these stimuli is for the animal to perform appropriate motor responses which, in a purely mechanical sense, may need to be different depending on what the animal is doing at the time. It is conceivable, then, that the fast nociceptive pathways represent different sensory channels which are individually inhibited or facilitated depending on the ongoing behavior or behavioral state of the animal. Thus, the same noxious stimulus, occurring during different behavior patterns, might evoke impulses in different pathways. Depending on the pathway(s) by which it arrives, the nociceptive message may be treated differently by the information-processing and response selection mechanisms of the brain. Thus, a nociceptive message ascending in one pathway may trigger different responses than the same message ascending in another pathway. An important factor which may contribute to this process is the brain’s need to obtain light tactile or proprioceptive information from these multimodal systems. As shown above (Table I), none of the 3 systems can be considered as purely nociceptive. Each has a complement of cells responsive only to light tactile stimuli, and, perhaps more importantly, each has a significant population of multimodal cells - units that respond both to light tactile and nociceptive stimuli. There is some evidence that there are qualitative differences in the types of innocuous information carried by the systems [ 361. Perhaps during a particular behavior pattern, the brain selects one type of information from a system and filters out the other types such as nociceptive inputs. Thus, when a system is functioning in a proprioceptive capacity, or monitoring light tactile stimuli, it cannot simultaneously act as a nociceptive system for that part of the body. However, the enormous biological importance of nociception makes it essential that this modality be operative in some form at all times. Therefore, one of the other systems must provide the necessary pain-signalling function for the duration of the behavior. When the ongoing behavior or behavioral state changes, the brain selects other classes of tactile information, perhaps from other systems. When this occurs, a new pattern of differential inhibition and facilitation is imposed on the systems, such that the previously suppressed nociceptive capacity of one system may
120
now be facilitated. In this way, the brain can always extract necessary t.actije it&rmation from peripheral systems, and still maintain vigilance regarding sudden injuly or threat of injury. The possibility that the DCPS-DCN, ScTLCN, and nSTT systems can be i~lclependently switched between nociceptive and light tactile modalities is consistent with this kind of model. Xjoreover, there is evidence for behavior-dependent inhibition of transmission through the ML [65,91,92,177]. There is an alternative model of the functions of the 3 lateral projection systems. The com~oIlents of t,he lateral group could be viewed as behaviordependent “amplifiers” of nociceptive messages. One pathway (e.g., the nSTT) may be used as the primary rapid pain-signalling system, while the nociceptive impulses carried in the other systems are used to amplify or modulate the primary message in much the same manner as innocuous stimuli have been proposed to do [157,173,226]. The difference is that under this for~~lulation, nociceptive informatioI1 in one pathway is used to modulate nociceptive information in another pathway. This modulation could be eithrxr inhibitory or excitatory. The ongoing behavior pattern or behavioral &ate might determine whether these sup~IenleIlt~~7 pathways are open or closed, and thus indirectly affect the primary nociceptive message. iliowever, the form of the reaction to noxious stimuli is determined primarily by the responses triggered by the primary p~n-si~~li~~ system, and by the eomplex response selection mechanisms of the brain. A factor which may be of critical importance in determining how the lateral pain projection pathways are used is whether the animal has already sustained some serious injury. Tactile stimuli which would be innocuous to normal tissue might be ~~aii~fully damaging if applied to an existing wound. Escape mechanisms must therefore be activated in response to such stimuli. flowever, it may also be advant.ageous for the animal to tend the wound (cleaning, covering, and so forth). Such activities would also produce light tact,iltx stimuli. Thus, t~he same stimulus (for example, licking) would have vrlry different. effects depending on whether it is self-induced or coming from an tqxtermd source, such as another animal. While it. is entirely possible that such decisions are made by the brain, it may also be that t,he IW~VOUS system Wtually “ant,icipat,es” such situations at the spinal cord level. Thus, in a wounded, r~sfing animal, a “licking” message is, from the outset, channeled into systems which rapidly trigger escape reactions. Iiiowever, in a wounded, g~~>l~liq animal, the message may take an alternative route which does not itrovoku chscape reactions as readily. ‘rhcre arc’, of course, other possible roles for the fast, direct, multimodal systems, and there are other explanations for the presttnce Of several such systems. The above speculations, however, suggest new behavioral experiments and re-evaluations of present physiological data. Possible in~(?rac~~ons be&ucetl lateral and ~?le~ial ~rojec~io~l systems The anatomical and physiological properties of the SRT and pSTT SYStems make it unlikely that these systems serve to signal the need for imme-
121 diate action [24]. It has been suggested that they play a role in chronic, deeply unpleasant and diffuse pain, as well as subserving the longer lasting motivational-affective effects of noxious stimulation [ 1561. While the dorsal cord pathways and nSTT appear eminently suited for rapid transmission of phasic information, such as the threat or onset of injury, or sudden changes in a damaged area, the other ventral pathways seem best adapted to carrying tonic information on the state of the organism. Thus, an important, although perhaps not exclusive, role for these ventral systems may be to signal the actual presence of peripheral damage, and to continue to send that message as long as the wound is susceptible to re-injury. In this way, the slow nociceptive pathways may in part determine the level of arousal or the general behavioral state necessary to prevent further damage, and to foster rest, protection, and care of the damaged areas, thereby promoting healing and recuperative processes. Activity in the SRT and pSTT may also affect the switching mechanisms which operate on the fast systems. Perhaps they “set the bias” on the DCPSDCN, SCT-LCN and nSTT systems, influencing them more toward the selection of nociceptive information from a damaged area. As healing proceeds, activity in the medial systems decreases and the normal balance between light tactile and nociceptive inputs in the lateral projection systems is restored. An experimental approach for determining the type of mechanism which may be involved in these interactions is suggested by the effects of morphine, which appears to act predominantly at brain stem sites [ 143,144]. Morphine generally diminishes tonic post-surgical pain, but has less effect on the pain produced by sudden movements or removal of stitches. In contrast, nitrous oxide at analgesic dosages seems to diminish both the phasic and the tonic pain. Thus, the two major systems may be subserved or controlled by different neurochemical mechanisms which are selectively affected by different pharmacological agents. Implications for the treatment of pain The existence of functional pain-signaIling pathways in the dorsal spinal cord could have important implications for the surgical treatment of pain. It suggests an explanation for the failures of ventrolateral chordotomy, even bilaterally and at several levels, to relieve chronic pain. Although the ventral tracts are obviously of great importance in nociception, the presence of dorsal pain-signalling pathways, which may be quite variable from individual to individual, complicates the neurosurgical treatment of pain. Neurological tests for assessing the presence of these auxiliary pathways could be of great value. Any treatment of pain must also be considered in terms of its effects on inhibitory mechanisms. The data reviewed above suggest that pain is not governed simply by a balance of excitation and inhibition in a single system, but rather in multiple, interacting systems. Any therapeutic manipulation, whether it destroys an ascending system or excites a descending one, could
122
therefore
alter t.he e~~itator~~-inhibitor interactions in the rema~I~in~ SYS‘Ihis complex dynamic balance among several systems may account for the variability encountered in all forms of pain treatment, including sur@c& f23lj and electrical stimulation 11351 methods.
tems.
The above considerations also suggest that pain-signaIling processes may according to the organism’s behavior and behavioral state. On the one hand, proprio~eptive and tactile stimuli occurring during particular behavioral patterns might have specific inhibitory effects on pain transmission. On the other hand, it is possible that ~oncomit~t with the behavioral patterns themselves and the motor commands that produce them, differential effects are exerted directly on the multiple pain-signalling systems to change the relative activity among them. This could alter not only the perceived intensity of noxious stimulation, but also the form of the organism’s reaction to it. Thus, the individual’s environment and psychological history [ ISS], both of which are antecedents of behavior, may in part control the physiologic mechanisms which mediate pain, perhaps even at the level of the first synapse. vary
i~~I~NO~~~RGEM~N~S
This study was supported by Post-doctoral Fellowship l-F32-NS05099-01 to Dr. Dennis from the United States National Institute of ~eurolo~c~ and Communicative Disorders and Stroke, and by Grant A7891 to Dr. Melzack from the National Research Council of Canada. The authors express sincere thanks to Drs. A.G. Brown, K.L. Casey, J.D. Loeser, A.J. MeComas, B.S. Nashold, and P.D. Wall, for their helpful comments and criticisms of earlier drafts of this paper. REFERENCES i\lbt~-F~~~~:~~d,D. and
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Pain, -1 (1977) 97-132 @ Elsevier/North-Holland
Review Article
Biomedical
______
PAIN-SIGNALLING SPINAL CORD
STEPHEN Department
(Accepted
G. DENNIS
SYSTEMS IN THE DORSAL AND VENTRAL
and
of Psychology,
June
Press
Bnd,
RONALD .llcGill
MELZACK University,
;2lontreal,
Que.
