69 Pain, 3 (1977) 69-'80 © Elsevier/North-Holland Biomedical Press
COMPARATIVE STUDY O F PERCEIVED PAIN AND NOCICEPTIVE FLEXION REFI,EX IN,MAN
JEAN CLAUDE
WILLER
Laboratoire de Physiologie, Facult~ de Mddecine Saint-Antoine, 75571 Paris Cedex 12 (France)
(Accepted July 21st, 1976)
SUMMARY
The purpose of this study was to compare the amplitude of the flexion reflex of the biceps femoris muscle (BF) with the intensity of the painful sensation elicited by a nociceptive stimulation resulting from application of a constant-current either on the sural nerve or on the skin in its distal receptive field.: Experiments were carried out on 15 normal volunteers. It was observed that: (1) Stimulation of the sural nerve (either on or through the skin) elicits two different reflex responses in the BF: the first (RII) is of short latencY, low threshold and corresponds to a tactile "eflex. The second (RIII) is of longer latency and higher threshold, and corresponds to a nociceptive reflex. The threshold of RIII was found to be the threshold of a pain sensation. (2) Stimulation of the skin elicits only a late nociceptive (RIII) response in the BF. The threshold of this response was also found to be that of pain. (3) The thresholds of both pain and RIII were found to be higher for sural nerve stimulation (10 mA) than for cutaneous stimulation (5 mA). It was suggested that the large diameter cutaneous fibers could have an inhibitory effect on both pain and the nociceptive reflex. This was supported by the resu.its obtained during a selective ischemic block of the largest diameter fibers in the sural nerve, when a 10 mA stimulation was applied to the nerve. In this case, a decrease of the RII reflex was observed in BF, together with an increase of both RIII and pain sensation. Functional implications of these result~ are discussed.
INTRODUCTION
(1) The desire to understand the feeling of pain and to evaluate its role in life and behavior of man has preoccupied many generations of physiologists
70 and philosophers. Even today: this understanding is far from complete, and research for e~.method of measuring pain still remains a real problem. The difficulties encountered in every objective study of pain are multiple. They may be partly explained by the po!ymorphic nature of pain sensation a n d b y the absence of limits of pain appreciation, but are also due to the special characteristics of pain sensation: (a) while it is true that the sensation of pain may always be increased by augmenting the stimulus intensity, it may also be modified by anxiety [13,17,47] or by the degree of motivation of the subjects with regard to the stimulus [5--7]; (b) the form of energy activating the pain receptors is not specific [27]; (c) the somatic and autonomic reflex mechanisms may also be initiated by other phenomena, independent of pain, ~uch as fear or surprise [ 8]. (2) Techniques for measuring pain in man may vary according to the adequate s¢imulus used by different authors, for instance: thermal [14] mechanical [ 36], chemical [ 25] or electrical cutaneous stimulations [ 17,31], or chemical stimulation of the peritoneum [27]. In this study, the threshold of painful sensation was measured during stimulation of nerve fibers from an area of the skin innervated by the sural nerve, which, it appears, transmit preferentially messages originating froni pain receptors. (3) Electrical stimulation of the sural nerve, a cutaneot~s nerve of the lower limb, evokes in man a two component reflex response in the lower limb flexor muscles [20,26]. The first (RII), short latency component, is initiated by the acti~ration of myelinated cutaneous fibers of large diameter and low threshold. The second response (RIII), of longer latency, appears at higher stimulus intensities, where smaller diameter fibers are also activated. Many authors have shown, in animals [1,24,29,50] and in man [11,15, 16] that the c:.~taneous fibers of large diameter (Lloyd's group AII [28]) convey tactile message:; triggerec', by light touch or pressure, while pain sensation is transmitted l)y smaller fibers, especially by group III afferents. According to some auti~ors [ 21,48], there is a close re!ationship between the RII reflex and tactile :~ensation and between the RIH ._ ~ -- and the sensation of pain. The existence of these relationships present a certain interest in establishing me~;hods f,)r measttring pain, since they allow the comparative study of threshold and intensh;y of pain sensation a~d of the nat(Ire and amplitude of the afferent volley responsible for this s-2nsation. This was the method used in the