(Canada)
1977)
SUMMARY
A review of the literature on pain-signalling systems in the spinal cord provides convincing evidence that nociceptive information is transmitted by multiple ascending systems. These systems include: (1) the postsynaptic fibers of the dorsal columns which relay in the rostral dorsal column nuclei; (2) the spinocervical tract which relays in the lateral cervical nucleus; (3) the neo-spinothalamic tract which ascends directly from cord to thalamus; (4) the paleo-spinothalamic tract which projects to the midline-intralaminar thalamic regions; and (5) the spinoreticular system which sends fibers throughout the brain stem reticular formation. In addition, the diffuse, polysynaptic, propriospinal systems may also carry pain-related information. The data indicate that the first 3 systems, which comprise the “lateral” group, are generally similar to each other on at least 4 dimensions: modalities represented, conduction velocities, loci of origin, and areas of termination. However, despite their overall similarities, there are clear differences, particularly in the precise modes of termination and routes of ascension. Moreover, they appear to be controlled differently by the inhibitory systems descending from the brain. The other 3 systems, which constitute the “medial” group, appear to have the same modality spectrum. However, they differ from the lateral group on other dimensions - they conduct more slowly; their cell bodies tend to be located more deeply in the spinal grey matter; and, most importantly, their patterns of termination are grossly different from those of the lateral group. Several speculative proposals are presented to explain the functions and possible interactions among the various systems. These proposals emphasize two main factors: (1) the possible influence of on-going behavioral sequences on the relative activity among the systems; and (2) the possible effects of existing tissue damage on the mediation of subsequent noxious stimuli. Although these proposals are speculative, they are amenable to experimental investigation. Implications for the treatment of pain are discussed.
Contemporary theories of pain maintain that the major spinal pain-signalling systems lie in the ventral half of the spinal cord. These projection systerns include the neo- and paleo-spinothalamic tracts, the multisynaptic propriospinal paths, as well as the spinoreticular fibers that course medially into the reticular formation and limbic systems. These systems, it is assumed, underlie the sensory-discriminative and affective-motivational dimensions of pain [156]. In contrast, the long ascending pathways in the dorsal half of the spinal cord, particularly the dorsal column and spinocervical tracts that project to the brain via the medial lemniscal system, are traditionally held to play no direct role in pain experience. Specificity theory maintains that the dorsal cord projection systems mediate fine tactual discrimination, spatial locahzation at the skin, and proprioceptive-kinesthetic functions. Pattern theory [173] proposes an additional function: the inhibition of pain signals transmitted from small peripheral fibers to dorsal horn cells that subsequently project through the ventral pathways. The gate control theory [156,157] agrees with this inhibitory property but proposes yet a further role for the dorsal cord pathways: that of a central control trigger that activates memories, pre-set response strategies, and other central neural processes that exert control, via descending pathways, over inputs ascending in the ventral pain pathways. Clearly, none of the contemporary theories proposes a direct role for the dorsal spinal pathways in pain perception and response. Several reviewers have recently reiterated these basic views [ 1,24,118,228, 2361. However, they also point out that an increasing amount of experimental evidence does not readily fit any of the contemporary theories. In particular, it is becoming apparent that the dorsal cord pathways may play a more direct role in pain perception than was previously thought. The evidence for this view comes from numerous physiological and behavioral experiments, no one of which constitutes conclusive proof, but all of which, taken together, present a consistent picture. The purpose of this review is to present the evidence in the context of a general summary of spinal pain-signalling pathways. The data, we believe, show that in addition to the major pain tracts in the ventral cord, there are small, functional pain-signalling pathways in the dorsal cord of all mammalian species, including the human. We cannot specify the precise role of these dorsal pathways, nor indeed of any ascending pathway, in pain perception and response; we shall only speculate on what they might be. While the inferential nature of this conclusion is fully recognized, as is the vulnerability of some of the evidence, we suggest that the importance of this hypothesis to the understanding of pain, and its therapeutic control, warrants its presentation. At the very least, it may stimulate research on hitherto unconsidered problems.
99 PHYSIOLOGICAL
EVIDENCE AND ANATOMICAL
CHARACTERISTICS
The presence of specific mechanical and thermal nociceptive neurons in peripheral nerves has been well documented [19,52,115]. Also well established is the representation of these neurons, either as specific relays or as convergent “multimodal” relays, throughout the spinal grey matter [61,93, 99,106,115,185,224,227,237]. How this nociceptive information is distributed from the spinal grey to the various long ascending pathways in the spinal white matter has been of concern to investigators for many years. The picture which is emerging is one of widespread distribution to all areas of the white matter [ 361, including the dorsai and dorsolateral areas. Dorsal column system Physiology. The dorsal columns (DC) are composed chiefly of primary and secondary afferent fibers ascending to the dorsal column nuclei (DCM) in the caudal medulla. For decades the dorsal columns have been viewed as carriers only of innocuous tactile or proprioceptive information. While this still appears to be the case for the DC primary afferent fibers, it can no longer be said of the secondary afferents. The first conclusive demonstration that dorsal column postsynaptic (DCPS) fibers carry pain-related information was made by Uddenberg [219, 2201, although others [ 39,233] had hinted at their existence. Of 295 axons recorded in the cat’s cervical dorsal columns, 79 (26.8%) were found to be transsynaptically activated from small to medium sized peripheral fields. All were found to give a rapidly adapting discharge to hair movement, but an unspecified number also exhibited a sustained, high-frequency discharge to noxious pinch. The peripheral fields for the nociceptive and light tactile responses were found to be co-extensive; no such fibers were found among the primary afferents sampled. Uddenberg’s results have recently received compelling confirmation by Angaut-Petit [8,9,182]. Also recording from the feline dorsal columns, she found that 92 units (9.3% of DC fibers) were DCPS axons. Of these, 77.2% responded differentially to both gentle and noxious stimuli, and 6.5% responded only to noxious mechanical stimuli, while the remainder were activated only by light mechanical stimuli. Moreover, an unspecified number were sensitive to noxious thermal stimuli, exhibiting a sustained, high-frequency discharge once the skin temperature exceeded 45°C. Some units were sensitive to cooling, as noted also by Uddenberg [ 2201. Cells exhibiting similar properties have also been observed by Angaut-Petit [9,182] in the rostra1 and ventral nucleus gracilis. Of 134 units recorded, 41.8% were hair- or touch-activated, and 26.9% responded only to tapping on the skin. The remainder (31.3%) were differentially sensitive to both gentle and noxious mechanical stimuli, and responded well to noxious heat. Transections of the spinal cord, sparing only the dorsal columns, did not greatly alter these cells’ responses to either noxious or gentle stimuli, indicating that they are activated by DCPS fibers. Dart and Gordon [ 711 have also observed pain-related units in the DCN; however, these cells were activated
100 L)y fibers in the dorsolateral funiculus. DCN cells which might have been nociceptive have been reported by others [96, 147 1. The above experiments clearly establish the presence of pain-signalling information in the DCPS-DCN system of the cat. Whether this is true for all mammals, or simply a peculiarity of the cat, cannot be said with certainty. There are as yet no comparable data for primate species. ,4natomical characteristics. One of the principal unanswered questions regarding the DCPS-DCN system is whether its information, particularly the nociceptive type, is transmitted rostrally, or whether it carries out its functions exclusively within the DCN. Present evidence is consistent with both possibilities. Fig. 1 summarizes the basic nruroanatomy of the DCPS-DCN system. In the spinal cord, the DCPS fibers lie deep within the dorsal columns, ventral to the bulk of cutaneous primary afferents [8,219]. They ascend the DC ipsilateral to their receptive fields, and synapse preferentially in the rostral and ventral portions of the DCN [9,200,201,219]. Primary afferents tend to terminate in the caudal and superficial areas of the DCN. The cytoarchitecture [ 130,200,201] and physiological characteristics [ 96, 98,147] of these DCN regions differ significantly. As indicated in Fig. 1, virtually all the DCN efferents cross the midline in
Nuclcur Nucleus
Cunsotur Grorilis
21,
21. 105,
SC/K
105,
MGm
26.
109, 105,
109. 130, 130,
136, 136, 136
(142).
206
141. 193
1225) 225
193
Fig. 1. Summary of the neuroanatomy of the dorsal column postsynaptic (DCPS) system. Postsynaptic fibers, many of which respond to noxious stimuli, ascend the dorsal columns to the rostra1 dorsal column nuclei (DCN), and are then relayed to various brain structures. Numbers are references to published articles reporting the terminations of the DCN. Numbers in parentheses are reports in which the evidence for terminations in a parbut in which the conclusion is not explicitly stated. Abbreviaticular region is suggestive, nucleus of thalamus; PO, posterior thalamic group; ZI, tions: VPL, ventroposterolateral zone incerta; SC/IC, superior and inferior colliculi or collicular plate; MGm, medial part reticular formation; PT, pretectal of medial geniculate body; MRF, mesencephalic regions; NR. red nucleus, (Note: Figs. l--3 are meant to neuroan;rtomy of the systems depicted. For this reason, been given detailed attention. In particular the problem identification of subnuclei within structures deserve a ran be given here. For a more precise understanding of tems. the reader is urged to consult the original articles.)
convey several
a general important
overview of the issues have not
of species differences and the more detailed presentation than the neuroanatomy of these sys-
101 the lower brain stem, and ascend to higher levels in the medial lemniscus (ML). There is no doubt that all regions of the DCN contribute axons to the ML [21,54,55,71,96,105,130,136,205]. However, the magnitude of the rostral DCN projection and the type of information it contains are not entirely clear. Kuypers and Tuerk [ 1301 found that a substantial number of rostral DCN cells do not show retrograde degeneration when the ML is cut. Similarly, Gordon and Jukes (96) estimate that only about one-third of the cells can be antidromically activated from the ML. However, these investigators raise two technical points regarding their studies: first, the rostral DCN projection is rather diffuse and is not confined to the main body of the ML; second, if the DCN cells have collaterals to other regions (e.g., within the DCN), in addition to their ML axons, a significant portion might escape retrograde degeneration following ML lesions. Both possibilities would tend to produce underestimates of the rostral DCN contributions to the ML. There is little evidence regarding the modality properties of the rostra1 DCN projections. Dart and Gordon [71] found that none of their 15 nociceptive cells projected past the DCN, while about 30% of other types did. However, their studies were concerned with DCN cells activated by the dorsolateral funiculus, not by the dorsal columns. Brown et al. [ 441 reported axons in the ML which apparently had nociceptive capabilities, but their origins were not traced. Kuypers and Tuerk [130] have offered the intriguing speculation that the rostral DCN cells which do project through the ML receive convergent inputs from many other rostral DCN cells, and as such may code stimulus intensity. However, this is speculative. Clearly, there is as yet no conclusive evidence for the rostral projection of nociceptive information from the DCN. But neither can the possibility be ruled out, since the appropriate experiments have yet to be reported. In view of the rather high proportion of rostral DCN cells which have a nociceptive component (e.g., 30% [9]), and the fact that at least one-third or more of all rostra1 DCN cells project rostrally, it is possible that at least part of the pain-related DCPS information is in fact relayed to higher brain structures. Fig. 1 lists the regions in which DCN axons have been found to terminate, and which may therefore be the recipients of the pain-signalling DCPS information. The main somatosensory nucleus of the thalamus (VPL) is the principal site of termination, although other areas clearly receive fibers. Not indicated in the figure is the suggestion by several workers [ 105,136] of differences between rostral and caudal DCN projections. They report that, in rats and cats, the caudal DCN projection is more restricted to the VPL and MGm, while the rostral DCN terminates in the other regions listed, in addition to the VPL and MGm. Boivie [ 211, however, saw little difference between the rostral and caudal DCN terminations. Of particular interest are the DCN projections to the posterior thalamic complex (PO), which has been found to contain nociceptive cells [68,183], and to the zona incerta (ZI), which is regarded as the rostral extension of the mid-brain reticular formation [217]. Projections to cortex from VPL [217], MGm [ 197, 2211, and PO [ 691 have been identified.
102 Sunzmry. A small system of secondary (and perhaps hight%r order) affertnts has been d~~nlonstrated in the feline dorsal columns. These ;t\;ons are capable of carrying ~~~~l-si~l~ii~lg i~lforl~~ation to the rostra1 parts of the dorsal column nuclei. Some appear to be rxclusively nociceptive. Projection of this information to various thalamic and collicular regions and to the zona incerta is possible, as is a subsequent relay to cortex. The primate homolog of this system has yet to be demonstrated; however, its existence is suggested hy indirect evidence t,o be presented in later sect,ions. Spinocervicothala~nic system Physiology. The spinocervical tract (SCT) [ 1631 ascends the dorsolateral spinal funiculus to the lateral cervical nucleus (LCN) [ 331. Neurons which respond to noxious mechanical and thermal stimuli have been amply demonstrated in the feline SCT-LCN system ~41,42,50,97,138,159,179,188]. A substantial portion of these fibers respond to stimulation of peripheral ,316 and C fibers [45,47,159], and some show the “wind-up” effect [159,160] characteristic of pain-signalling systems at the spinal and midbrain levels [ 151. The ease with which pain-signalling information can be demonstrated in the feline SCT-LCN, coupled with the difficulty in demonstrating the presence of a neo-spinoth~a~n~c tract in this species [ 5,165], has led some investigators to suggest that the feline SCT-LCN system is simply the homolog of the primate neo-spinothalamic tract [5,209,224]. However, as will be shown below, the cat does have a functional neo-spinothalamic tract, in addition to the well-developed SCT-LCN system, making the homology argument less attractive. More recently, records have been obtained of primate SCT-LCN units which respond to noxious stimulation [ 49,107,191], Bryan et al, [ 491 found that of 25 SCT cells activated by light tactile stimuli, 11 (43?) showed an increased discharge to intense mechanical stimulation. Six of 16 cells tested were sensitive to noxious heat (42°C). One cell responded exclusively to noxious stimL]lation, Thus, in primates as well as in cats, the SCT-LCN SYStern may be a pain-s&milling system. ilnatomical characteristics. Fig. 2 summarizes the neuroanat,omical characteristics of the SCT-LCN system. Although its existence was at one time denied in primates, the SCT-LCN system has now been identified in all higher species, including the human [ 100,101,125,161,172,218]. Truex et al. 12181 report that the size of the human LCN varies greatly among individuals. It was identified in 9 of 16 cords examined, and was well developed in two. In the remaining seven it could not be identified. This has led Kerr [ 1181 to conclude that the SCT-LCN system is “vestigial” in humans. However, while the SCT-LCN system in man is less well developed than that in carnivores [ 102,103,127,164,218], it does not rule out the possibility of a functional role for the SCT-LCN system in those people in whom it is present. As indicated in Fig. 2, the SCT axons ascend the dorsolateral funiculus ipsilateral to their receptive fields. Approximately 75% of the fibers termi-
103 Midline VPL:
6,
23,
137, Caudol Medulla
Dorsal
Lateral High
Cervical
Cord
(Cl -‘Xl
Column
100,
103,
131.
141, 165
PO:
23,
70
MGm:
23.
141
21:
137
CM-PI:
137
Cervical
I
Spinal
Cord
Fig. 2. Summary of the neuroanatomy of the spinocervicothalamic system. Postsynaptic fibers ascend the spinocervical tract (XT) and terminate mainly in the lateral cervical nucleus (LCN) although some also reach the rostra1 DCN. A subsequent relay through the medial lemniscus is shown. Numbers are references to articles reporting the terminations of fibers from the lateral cervical nucleus. CM-Pf, centrum medianum-parafascicularis complex; other abbreviations as in Fig. 1.
nate in the LCN [ 2111, the remainder probably going to the rostra1 DCN [ 71,95,172,201,202,212]. The latter includes a nociceptive component [ 711. Other sites in the medulla (e.g., the lateral reticular nucleus and medullary central grey) receive a few fibers from the dorsolateral funiculus, but it is uncertain whether these are SCT axons [ 1721. The LCN efferents cross the midline in the caudal medulla and ascend in the ML along with the DCN efferents [23,54,100,141,165]. Collaterals synapsing within the LCN have also been suggested [ 971. The LCN terminations are summarized in Fig. 2. Like the DCN projections, the main somatosensory thalamic nucleus (VPL) is the principal site of termination for the LCN fibers. In fact, some of the DCN and LCN projections to this region have been found to converge on a group of cells which surround the somatotopic (and presumably caudal) DCN projections [ 6,131]. The other terminal zones also appear to overlap with the DCN projections to some degree. A direct neuroanatomical route to the reticular formation has not been demonstrated, except perhaps for very small projections noted by Nijensohn and Kerr [ 1721 and Nauta and Mehler (cited in ref. 171). However, electrophysiological studies suggest an input to the reticular formation [ 1621 and subthalamic complex [76] from the dorsolateral funiculus. In addition, SCTLCN information is relayed to several areas of cortex [ 6,24,85,163,174]. Summary. The spinocervical tract is a somatosensory pathway that ascends in the dorsolateral funiculus of the spinal cord. It appears eminently capable of transmitting pain-signalling information to rostral levels of the cord in both primates and carnivores. After relaying in the lateral cervical nucleus, the information is projected to the somatosensory thalamus and adjacent areas, and may reach the reticular formation. The pathway is also represented at the cortex.
104
dledial lernniscus The DCN and LCN projections through the ML make the latter a key structure in the analysis of the nociceptive capabilities of the former. However, little is known about ML physiology. Brown et al. [44] report that 9 of 52 lemniscal units activated by hair follicle receptors also showed a sustained discharge of higher frequency to pressure on the skin. For some units, noxious pressure was required to evoke this slowly adapting discharge. Since the bulk of ML fibers come from the DCN, it is possible that these neurons are the rostral relays for the nociceptive DCPS-DCN cells, although some may be SCT-LCN axons.