first part of this study. However, being based on direct electrical stimulation of a peripheral nerve, it did not allow the cutaneous receptors, which are the origin of pain reception, to be tested. For this reason, in later experiments, electrical stimulation of the skin was employed. The skin is innervated by cutaneous nerves which run with blood vessels through the subcutaneous tissues. These nerves branch and penetrate the dermis, forming a double pJexus lying parallel to the skin surface. The first description of these structures was put forward by Ruffini [35], who described a deep dermal plexus from which fibers branched at irregular intervals towards a second, more superficial, dermo-epiderrr, al plexus. According to
71 Winkelmann [49], the fibers of the deeper plexus are larger in diameter (AII) than those of the more superficial plexus (AIII and IV). Moreover, this author observed that these small nerve filaments ~.~fgroup AIII and IV may also enter the epidermis. It is t h o u g b t that the fibers o f this superficial plexus, terminating in open complex loops or ?xound the superficial blood capillaries, act here as adequat~ pain receptors [ 27,43--45]. The experimental approach described here differs from others in that an attempt was made to activate the small branches of the supe:fficial plexus selectively. An electromyographical record of the reflex responses of a flexor muscle of the lower limb was made, together with a study of somatic sensation, in particular the threshold of pain, under two experimental conditions: (1) electrical stimulation of the sural nerve; (2) electrical stimulation of the skin within the distal cutaneous field of this nerve. METHODS
The experiments were carried out on 15 subjects (10 males, 5 females), young adults, medical students or physiologists ha~¢ing alreaay pm~icipated in experiments of this kind and thus already familiar with the experimental atmosphere and with the pain inducing stimuli. The experimer~tal procedure was explained previously to the subjects in order to avoid any element of surprise. During the sessions, the subjects were comfortably iastalled in an armchair specially designed to obtain a good muscular relaxaiion.
Stimulation and recording Stimulation of the sural nerve (n. suralis) was performedl: (1) Percutaneously, using a pair of tinned copper electr6des, each 1 sq. cm, applied to the skin 2 cm apart, over the external retro-malleolar pathway of the sural nerve. The skin had been previously abraded and degreased, and a saline solution ensured electrical conduction such as the inter-electrode resistance (1000--2000 ~ ) did not change significantly during the course of the experiment. ( 2 ) Transcutaneously, by means of a pair of steel needle electrodes, insulated to t h e tip, placed through the skin on the sural nerve, at its external retro-maUeolar pathway, and spaced at about 2 cm. Electrical stimulation of the skin in the distal receptive field of the sural nerve was performed with surface electrodes, using the procedure described previously. In each case, stimulation consisted of a volley of 10, 1 msec rectanCalar pulses delivered over 20 msec (300--400 Hz). This stimulus was delivered using a constant-current stimulator, cathode being placed proximally. Stimulus strength, varying between 1 and 18 mA, was recorded with an intensity probe (Tektronix 134) and CRO displayed. Electromyograms (EMGs) were recorded from the biceps femoris muscle (bicep femoris, capitis brevis, BF) since certain authors [3,20] have shown that this muscle is the earliest reflexly generated activity in the lower limb of normal man. Recordings were made using the technique described by Hugon
72 [21], and the EMGs were displayed on a storage oscilloscope after amplification. Ischemia of the sural nerve, performed on 7 subjects in order to block the large diameter fibers selectively, was obtained by using a pneumatic tourni, quet, placed in the ankle regio~, above the articulation of the foot and the stimulating electrodes. The pneumatic cuff pressure was maintained constant for 15--20 min, at twice the maximal arterial blood pressure. The temperature of the stimulated foot was 33 ± 2 ° C, and remained stable throughout the course of each experiment, except during ischemia where it fell by 3--4°C distal to the cuff. Room temperature was 20 + 2 ° C. The reflex threshold was then defined as the stimulus intensity giving 60--70% of responses. Measurement o f sensations Using a method described by Gybels (personal communication, 1974) modified slightly for the requirement of this study, the quality (tactile and painful) and the intensity of sensation was represented on a linear scale of 10 cm, centered in the middle of a sheet of paper (15 cm X 20 cm). Each subject bad to indicate the type and intensity of sensation by means of a point placed on this {Fig. 1). The left of the: scale represented tactile sensations while the extreme right represented intense and unbearable pain. Somewhere between these two poles was situated ~,he pain threshold. This method of study had the advantage of being able t~) quantitate the sensation more precisely than purely verbal methods. Certair. preliminary precautions were necessary: (1) Preliminary test sessions lasting about 1 0 m i n were made during which stimuli at variou~ intensities (1--18 mA) were given ran(~omly, giving rise to tactile sensation, slight pain o~' extreme pain. At the end of the trial period, each subject presented a stable level of sensation for a st:mulus of given intensity. The pain threshold was then determined usir, g the staircase limits method [38], with 4 serie~ of increasing stimulation and 4 series of decreasing stimulation. (2) In order that the subjects were not influenced by their own results in previous tria~s, the sensation score sheets were replaced every 3 or 4 tests. (3) In order to eliminate interference phenomena "{3 O
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Fig. 1. l~h~s figure gNes an example for one subject of the sensation scale, as a function of intensity ~f stimulation. The left extremity of the line represents tactile sensations, whereas sl:rong and excruciating pain sensations are tocated at the right extremity. The pain thresaold is indicated by the dots draw,~ by the subject for a stimulation at pain threshold.
73 due to the permanent attention and expectation on the part of the subje :g~ test series were begun at random time intervals. Outside test periods, the subject was told to remain calm and relaxed. These precautions were necessary since it is knewn that attention may modify both spinal motoneuron excitability [2,4] and perception of pain [17,47]. Under these conditions, each experimental session lasted an average of 30 min, and the subjects :showed a stable pain threshold throughout the examination and at successive tests repeated at 48 h intervals. Liminal pain was described as a sharp sensation, like a pin-prick localized at the point of stimulation. Each subject was tested at least 3 times. Sensations were measured on the scale and were quantified in arbitrary units (A.U) from 0 to 10.
Analysis o f results Individual and group analysis of the mean and variance of the numerical values of the parameters studied were made for each stimulus intensity. Regression ii~.es were calculated using the method of least squares. The s,:gnificance of variation within and between individuals was determined by means of a complete equilibrated factorial analysis and by a Student t test. RESULTS
(1) Stimulation o f sural nerve As described in the Introducti,,n, electrical stimulation of the sural ne~.we, percutaneously or transcutaneously, evokes two types of reflex activity in the muscle BF (Fig. 2A). The first response (RID has a short latency (40--70 msec) and a low threshold (5 +- 0.6 mA). This response was not feund du~'ing the first recording session for 7 subjects, probably because they were not well relaxed. However, during following sessions, the results were better, and the response RII was observed in all subjects. In every case, the threshold stimulation for the response RII produced a tactile sensation, comparable to that produced by rhythmic percussion of the skin with a reflex testing hammer. The sensation was localized at the point of stimulation and was often accompanied by tingling sensations in the receptive field of the sural ne~-ce. The second response (RIII) had a longer latency (90--130 msec) and a higher threshold (10+ 1 mA). Stimulation at 10 mA provoked a liminal pain sensation of the pin-prick type, localized at the stimulating point.
(2) Stimulation of the skin Electrical stimulation at 10 mA applied to the skin in the distal receptive field of the sural nerve evoked an isolated RIII r~sponse in the muscle, BF (Fig. 2B). This reflex response was of large amt,litude and corresponded clearly to suprathreshold activation of the small diameter myelinated ,:utaneous fibers (AIII). Such a stimulation produced a sensation of intense ,ain, brief and burning, associated with the stimulating electrodes. The response thresholds (RIII and pain) under these conditions ~ere 5 +- 0.5 mA. No P~II response was ever observed in any subject.