Nco-spinothalamic tract Physiology. The neo-spinothalamic
tract (nSTT) ascends from the ventral and ventrolateral regions of the spinal cord to the thalamus. Its capacity for carrying both light tactile and pain-related information, especially in primates, is firmly established [ 4,11,88,190,191,214,215,232]. For example, Treviiio et al. [214] report that 30% of primate nSTT fibers require intense mechanical or thermal stimulation, while 38% respond to hair movement, 21% to light pressure, and 11% to stimuli affecting deep, subcutaneous structures. Price and Mayer [ 1901 estimate that 12.2% of ventrolateral cord units are exclusively nociceptive, 26.8% are sensitive only to gentle tactile stimuli, and 61.0% are multimodal (responding to both light and noxious stimuli). While primate nSTT units are easily studied, some difficulty has been reported in obtaining satisfactory recordings from comparable feline cells [ 51. However, the use of more sensitive signal-averaging techniques [ 148, 2161 and recordings from cervical cord regions, instead of the usual lumbar preparation [82], have clearly revealed the presence of the feline nSTT. Pomeranz [184] observed nociceptive units in the feline ventrolateral cord, some of which may have been nSTT fibers, and evoked potentials due to C fiber stimulation have been recorded in this region [ 1401. It is apparent then that the cat does indeed have an nSTT, as does the primate. In both, the systern clearly carries nociceptive information. Anatomical characteristics. The ascending route taken bv nSTT axons is distinctly different than in the dorsal cord pathways. As shown in Fig. 3, the fibers cross the midline in the spinal cord and ascend predominantly in the ventrolateral spinal quadrant. A ventral division is also present. No further synapses are intercalated between the cord and brain levels in the classical nSTT pathway. Fig. 3 also summarizes the brain regions in which ventral and ventrolateral cord fibers have been found to terminate. The segregation of these terminal zones into 3 separate groups illustrates the fact that several major systems ascend from the ventrolateral cord to the brain. Group A represents the terminations and includes the nSTT and spinotectal systems. “ML-like” Group B lists intralaminar and midline thalamic nuclei which are considered the terminal zones for the paleo-spinothalamic tract (pSTT). Group C corresponds to the spinoreticular tract (SRT) whose anatomical differentiation
105 Group A
,_-. ‘,. ’ \,..
.*,’ .
,_.\ ,l
I
VPL.
7, 27, 151-154,
TRN: PT:
27,
31, 90, 171
119.
122,
137,
31. 90
137
Group
C
7, 27, 31. 137, 151-154, 171 31, 119, 137, 151-154, 171
Fig. 3. Summary of the neuroanatomy of the ventral and ventrolateral cord pathways, including the neo- and paleo-spinothalamic tracts and the spinoreticular system. Postsynaptic fibers, including those which cross the midline in the spinal cord, ascend directly to brain structures. Three separate groups are shown. Numbers are references to published articles as in Fig. 1. Abbreviations: TRN, thalamic reticular nucleus; CL, centralis lateralis; \lD, medialis dorsalis; Pf, nucleus parafascicularis; CM, centrum medianum; RF, brain stem reticular formation; CG, brain stem central grey; others as in Fig. 1.
from the other ventral tracts has recently been made clear by the elegant studies of Kerr and Lippman [ 121,122]. The pSTT and SRT systems will be considered in a later section. The group A terminations are clearly similar to the areas listed in Figs. 1 and 2 for the DCPS-DCN and SCT-LCN systems. However, there are specific differences which will be discussed below. The VPL is considered a major terminal zone for nSTT fibers in the primate and has been frequently listed as such for the carnivore. However, Boivie [22,24 1, using a more rigorous definition of VPL, has found in cat that the nSTT terminates in a transitional zone between the VPL and the more rostral ventralis Iateralis. Whether this anatomical species difference underlies a functional difference remains to be determined. Te~inations in other thalamic and subth~amic areas in the vicinity of the ventrobasai thalamus have also been found as shown in Fig. 3. Tectal connections are present, as they are in the DCPS-DCN system, and their possible association with central grey projections has been noted [152]. In view of the extensive thalamoco~ic~ efferents from the group A nuclei (see above), the projection of nSTT information to the cortex is probable [ 241. Recently, Eidelberg et al. [84] reported the rather precise convergence of the nSTT and dorsal cord information onto cortical units. Similarly, Curry and Gordon [70] have found convergence of the 3 pathways on units
106 in the PO thalamic complex, somc~ of which may project to corks [ 69 1. The anatomical differences bet,ween the ventral and lateral nco-spinothalamic tracts are few but significant [ 1191. However, these may be related mainly to the mediation of subcutaneous, deep-field sensations since physiologically the ventral and Iat,eral components seem to differ only in this modality [ 111. Summary. The neo-spinothalamic tract transmits pain-signalling information from the ventral half of the spinal cord to the brain of primates and carnivores. Its terminations are generally similar to those of the dorsal cord projection pathways, although its axons are in close proximity to those of other spinal systems ascending to a variety of rostral areas. Cortical project,ion of the nSTT information occurs and is in part convergent with the cortical projections of the dorsal cord systems. Comparisons among the systems The preceding sections indicate the widespread distribution of nociceptive, thermal, and tactile information to three major ascending somatosensory systems in the dorsal and ventral spinal cord. The transmission to the brain of this information, including nociceptive signals, has been demonstrated for the nSTT and SCT-LCN systems. Furthermore, there is suggestive, though indirect, evidence for a rostra1 projection of the DCPS-DCN
TABLE
Light
I
DCPS-DCN
SCT-LCN
nSTT
SCT-LCN
9, (39),
12, 7.5, 97, (1 15) 138, 159, 166, l79,lHH
82, 118, (lHl), 216
19, (191)
12, 50, 97, 179.18H
(115). (1X-l)
118.
-19. (191)
12, 18X
(115).
(129).
-19, (191)
129, (181), (191), 232
(115), 148,
19, (107). (191)
4, 5, 11, 88, (190) (191) 232
220
tactile
Noxious tactile
9, (39)
Noxious thermal
9
Multim od al
82,
’
138, 12, (115) 159, 179,188
* Table entries are references tems. Numbers in parentheses modality type in a particular In some cases, the conclusion that of the present authors.
(181), 216
5, 11, 88, (181), (190), (191), 211.232
5. 11,58,
(lSl), (191).
(181) $33) 9 220
nSTT
(ISA),
to articles reporting the modality represent reports which imply the system, hut in which the conclusion is inferred hy the cited authors; in
129.
(199), 211,232 (190),
21-1.
types in the listed syspresence of a particular is not explicitly stated. others, the inference is
107 nociceptive information. It appears necessary, then, to re-examine present views of the neural basis of pain perception and response to account for the presence of multiple pain-signalling pathways from the spinal cord to the lateral thalamus. The present section compares these systems on several physiological dimensions. Table I presents a compilation of published reports on the representation of 4 basic modality types in the feline nSTT, DCPS-DCN, and SCT-LCN, and primate nSTT and SCT-LCN. Although different authors have used different classification schemes, the one shown in the table represents a convenient way to compare the reports. Table entries are references to articles which demonstrate the existence of the modality type in the system listed. The table reveals a clear similarity among the systems with regard to the qualitative modalities represented. No system can be claimed as having the exclusive ability to mediate either nociception or light touch. However, there may be some important differences superimposed on this pattern of general similarity. Brown [36], for example, has noted differences in the types of light tactile information carried in the feline dorsal cord systems. Neural activity from Pacinian corpuscles, slowly adapting types I and II touch receptors, and pad and claw receptors is projected through the DC, but not apparently through the SCT, while the SCT rather than the DC carries activity from the ubiquitous, highly sensitive down-hair receptors. Whether such differences are also present in the specific types of nociceptive information they carry has not been determined. There may also be quantitative differences among the systems that are not indicated in Table I. For example, cells that are exclusively nociceptive make up only 6.7% of the feline DCPS-DCN units [9], but possibly up to 20% of the SCT-LCN [42]. Bryan et al. [49] found only one nociceptor among 32 units sampled in the primate SCT, while Willis et al. [232] report some 30% in the nSTT. While it is difficult to assess the magnitude of quantitative differences due to procedural variations, particularly in the type or depth of anesthesia, the available data suggest different biases among the three systems in the mediation of particular somatosensory modalities. However, exclusivity in any one modality appears to be ruled out. A general similarity among the nSTT, SCT-LCN, and DCPS-DCN systems is also evident on two other physiological dimensions: conduction velocity (Fig. 4) and loci of origin (Table II). The entries in these tables are again references to articles reporting the particular conduction velocities and/or ranges and locations of cell bodies. Fig. 4 shows the axons of each system to be well myelinated and typically conduct impulses in the range of 30-60 m/set. This is substantially faster than the C and A6 fibers which carry nociceptive information from the periphery. It must be remembered, however, that larger axons and cells are more readily observed in single unit studies, and that larger axons conduct faster than smaller [ 113,114]. Thus, some conduction velocity estimates may be biased toward higher values. There is some indication from the table that the feline SCT-LCN may be faster than the DCPS-DCN or nSTT sys-
Feline
Primate
IOOL
80 -
I
: ;60 E
220
t” L 2 40
20
-’
1
11381 42
211 SO
I
II
82
216
49
-
A DCPSDCN
SCT~LCN
“STT
scr--LCN
terns, and this has direct support [56,174,211]. In the monkey, the nSTT appears to be faster than the SCT-LCN system [AS]. Table II lists results on the cells of origin of t.he t.hree systems. The only evidence on the origins of the DCPS-DCN axons comes from Rustioni and Dekker [203], who summarize dat,a showing DCPS cell bodies in the dorsal horn. The other systems have been more extensively studied. Again the table reveals no remarkable differences. Resed’s [196] laminae IVand V are most often reported as sources, and in many reports are ideIltified as the main sources. On the basis of electrophysiological studies on lumbar preparations, Trrvitio et al. [216] have suggested that the feline nSTT cell bodies are more concentrated in laminae VII and VIII than the SCT cell bodies [50,188]. However, the use of cervical preparations has revealed dorsal horn contributions to the feline nSTT, including a cell Iocalized in lamina I [SZ]. SIore recently, Treviiio and Carstens 12131, using the horseradish perosidase method, have essentially confirmed the electrophysiological results in monkey and cat, including the differences between feline lumbar and cervical dorsal horn contributions. The anatomical method also revealed a clear projection to lateral thalamic regions from lamina I ceils in the cervical and lumbar cord of both species. Lamina I contributions to the systems are of interest since this region of the dorsal horn has been shown to contain a high proportion of purely nociceptive cells [61,63,129]. The axons entering the spinal tracts from lamina I have been found to conduct at a significantly slower rate than projections from other laminae [49,189,215,232]. It has also been
109 TABLE
II
LOCATIONS
Lamina (Rexed)
OF CELLS
OF ORIGIN
OF FELINE
AND PRIMATE
SPINAL
TRACTS
Primate
Feline
SCT-LCN
nSTT
SCT-LCN
nSTT
(SO), (115)
82, (7 29), 213
49
11, 88, (129), (190), 213-215, 232
50, 83, 111, (115), 188
(115),
49, (191)
11, 88, (190), 213-215, 232
\’
50, 83, 111, 188
82, 213,
49, (191)
4, 11, 88, (190), 213-215, 232
VI
50, Ill, 188
82, 216
49
11, 88, (190), (191), 214, 215, 232
50,188
213, 216
49
(190), 232
50
82, 213, 216
49
213.-215,
DCPS-DCN I
IV
VII \‘I11
203
-
*
213 216
213-215, 232
* Table entries are references to published articles. Numbers in parentheses refer to articles in which the suggestion is made (or is inferred by the present authors) that the cells of origin of a particular system are found in a particular spinal lamina, but in which the identification is not explicitly stated.
suggested that cutaneous receptive fields tend to increase in size from lamina I to deeper laminae [ 111. Summary. Similarities among the nSTT, SCT-LCN, and DCPS-DCN systems are apparent on several dimensions. Each has been shown to carry nociceptive, thermal, and light tactile information. Each originates, in part, from the dorsal horn of the spinal grey, and projects predominantly to the nuclei of the lateral thalamus (ventrobasal, posterior, and subthalamic complexes). Each is rapidly conducting. However, although generally similar, the systems are not identical. Certain qualitative and quantitative differences have been identified, although their magnitude and importance are difficult to assess. Two additional differences are considered in the following section. Differences
among the systems
On the basis of the previous discussion, it is tempting to consider the nSTT, SCT-LCN, and DCPS-DCN pathways as equivalent systems in somatic sensation. Their similarities, at least in a broad sense, are clear. However, there are also several significant differences among them, suggesting that they may actually function in different ways or under different circumstances. Two key differences are discussed below. Anatomical differences. As shown in Figs. 1, 2 and 3, the DCPS-DCN,
110
XT-LCN and nSTT systems all terminate predominantly in the nuclei of the lateral diencephalot~~ However, within these nuclei, the 3 systems show differences in the reiative densities, locations, or modes of termination. Boivie [21-231 has studied the projections of all 3 systems in the cat. He found that nSTT terminations are more concentrated in the rostra1 ventrobasal thalamus in a zone of transition between the VPI, and the ventralis lateralis. The DCN and LCN projections were identified in the VPL proper, with the LCN terminals tending to be unevenly distributed while the DCN fibers were found relatively evenly throughout. All systems were found to terminate in the medial part of the PO complex (Porn). However, the densities and precise locations of termination differ somewhat. For example, overlap between the DCN and LCN fibers was found in the rostra1 POm, while the caudal regions receive only DCN fibers. More recently, Boivie [ 20,241 has summarized studies on the termillat.~ons of the DCN and nSTT in monkeys. As in the cat, the nSTT terminals tend to accumulate more rostrally in the ventrobasal thalamus, but do not obviously exceed the boundary of the VPL. In this species, the DCN and nSTT terminals clearly overlap in VPL. However, the nSTT fibers tend to terminate in “bursts” or clusters in the VPL [20,119,151], while the DCN terminals are more evenly distributed ]20,26]. Lund and Webster [136,137,229] have studied the terminations of the ascending somatosensory systems in the rat. They also found that the nSTT fibers tend to terminate rostral to the bulk of the DCN fibers, although the two systems overlap. In this species, ZI projections were attributed to the DCN, and by inference to the LCN, but not to the nSTT, unlike the pattern in cat 1221. While it is difficult to say precisely what these differences mean, their occurrence suggests that the DCPS-DCN, SCT-LCN, and nSTT, although generally similar, may not have identical functions. That all 3 systems reach overlapping regions of the lateral diencephalon is clear; however, it is equally clear that they do not terminate in precisely the same ways in these regions. Moreover, as shown in Figs. 1-3, their routes of ascension are obviously different. Inhibitory control, Recent evidence suggests that the descending inhibition exerted on the DCPS-DCN, SCT-LCN and nSTT systems may differ. Brown and co-workers [ 37,38,45,46,48] have demonstrated extensive descending control on the feline XT-LCN system. The inhibition can be triggered by stimulation of the contralateral dorsolateral and ventromedial cord and the dorsal columns. SCT inhibition has also been observed from stimulation of the mesencephalic tegmentum, central pontobulbar core and several cerebellar regions [ 2091. More recently, specific cortical regions have been found to exert strong inhibition on SCT cells 140,431, although LCN cells have been found to be unaffected by such stimulation [97]. Decerebration, however, does not abolish SCT inhibition, indicating both cortical and subcortical sources [ 371. of great interest is the modality specificity of descending control. The
111
inhibitory effects appear to be exerted predominantly on the nociceptiue signals in the SCT-LCN system, while the light tactile responses remain relatively unaffected during stimulation [ 37,38,237]. As might be expected, C fiber input is reduced preferentially over A fiber input [ 461. In contrast, no such differential inhibition has been reported by McCreery and Bloedel [ 1481 who studied the feline nSTT system. They found a general depression of unit activity when RF sites, particularly the caudal part of the nucleus gigantocellularis, were stimulated. Also unlike the SCT-LCN system, they found no inhibitory effect during cortical stimulation [ 1491, although this might have been due to the level of anesthesia [ 401. In primates, cortical stimulation has been found to inhibit nSTT unit activity [66,67]. Moreover, in this system, the cortical inhibitory control is directed predominantly at the light tactile inputs, leaving the nociceptive responses, particularly those from lamina I, generally intact. This is in clear contrast to the feline SCT-LCN inhibition pattern. However, the nociceptive responses of primate nSTT units, including those in lamina I, can be inhibited by stimulation of the nucleus raphe magnus [14]. Such stimulation is consistently more effective in inhibiting the A6 inputs than the larger A fiber inputs. This suggests a pattern just the reverse of that produced by cortical stimulation. That some form of inhibition can be exerted on all pain-signalling systems is strongly suggested by behavioral studies using focal brain stimulation to produce analgesia [ 134,144,146,204]. There is little direct information on inhibitory control of the DCPS-DCN system. A potentiation of both evoked and spontaneous discharge rates has been observed in spinal, as compared to intact, anesthetized cats [9] suggesting some form of descending control on DCPS fibers. The bulk of corticofugal fibers that terminate in the DCN do so in the rostra1 areas, where the majority of DCPS fibers also terminate [ 1301. There is indirect evidence that suggests differing inhibitory control on the DCPS-DCN and SCT-LCN systems. Carli et al. [56] recorded evoked potentials in the ML and found that REM bursts in sleeping cats produced phasic depressions of the ML response to peripheral nerve stimulation. The depression was 50% greater on the dorsal column component of the evoked potential than on the SCT-LCN component, suggesting differential inhibition on the two systems. However, it is not known whether the DCPS-DCN system in particular was affected. No differential inhibition was observed during other stages of sleep. Summary. Although further information is needed, particularly direct comparisons among the 3 systems under identical conditions, the present evidence suggests relative differences in the anatomy and inhibitory control of the DCPS-DCN, SCT-LCN and nSTT systems. The possibility that the transmission within the systems can be “switched” to carry selective information on one modality or another ~- pain or light touch - is highly intriguing. Contrasts with the pSTT and SRT systems Fig. 3 depicts 3 somatosensory systems
ascending
from the ventral spinal
112
cord. C)nt?, the nST’l’, has been discussed abovcl. Th!’ other two systems, the l)S’l’T (group B) and SRT (group C), are 1)riefly described in this schction, with particular reference to their possible involvement in nociception and their general characteristics. Although there has been much controversy over precise terminology [ 1511, the pSTT projections to the midline and intralaminar thalamic nuclei have been identified in virtually all mammalian species studied [ 151,1533. Mehler [ 1511 has indicated that the pSTT system differs little from species to species. The nSTT system, on the other hand, shows clear species differences in size and precise route of ascension. The pSTT is considered to cross the midline in the spinal cord [ 121,122], although some input may be homolateral. The fibers projecting directly from spinal cord to thalamus are few in number [25]. The projection of nociceptive signals to the midline-intralaminar nuclei has been demonstrated by several investigators [ 2,3,59,128,181]. However, the magnitude of the nociceptive contribution has been questioned [ 1761. Possibly the depth of anesthesia is a factor in this disagreement, since this has been shown to influence the observed properties of midline-intralaminar cells [ 591. The modality types reported for the midline nuclei are similar to those listed in Table I, although there is disagreement on the relative proportions of each. Receptive fields are generally very much larger than in the dorsal cord or nSTT systems. The spinoreticular system (SRT, group C in Fig. 3) is generally agreed to be substantially larger than the pSTT system, and has also been considered as phyletically constant [151,153]. The terminations of spinal fibers in the reticular formation form a complex pattern involving a variety of RF sites. The details are reviewed elsewhere [ 151,186]. Recently, Kerr and Lippman [121,122] have determined that the SRT projections do not entirely conform to the spinal cord diagram shown in Fig. 3. Using the technique of midline myelotomy - severing the axons crossing the spinal commissures by a longitudinal cut along the midline - they observed only sparse degeneration in the RF. Thus, most of the SRT axons apparently ascend the spinal cord ipsilateral to their cell bodies, instead of the contralateral scheme shown in Fig. 3. However, the possibility of bilateral, or even predominantly contralateral, receptive fields for these axons is not ruled out. By and large, the spinal input to the RF is diffuse, multisynaptic, poorly somatotopic if at all, and often highly convergent with other sensory modalities [ 161 and non-spinal RF connections [ 281. Physiologically, the units of the SRT have been shown to include the [ 12,15,17,53,57,58,60,87,139,186,223,2351, types listed in Table I although the relative proportion of each is debated [ 1751. The receptive fields of these cells are generally agreed to be larger than those of the dorsal cord or nSTT systems. The relay of SRT information to structures further rostral appears likely [ 251. While the modality types of the pSTT and SRT resemble those of the dorsal cord pathways and nSTT, they appear to differ somewhat on other phys-