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(3) Measurement of sensations A quantitative study of sensation as a function of the intensity of stiraulation showed a homogeneity of behavior for each subject and ~ s o between ~_ubjects, with respect to the stimulus and the scale of sensation, both for cutaneous and direct .~ur~ nerve stimulation. After 10 rain trah~h~g, each subject established a stable relationship bei, ween the intensity of stimulation, the perceived sensation and its position on the scale. Nc sig~iEicant difference of tactile or pain sensation for a given stimulus int, ensity was noted, either for individual (t = 1.52, df = 28, N.S.) oi betweer, subjects (t = 1.67, df = 428, N.8.) during different recording sessions. Under these conditions there was a very significant relatior, ship h,etweer~ the sensation (tactile or painful) and the iptensity of the stimulation applied to the sural neiwe (r = 0.92, df = 226, P < 0.001) or to the skin ( r - 0 . 9 6 , df = 202, P < 0.001). However, a given stimulus was felt more st~o~gly when it, was applied to the skin, as is shown by the s~ift of the reg~'ession line towards lower intm=sities (Fig. 3). Study of the pain threshold using this basis showed that stimulation of t,he surel ~.e~ie became painful at 10 _+-?~ mA of stimulation intensity, corresponding to 3.5 _+.0.2 A.U on the sensation scale. In contrast, skin stimula. tion became painful at 5,0 ~ 0,6 raA, corresponding to 3,7 + 0.2 A.U on the same sensa6,o.n scale, There is nc significant difference between the sansa-
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STIMULATION (I)
Fig. 3, Regression curves of sensations (S) as a function of stimulation intensity when stimulation is applied on the skin (*) and on the sural nerve (f.r). Hatched area shows the pain ~hreshold zone for alt subjects. Arrows indicate tbe t h r e s h o l d of the RIII reflex for each situation. N o t e t h a t (1) pain occurs precociously it'. ease of skin stimulation, and (2) there is a e!ose relationshio between the pain threshold and the RIIt reflex in b o t h experimental eond,!ions.
tions of pain threshold evoked by ~ne two methods. This suggests that the liminal sensations are identical in the two cases• These r~sults .~how the existence of a close relationship betwee,.~ the threshold of the reflex response R[II and the threshold of pain sens~iAon, whether stimulation is applied directly to the nerve or on the skin• However, the threshoId ¢4iraulus intensity of the reflex response and of pain perception were clearly lower for cutaneous stimulation (5 mA) than for direct stimulatim,, of the he;re trunk (10 mA). This discrepancy is associated with the fact that the reflex RII was absent, when the skin was stimulated. This suggests that the large diameter fibers of the sural nerve could have m~ inhibitory action on both the nocieeptive reflex acti~,ity and on the pain apprecation mechanis~s. In order to verify this hypothesis, an isehemic block of the large diameter fibers of the sural nerve was periormed on 7 subjects during test stimulation of the sural nerve at i 0 mA intensity. Towards tho 6th--gth min of ischemi~, the RI! response was redu.cud while the g ! I I response was increased. At the same time, pain sensation, which had been at threshold be~'ore t b.e ischemic block, became more acute and intense. After 12--t.5 rain of isehemia, the response l~II was completely abolished while the R!!! re@on.~e was stii! further increased in amplitude, decreased in latency and was clearly suprathreshold (Fig. 4). in paral!el, pain sensation was intense and identical f,o
76 RII
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Fig. 4. Polysynaptic reflex re~ponses recorded in BF, elicited by a 10 m A sural nerve stimulation, during a selective block (ischemia) of the large diameter fibers (AII) of this nerve. A: control responses (before ischemia). B. reaponses obtained after 6--8 min of ischemia. C: responses obtained afi:er 12--15 rain of ischemia. Note that RII decreases in B and is absent i~, C, whereas RIII increases progressN ely with ischemia.