113 iological dimensions. For example, the cells of origin, as determined by electrophysiological methods [ 5,25,87,132], appear to be concentrated exclusively in the deep spinal laminae (VI-IX). Both lumbar and cervical preparations have been studied. Treviiio and Carstens 12131, using the horseradish peroxidase method, found labeled cells only in lumbar laminae I, VII and VIII, even when the original injection included parts of the RF and midlineintralaminar nuclei. The pSTT and SRT may also conduct impulses more slowly than the dorsal cord pathways and nSTT [3,86,89,117,128,175,176, 1862231. When the evoked response latencies to a peripheral stimulus are recorded, it is generally found that those central structures receiving dorsal cord and nSTT input (VPL, PO, ZI) are activated prior to the RF or midlineintralaminar regions [ 86,89,128,176]. The difference is readily observed when comparing VPL responses against others, but PO and ZI responses also tend to occur sooner than RF or midline thalamic responses. Although the differences are not large and the distributions overlap, the direction of the difference seems clear and replicable. Summary. Two ventral cord systems, the pSTT and SRT, have been found to contain a proportion of cells that respond to noxious peripheral stimulation. Light tactile cells are also present in both. These systems appear to differ from those of the dorsal cord and nSTT with respect to loci of origin and conduction velocities. However, by far the greatest difference between the two groups is anatomical: the fibers of the pSTT and SRT turn medially to synapse in the reticular formation and midline-intralaminar thalamic nuclei, as opposed to the lateral course of the dorsal cord and nSTT systems. These contrasts suggest that the pSTT and SRT may be involved in aspects of pain fundamentally different than those of the nSTT, SCT-LCN, and DCPS-DCN. BEHAVIORAL
EVIDENCE
Although the physiological studies are highly suggestive, they do not necessarily establish the behavioral relevance of the dorsal cord pain-signalling pathways. That nociceptive information is carried by these systems seems undeniable; whether this information contributes to pain perception and behavior is not clear from the above data. However, research on the behavioral effects of spinal cord lesions and central electrical stimulation suggests that the dorsal cord projection pathways, in addition to the ventral pathways, can and do act as pain-signalling systems in the conscious, freely responding animal. Stimulation studies Medial lemniscus. Electrical stimulation of the medial lemniscus at pontine or midbrain levels is highly aversive. It motivates vigorous escape responding in rats and cats, and is described by human subjects as painful. In the rat, lemniscal stimulation provokes clear signs of distress: cringing, writhing, running, jumping, and some vocalizing [ 30,77,78,81,123,178]. Some rats show vigorous licking of contralateral fore- or hindpaws, or wiping of the ipsi- or contralateral muzzle, in a manner clearly suggestive of aversive
sensations referred to these regions. When trains of elcctrid pulses are delivered to the ML via chronically implanted electrodes, and the rats are allowed to turn off stimulation by pressing a lever, escape responding can be maintained at high rates, even after several months of daily sessions. Measurements of refractory period distributions [80,234] of the axons responsible for the aversive effects have indicated the presence of at least two functionally aversive axon populations in the rat ML [ 78,123]. Their sources, however, remain to he experime~ltall~7 determined. Electrode placements in the dorsolateral tegmentum, where presumably the rodent nSTT is located, are also highly aversive when st,imulated [ 1231. Studies in the cat also clearly demonstrate the aversive effects of ML stimulation [ 10,74,198,208]. Particularly convincing are the studies of Aoki and Nakao [ 101 who report that, of 310 electrode placements throughout the pontine brain stem, only those in or near the ML motivated reliable escape behavior (lever pressing). It seems unlikely that current spread to adjacent regions could account for these results since electrode tips actually located in these regions were often ineffective. Stimulation also produced pain-suggestive screeching and hissing, as well as a number of the stereotyped motor components reported in rats [ 771. Similarly, Spiegel et al. [ 2081, who make a clear distinction between nSTT and ML sites, report crying, hissing, struggling and flight reactions to ML stimulation. Stimulation of the ML also produces reports of pain or thermal sensations in man [ 104,167,168,170]. During stimulation of midbrain lemniscal sites, patients report distinctly aversive sensations once the stimulus frequency has reached a sufficiently high level. At frequencies below 60 Hz, only movement sensations or tremor are produced; at frequencies exceeding 120 Hz, the sensation is described as “hot and painful”. It is significant that the painful sensation is referred only t,o contralateral peripheral sites, indicating the activation of a predominantly crossed system. Nashold et al. [ 1701 also obtained reports of contraIateral pain from stimulation of the midbrain nSTT. However, nSTT pain is described as “brighter, sharper” than that evoked by ML stimulation, and appears at stimulus frequencies of about 60 Hz. Thus, stimulation of either the ML or nSTT can elicit sensations of distinctly negative effect, which are referred to contralateral peripheral sites, although the nSTT requires a lower stimulation frequency to produce this effect. The ML and nSTT sensations contrast sharply with the poorly localizable and highly intolerable sensations produced by stimulation of more medial midbrain sites where the SRT and pSTT fibers are located [ 1681. Other sites. At the spinal cord level, reports of sharp, burning pain are elicited during electrical stimulation of the ventrolateral cord [ 110,145], although this is by no means a universal observation [ 941 (LoeSer, PerSOnal communication). Electrical stimulation of the dorsal columns, by either surface [ 1691 or depth electrodes ]llO], has not been found to produce Pain, although distressingly unpleasant “shock-like” or “throbbing” sensations have been elicited. Mechanical stimulation of the dorsal columns, however, Morehas been reported to produce intense, localized pain [51,207,231].
115 over, Sourek 12071 has found that the peripheral sites to which patients refer the pain correlate precisely with the somatotopic organization of the dorsal columns. Thus, the insertion of a fine needle into the medial part of the fasciculus gracilis produces pain sensations in more distal dermatomes; stimulation of the lateral regions causes pain in higher dermatomes. When the midline is crossed, the pain shifts to the other side of the body. This curious effect may reasonably be attributed to axon injury discharges ascending in a dorsal column pain-signalling system. Such discharges would be expected to be of much higher frequency than those produced by electrical stimulation, Stimulation of the ventrobasal thalamic complex is also aversive to animal and human subjects [ 18,‘72,73,104,108,178,195,198]. Hassler [ 1081 elicited strong, localized pain from the basal parvocellular part of somatosensory thalamus, which contrasted with the somewhat more generalized contralatera1 pain produced by nSTT stimulation. Convergence of ML and nSTT fibers in this region is likely. Pain felt in the contralateral part of the body is also produced by stimulation of the tectum in humans [ 1971 and lower animals [ 2081. Summary. Direct electrical stimulation of CNS structures associated with either the dorsal cord projection pathways or the nSTT has been found to produce localized pain sensations which are capable of motivating escape behavior. It is therefore suggested that the dorsal cord pathways, like those in the ventral cord, are involved in the organism’s pain perception, motivation, and response mechanisms, and may thus be a natural part of the pain process. That pain can be elicited from the human ML suggests the presence of a functional DCPS-DCN and/or SCT-LCN system of the type found in lower species. Lesion studies Although behavioral studies employing spinal cord lesions have inherent difficulties in interpretation, they are useful as general indicators of function. This is especially true when the data are considered in the light of physiological studies, which establish the presence of particular cell types in a particular region, and stimulation studies, which suggest the behavioral relevance of impulse activity in a particular region. Dorsal spinal cord. Total dorsal cord hemisection, which interrupts the DC and SCT systems but spares the ventrolateral pathways, has been shown in cats to produce analgesia with a gradual postoperative recovery of pain perception [116]. Ventrolateral lesions were less effective in producing analgesia. Levitt and Levitt [ 1331 observed similar effects, reporting temporary impairments in pain reactions when the feline dorsolateral cord was sectioned. The impairment was more permanent when a dorsal cord hemisection was performed. However, isolated dorsal column lesions have been found to have little analgesic effect [ 1581. Levitt and Levitt [133] also noted that dorsal cord lesions did not completely abolish pain. Rather, the deficit was described as a failure to localize the source of the noxious pinch.
116 A response described as “general agitation” was still exhibited when the lcsioned animals were pinched. Christiansen [ 621 has noted similar effects in the macaque. Breazile and Kitchell [32] lesioned all but the dorsal columns and one dorsolateral funiculus of the pig’s spinal cord, and found that painsuggestive responses to noxious heat on either hindlimb could still be elicited, although the threshold was markedly raised. When the remaining dorsolateral region was sectioned, leaving only the dorsal columns intact, pain-suggestive reactions were strongly impaired. In this species it appears that the dorsolateral cord is capable of bilateral pain mediation. In monkeys, Vierck et al. [222] studied the effects of cord lesions on lever-pressing responses to escape electric shock to the flanks. Unilateral ablation of the dorsal columns reduced reactivity to shock on the ipsilateral side. Unilateral ablation of the dorsolateral funiculus tended to increase reactivity to ipsilateral shock. However, neither of these lesions significantly altered the threshold for responding. When the contralateral ventro- and dorsolateral regions were cut, a reduction of reactivity and an elevation of threshold were observed. These effects could be amplified by inclusion of the ipsilateral dorsal columns in the lesion. These data have been confirmed in part by Denny-Brown et al. [79]. Thus, in the monkey, the dorsal and ventrolateral columns could both be involved in pain signalling with the ventrolateral cord being the dominant substrate. The hyperreactivity produced by isolated dorsolateral lesions argues against a direct pain-signalling role for pathways in this region. However, it is possible that the interruption of descending pain-inhibitory systems may override the effects of SCT lesions in this species. In man, attempts have been made to relieve phantom limb pain by sectioning portions of the dorsal columns ipsilateral to the stump [ 34,35,187]. This operation generally produced relief of pain while sparing or only slightly impairing other tactile functions [ 64,192]. The best results occurred in patients whose pain had a “cramping” rather than sharp or burning quality. However, the pain often returned after several months. Although the operation is no longer recommended, the partial success of dorsal column section in relieving certain types of pain is consistent with a direct involvement of the dorsal columns in pain mediation. Similarly, Sourek [207] has attributed some of the therapeutic benefit of commissural myelotomy to incidental damage to midline dorsal column fibers. Ventral spinal cord. Surgical section of the ventrolateral spinal tracts is frequently performed to relieve chronic pain in man, although it is substantially less effective in lower animals. The therapeutic value of ventrolateral chordotomy has been extensively reviewed by White and Sweet [ 2311 who conclude that permanent pain relief can be expected in at least 50% of cases. Continuing improvements in techniques for precisely localizing the lesions [ 94,110,145] may increase the percentage of success. However, White and Sweet [ 2311 also document a distressing number of failures. In some cases, analgesia lasted only a few days or months; in others, pain returned after several years. It has been suggested [ 1501 that failures may be due to the spar-
117 ing of ventrolateral pain fibers. Others [ 120,231] argue against this, pointing out that no matter how complete the transection, pain can eventually return. Moreover, a second or third chordotomy, performed following failure of the first, seldom improves the long-term result [ 230,231]. It seems unlikely that ventrolaterai pain-signalling fibers would survive multiple lesions by competent surgeons. Extending the lesion to include the ventral tracts also does not substantially improve the result [ 2311, The failure of chordotomy to abolish chronic pain in all cases is consistent with the notion that spinal tracts, other than those in the ventrolateral cord, can carry pain-signalling information. Studies on the post-chordotomy pain threshold support this conclusion [ 124,180]. King [ 1241 found that chordotomy patients, including those who experienced prolonged pain relief, continued to report pricking pain in response to cutaneous or C fiber electrical stimulation. The threshold on the ~llordotomized side was approxima~Iy 50% higher, however. King also reported that 20% nitrous oxide was sufficient to restore the level of clinical analgesia in patients whose analgesic area had contracted in the months following the operation. On this basis, he suggested that a polysynaptic system, perhaps in the spinal grey, mediates pain following chordotomy. Interestingly, however, it has been reported that SCT-LCN cells are also highly sensitive to nitrous oxide [126,210]. It is apparent, then, that even in the absence of the ventrolateral tracts, peripheral noxious stimuli can still be perceived, although less readily than preceding chordotomy. That ventrolateral chordotomy works is evidence that this cord region is important in pain sensation. That it does not work all the time is evidence that these tracts are not the exclusive mediators of pain sensation. Summary. Surgical lesions in either the dorsal or ventral spinal cord have been found to decrease pain sensitivity in several species. However, no isolated neurosurgical lesion can be considered universally effective in abolishing pain. In primates, ventral cord lesions are most effective; yet some pain sense persists after such operations, and there is evidence that dorsal cord lesions may potentiate the effects of ventrolateral chordotomy. In sub-primates, dorsolateral cord lesions are temporarily effective, and can be potentiated by inclusion of the dorsal columns in the lesion. Thus, several spinal systems appear to participate in pain mediation, with no single one absolutely essential to it. IMPLICATIONS
The evidence reviewed above is consistent with the hypothesis that functional pain-signalling fibers are present in both the dorsal and ventral regions of the spinal cord. Three of these systems - the DCPS-DCN, SCT-LCN, and nSTT - are comparable on a number of physiological and anatomical dimensions. They all respond to mechanically produced skin damage, to heating the skin to painful levels, and to electrical stimulation of A6 and C fibers. Each conducts rapidly and is capable of sending its messages, via the lateral
118 thalamic nuclei, to the highest levels of the neuraxis with relatively few intercalated synapses. In other ways, however, the systems differ. Each is a distinct anatomical structure, which retains its own particular characteristics. Moreover, it is likely th::t ‘hey are controlled differently by the various inhibitory systems of the CNS. It is apparent, then, that the DCPS-DCN, SCT-LCN and nSTT are not merely redundant systems, each performing precisely the same function, but separate entities, each with its own particular role in the overall scheme of nociception. In addition to the above mentioned pathways, there appear to be at least two other spinal systems which could be involved in pain: the SRT and the pSTT. These pathways project medially to the reticular formation and paleothalamic regions, and thence to the limbic system. Compared to the dorsal cord pathways and nSTT, the medial ascending systems are relatively slow, indirect and highly convergent. Such properties are also shown by the multisynaptic propriospinal systems whose possible involvement in pain has been suggested [ 13,791. The emerging picture, then, is of two basic groups of pain-signalling systems, each group having several distinct components. For convenience we shall use the term “lateral” to refer to the dorsal cord and nSTT projection systems, and “medial” to refer to the SRT, pSTT, and propriospinal pathways [ 891. These two kinds of systems, often under different terminologies, have been proposed as playing distinctly different roles in pain [ 1,24,27,29, 156,236]. For example, under the Melzackxasey conceptualization, the fast, direct systems mediate sensory-discriminative and central control triggering functions, while the medial systems mediate the affective-motivational dimension of pain. While this model remains a current and useful description of pain mechanisms, the evidence reviewed above raises several new questions. For example, why do several individual systems appear to share the functions subserved by each general group? Is there a strict segregation of sensory-discriminative and motivational-affective fibers at the spinal levels, or are these dimensions “mixed” throughout the neuraxis? What are the exigencies governing the descending control of these various spinal pain-signalling systems? There are no simple answers to these questions. However, some speculations can be made. The role of the lateral projection systems The value of rapidly conducting, direct pain-signalling systems is obvious. Unless an organism reacts quickly, a stimulus which only threatens tissue damage may become overtly damaging. For example, if an animal steps on a thorn, the initial penetration may be minimally damaging. However, unless the animal immediately lifts the paw, the injury could become quite severe. Similarly, when an organism fights with another, or encounters objects which are injuriously hot or cold, appropriate response mechanisms must be rapidly activated if tissue damage is to be minimized. Obviously, spinal the reflexes play a role in this process. However, in many circumstances, appropriate action may require much more than simple reflex activity. It is
119