that provoked by cutaneous stimulation at 10 mA. Subsequent study of the threshold of ~he l~:III response and of pain sensation showed t h a t t h e y were now significantly ~:educed to 5--6 mA. DISCUSSION
Stimulation o f sural nerve, reflex activity and sensations Stimulation of the sural n e ~ e evoked in the BF muscle a tactile and a nociceptb,e reflex response: the threshold of the nociceptive reflex response wa~ identical with that of the p a n sensation. These results confirm those of others [ 21,22]. In case of the response Rll, many arguments are in favor of a tactile origin, h~ the cat~, light stimulation of the fur in the sural nerve sensory field evokes a poty~:ynaptic reflex of short latency in the tenuissimus musch: [23]; in man, the ~ole and s~.des of the toot are regions where a tactile stimulation (slight pres:mre)evokes at thresir~ld a flexion reflex in the BF muscle [142]. However, the RIII reflex res:~onse, initiated by stimulation of group AIII cutaneous fiber~ is a nociceptiv~: reflex response. Its threshold corresponds to
77 the pa;.n threshold. This response is Identified with the general flexion reflex described by Snerrin~on [37]. Furthermore, it has also been shown that the activation of ~ o u p AIiI fibers is painful in map. and in animals [9,15]. Similarly, it has been shown that in the posterior femoris nerve of the cat, there are fibei~s which conduct at 10--3~, m/sec which respond to sharp, painful pinching of the skin [32]. This confirms the participatmn of the group AIII tilers in painful sensation. In the experimental conditions desqrihed here, the stimulation intensities w~re probably not adequate for activation of g~oup IV fibers since it is known that the threshold of these fibers is 4 5 times higher than that of AIII fibers [15], and in order to recruit them, it would thus be necessary t.:., stimulate at 40--50 mA. Moreover, actiw~tion of the grouj~ iV fibers i~ chiefly initiated by cutaneous stimulations of bui'ning type or by the action of acid substances on tke skin [50~51]. On the other hand, a very late ~:eflex response (2000 msee) ascribable to group IV fibc~'s has been obse~wed in paraplegic man, which may be selectively evoked by cutaneous burning. Thus, it seems unlikely that the group IV fiber~ participate either in g~e reflex activity or in pain sensatior~ of these experimental conditions.
Stimulation of the skin, reflex activity and sensations Electrical stimulation applied to the skin in the distal receptive field of the sural nerve activates in particular the nerve filaments forming the superficial plexus and the free terminals consisting of myelinated fibers of small dian~eter (AIII) and non-m~ elinated fibers (iV), since the deep plexus, consisting mainly of group AH fibers which supply encapsulated receptors: is no';~ very sensitive to electrical stimulation, responding mainly to specific s~h~quiation of these receptors [12,49]. These facts sdggest that the cutaneous stimulation used in this wo'.."k activated the group A!! fibers very little, if at aii, and this expIain~ why the RII reflex could not be obtained. Only the r~ociceptive response (RIII) was recc, rded in the BF muscle, and the threshold of this reflex corresponde,il to tha~, of paiuhfl sensation, as in case of stim~dation of sural nerve. ~T,owever, the threshold of these responses (P~III and pain) was clearly lower in case of cutaneous stimulation (5 mA) than during sthnulatien of the sural ne~-ve (10 mA).