therefore essential to have a system which conveys the nociceptive message rapidly to the highest levels of the CNS. Its principal purpose is to trigger appropriate motor responses which minimize the damage done by any noxious stimulus. The dorsal cord systems - the DCPS-DCN and SCT-LCN and the nSTT appear to be well suited for such a role. Why three lateral projection systems? Injurious stimulation may occur under many circumstances. An animal may be attacked by another when it is awake or asleep. If asleep, the attack could occur during any of the various stages of sleep. If awake, the attack could come while it is food-gathering, drinking, nest-building, exploring a novel or familiar environment, grooming, copulating, and so forth. Similarly, objects which are sharp or at an extreme temperature may be accidentally encountered during any of the organism’s waking behavior patterns. The key to minimizing the damage done by these stimuli is for the animal to perform appropriate motor responses which, in a purely mechanical sense, may need to be different depending on what the animal is doing at the time. It is conceivable, then, that the fast nociceptive pathways represent different sensory channels which are individually inhibited or facilitated depending on the ongoing behavior or behavioral state of the animal. Thus, the same noxious stimulus, occurring during different behavior patterns, might evoke impulses in different pathways. Depending on the pathway(s) by which it arrives, the nociceptive message may be treated differently by the information-processing and response selection mechanisms of the brain. Thus, a nociceptive message ascending in one pathway may trigger different responses than the same message ascending in another pathway. An important factor which may contribute to this process is the brain’s need to obtain light tactile or proprioceptive information from these multimodal systems. As shown above (Table I), none of the 3 systems can be considered as purely nociceptive. Each has a complement of cells responsive only to light tactile stimuli, and, perhaps more importantly, each has a significant population of multimodal cells - units that respond both to light tactile and nociceptive stimuli. There is some evidence that there are qualitative differences in the types of innocuous information carried by the systems [ 361. Perhaps during a particular behavior pattern, the brain selects one type of information from a system and filters out the other types such as nociceptive inputs. Thus, when a system is functioning in a proprioceptive capacity, or monitoring light tactile stimuli, it cannot simultaneously act as a nociceptive system for that part of the body. However, the enormous biological importance of nociception makes it essential that this modality be operative in some form at all times. Therefore, one of the other systems must provide the necessary pain-signalling function for the duration of the behavior. When the ongoing behavior or behavioral state changes, the brain selects other classes of tactile information, perhaps from other systems. When this occurs, a new pattern of differential inhibition and facilitation is imposed on the systems, such that the previously suppressed nociceptive capacity of one system may
120
now be facilitated. In this way, the brain can always extract necessary t.actije it&rmation from peripheral systems, and still maintain vigilance regarding sudden injuly or threat of injury. The possibility that the DCPS-DCN, ScTLCN, and nSTT systems can be i~lclependently switched between nociceptive and light tactile modalities is consistent with this kind of model. Xjoreover, there is evidence for behavior-dependent inhibition of transmission through the ML [65,91,92,177]. There is an alternative model of the functions of the 3 lateral projection systems. The com~oIlents of t,he lateral group could be viewed as behaviordependent “amplifiers” of nociceptive messages. One pathway (e.g., the nSTT) may be used as the primary rapid pain-signalling system, while the nociceptive impulses carried in the other systems are used to amplify or modulate the primary message in much the same manner as innocuous stimuli have been proposed to do [157,173,226]. The difference is that under this for~~lulation, nociceptive informatioI1 in one pathway is used to modulate nociceptive information in another pathway. This modulation could be eithrxr inhibitory or excitatory. The ongoing behavior pattern or behavioral &ate might determine whether these sup~IenleIlt~~7 pathways are open or closed, and thus indirectly affect the primary nociceptive message. iliowever, the form of the reaction to noxious stimuli is determined primarily by the responses triggered by the primary p~n-si~~li~~ system, and by the eomplex response selection mechanisms of the brain. A factor which may be of critical importance in determining how the lateral pain projection pathways are used is whether the animal has already sustained some serious injury. Tactile stimuli which would be innocuous to normal tissue might be ~~aii~fully damaging if applied to an existing wound. Escape mechanisms must therefore be activated in response to such stimuli. flowever, it may also be advant.ageous for the animal to tend the wound (cleaning, covering, and so forth). Such activities would also produce light tact,iltx stimuli. Thus, t~he same stimulus (for example, licking) would have vrlry different. effects depending on whether it is self-induced or coming from an tqxtermd source, such as another animal. While it. is entirely possible that such decisions are made by the brain, it may also be that t,he IW~VOUS system Wtually “ant,icipat,es” such situations at the spinal cord level. Thus, in a wounded, r~sfing animal, a “licking” message is, from the outset, channeled into systems which rapidly trigger escape reactions. Iiiowever, in a wounded, g~~>l~liq animal, the message may take an alternative route which does not itrovoku chscape reactions as readily. ‘rhcre arc’, of course, other possible roles for the fast, direct, multimodal systems, and there are other explanations for the presttnce Of several such systems. The above speculations, however, suggest new behavioral experiments and re-evaluations of present physiological data. Possible in~(?rac~~ons be&ucetl lateral and ~?le~ial ~rojec~io~l systems The anatomical and physiological properties of the SRT and pSTT SYStems make it unlikely that these systems serve to signal the need for imme-
121 diate action [24]. It has been suggested that they play a role in chronic, deeply unpleasant and diffuse pain, as well as subserving the longer lasting motivational-affective effects of noxious stimulation [ 1561. While the dorsal cord pathways and nSTT appear eminently suited for rapid transmission of phasic information, such as the threat or onset of injury, or sudden changes in a damaged area, the other ventral pathways seem best adapted to carrying tonic information on the state of the organism. Thus, an important, although perhaps not exclusive, role for these ventral systems may be to signal the actual presence of peripheral damage, and to continue to send that message as long as the wound is susceptible to re-injury. In this way, the slow nociceptive pathways may in part determine the level of arousal or the general behavioral state necessary to prevent further damage, and to foster rest, protection, and care of the damaged areas, thereby promoting healing and recuperative processes. Activity in the SRT and pSTT may also affect the switching mechanisms which operate on the fast systems. Perhaps they “set the bias” on the DCPSDCN, SCT-LCN and nSTT systems, influencing them more toward the selection of nociceptive information from a damaged area. As healing proceeds, activity in the medial systems decreases and the normal balance between light tactile and nociceptive inputs in the lateral projection systems is restored. An experimental approach for determining the type of mechanism which may be involved in these interactions is suggested by the effects of morphine, which appears to act predominantly at brain stem sites [ 143,144]. Morphine generally diminishes tonic post-surgical pain, but has less effect on the pain produced by sudden movements or removal of stitches. In contrast, nitrous oxide at analgesic dosages seems to diminish both the phasic and the tonic pain. Thus, the two major systems may be subserved or controlled by different neurochemical mechanisms which are selectively affected by different pharmacological agents. Implications for the treatment of pain The existence of functional pain-signaIling pathways in the dorsal spinal cord could have important implications for the surgical treatment of pain. It suggests an explanation for the failures of ventrolateral chordotomy, even bilaterally and at several levels, to relieve chronic pain. Although the ventral tracts are obviously of great importance in nociception, the presence of dorsal pain-signalling pathways, which may be quite variable from individual to individual, complicates the neurosurgical treatment of pain. Neurological tests for assessing the presence of these auxiliary pathways could be of great value. Any treatment of pain must also be considered in terms of its effects on inhibitory mechanisms. The data reviewed above suggest that pain is not governed simply by a balance of excitation and inhibition in a single system, but rather in multiple, interacting systems. Any therapeutic manipulation, whether it destroys an ascending system or excites a descending one, could
122
therefore
alter t.he e~~itator~~-inhibitor interactions in the rema~I~in~ SYS‘Ihis complex dynamic balance among several systems may account for the variability encountered in all forms of pain treatment, including sur@c& f23lj and electrical stimulation 11351 methods.
tems.
The above considerations also suggest that pain-signaIling processes may according to the organism’s behavior and behavioral state. On the one hand, proprio~eptive and tactile stimuli occurring during particular behavioral patterns might have specific inhibitory effects on pain transmission. On the other hand, it is possible that ~oncomit~t with the behavioral patterns themselves and the motor commands that produce them, differential effects are exerted directly on the multiple pain-signalling systems to change the relative activity among them. This could alter not only the perceived intensity of noxious stimulation, but also the form of the organism’s reaction to it. Thus, the individual’s environment and psychological history [ ISS], both of which are antecedents of behavior, may in part control the physiologic mechanisms which mediate pain, perhaps even at the level of the first synapse. vary
i~~I~NO~~~RGEM~N~S
This study was supported by Post-doctoral Fellowship l-F32-NS05099-01 to Dr. Dennis from the United States National Institute of ~eurolo~c~ and Communicative Disorders and Stroke, and by Grant A7891 to Dr. Melzack from the National Research Council of Canada. The authors express sincere thanks to Drs. A.G. Brown, K.L. Casey, J.D. Loeser, A.J. MeComas, B.S. Nashold, and P.D. Wall, for their helpful comments and criticisms of earlier drafts of this paper. REFERENCES i\lbt~-F~~~~:~~d,D. and
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