Interaction of afferent t'olleys The data described here clearly show a~ interaction between the tactile and nociceptive afferents iuputs. It is tempting to explain this interaction by the existence of an inhibition exe~;ed at the spinal level by the tactile messages conveyed via the AiI fibers with the pain messages conveyeu by the smaller fibers and with the nociceptive reflex. An argument in favor ef this hypothesis is supplied by the results obtained with ischemic block of All fibers during sural nerve s~:Jmulatiol.~ at threshold (10 mA) for pain sensation and RIII reflex. When onliy the AII fibers were blocked, the tactile reflex response (RII) was abolished, while, the ~!ociceptive response (RI!I) and pa!n sellsation became c!ear~,y s~iprathresho}d. These results confirm the obselwa-
'78 tions of many authors [21,22,41], and may support the hypothesis of Melzack and Wall [ 30] stating that the activation of the large diameter cutaneous fibers provokes an inhibition of the pain messages carried by the smaller fibers. They are also similar to those of Hugon [21] who no~ed tha~ a tactile stimulus precedin~ a very painful stimulation applied to the:sural nerve had the effect of reducing the RIII reflex activity and of diminishing the sensation of pa~n initially described. Inversely, if the preceding stimulus was painful, there was a cumulative facilitation of the R~II response as well as a progressive at~gmentation in pain sensation. Many arguments are ia favor of the action of the AII fibers'on the group AIII fibers being due to a q inhibitory mechanism which is b o t h pre- and postsynaptic. The facilitation of the nociceptive reflex i:1 the absence of AII fiber activation may be {,xplained by a reduction in the level of presynaptic inhibition [30] or perh~ps by a facilitation of interneurons situated in the nociceptive pathway [ 4 ; ] . Many authors have shown that the cells of the layers V and I of Rexed [34] are very easily excited by sensory messages transmitted by small diameter fibers [10,18,33,39,40]. However, postsynaptic inhibition of the cells of layers IV and V has been observed following activation of large diameter, low threshold cutaneous fibers [19]. It is difficult to evaluate the importance and respective role of each of these inhibitory mechanisms in the control of pain sensation and in the modulation of the nociceptive reflex. ACKNOWLEDGEMENTS
The author expresses his thanks to M. Bonvallet for her advice and critical reading of the manu~cript, and to K. Grant-Neild for help with the English. REFERENCES 1 Adrian, E.D., The messages in sensory nerve fibers and their interpretation, Proc. roy. Soc. B, 109 (1931) 1--18. 2 Bathien, N., R~flexes spinaux chez l'homme et niveaux d'attention, Electroenceph. clin. Neurophysiol., 30 (1971) 32--37. 3 Bathien, N. and Bo~rdarias, H., Lower limb cutaneous reflexes in hemiplegia, Brain, 95 (1 972) 447--456. 4 Bathien, N. et Morin, C., Variations compar~es des r~flexes spinaux au cours de l'attention intensive et s4lective, Physioi. Behav., 9 (1972) 533--~38. 5 Beecher, H.K., Pain in men wounded in battle, Ann. Surg., 123 (~_946) 96. 6 Beecher, H.K., Relationship of significance of wound to the pain experienced, J. Amer. reed. Ass., 161 (1956) 1609. 7 Beecher, H.K., The Measurement of Subjective Response, Oxford University Press, Oxford, 1959. 8 Bergstrom, R.M., Du concept de perception dans l'~valuation. In: R. Janzen, N.D. Keidel, A. Hertz, C. Steiche~,e, J. Cambier, J. Charpentier e ~ . Laroche (Eds.). La Douleur, Masson, Paris, 1973, pp. 143--148. 9 Brookhart, J.M., Livingstone, W.K. and Haugen, F.P., Functional characteristic,q of afferent fibres from tooth pulp of cat, J. Neurophysiol., 16 (1953) 6 3 4 - 6 4 2 .
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80 33 Pomeranz, B., Wall, P.D., and Weber, W.U., Cord cells responding to fine myelinated afferents from viscera, muscle and skin, J. Physiol. (Lond.), 199 (1968) 511--532. 34 Rexed, B., A cytoarchitectonic atlas of the spinal cord 'n the cat. J. comp. Neurol., 100 (1954) 297--379. 35 Ruffini, A., Les dispositifs anatomiques de la sensibilit4 cutamie sur les expansions nerveuses de la peau chez l'homme et quelques autres mammif~res, Rev. g~n. Histo]., 1 (1905) 421--538. 36 P~ussei, W.J. and Tate, M.A., A device for applying nociceptive stimulation by pressure, J. Physiol. (Lond.), 248 (1975) 5--7P. 37 Sher~ington, C.S., Flexion-reflex of the limb~ crossed extension-ref~ex and reflex stepping and standing, J. Physiol. (Lond.), 40 (1910) 28--121. 38 Sidowski, J.B., Experimental Methods and Instrumentation in Psychology, McGrawHill, New York, 1966. 39 Wagl:~an, I.H. and P~ice, D.D., Responses of dorsal horn of Mac,wa mulatta to cutaneous and r.ural nerve A and C fiber stimuli, J. Neurophysiol., 32 (] 969) 803--817. 40 Wall, P.D., The laminar organization of the dorsal horn and effects of descending impulses, J. Physiol. (Lond.), 188 (1967) 403--423. 41 Wall, P.D. and Sweet, W.H., Temporary abolition of pain in man, Science, 155 (1967) 108--109. 42 Walshe, F.M.R., The physiological significance of the reflex phenomenon in spastic paralysis of !~wer limbs, Brain, 37 (1914) 269--336. 43 Weddell, G., The pattern of cutaneous innervation in relation to cutaneous sensibility, J. Anat. (Lond.), 75 (1941) 346--367. 44 Weddell, G., The anatomy of cutaneous sensibility, Brit. med. Bull., 3 (1945) 167-172. -,~ Weddel[, G. and Sinclair, D.C., The anatomy of pain sensibility, Acta neuroveg. (Wlien), 7 (1953) 135--146. 46 Wilson, V.J. and Burgess, P.R., Disinhibition in the cat spinal cord, J. Neurophysiol., 25 (1962) 392--404. 47 Wil~le~, J.C., Influence de i'anticipation de la douleur st-r le r6flexe nociceptif et les fr~quences cardiaque et respiratoire chez l'homme, Physiol. Behav., 15 (1975). 48 Wilier, I.C. and Bathien, N., Determination of an indication of pain by the saphenobicipit:q reflex ~ethod: physiological and pharmacological variation,;, Electromyogr. clin. Neurophysiol., 15 (1975) 127--135. 49 Winkelmann, R.K., Nerve Endings in Normal and Pathologic Skin, '~homas, Springfield, Ill., 1960. 50 Zotterman, .Y~T,ouch, pain and tickling, J. Physiol. (Lond.), 95 (1939) 1--28. 51 Zotterman, Y., Nervous mechanisms of touch and pain, Acta psychial,, neurol, scand., !4 (1939) 91--97.
COMPARATIVE STUDY O F PERCEIVED PAIN AND NOCICEPTIVE FLEXION REFI,EX IN,MAN
JEAN CLAUDE
WILLER
Laboratoire de Physiologie, Facult~ de Mddecine Saint-Antoine, 75571 Paris Cedex 12 (France)
(Accepted July 21st, 1976)
SUMMARY
The purpose of this study was to compare the amplitude of the flexion reflex of the biceps femoris muscle (BF) with the intensity of the painful sensation elicited by a nociceptive stimulation resulting from application of a constant-current either on the sural nerve or on the skin in its distal receptive field.: Experiments were carried out on 15 normal volunteers. It was observed that: (1) Stimulation of the sural nerve (either on or through the skin) elicits two different reflex responses in the BF: the first (RII) is of short latencY, low threshold and corresponds to a tactile "eflex. The second (RIII) is of longer latency and higher threshold, and corresponds to a nociceptive reflex. The threshold of RIII was found to be the threshold of a pain sensation. (2) Stimulation of the skin elicits only a late nociceptive (RIII) response in the BF. The threshold of this response was also found to be that of pain. (3) The thresholds of both pain and RIII were found to be higher for sural nerve stimulation (10 mA) than for cutaneous stimulation (5 mA). It was suggested that the large diameter cutaneous fibers could have an inhibitory effect on both pain and the nociceptive reflex. This was supported by the resu.its obtained during a selective ischemic block of the largest diameter fibers in the sural nerve, when a 10 mA stimulation was applied to the nerve. In this case, a decrease of the RII reflex was observed in BF, together with an increase of both RIII and pain sensation. Functional implications of these result~ are discussed.
INTRODUCTION
(1) The desire to understand the feeling of pain and to evaluate its role in life and behavior of man has preoccupied many generations of physiologists
70 and philosophers. Even today: this understanding is far from complete, and research for e~.method of measuring pain still remains a real problem. The difficulties encountered in every objective study of pain are multiple. They may be partly explained by the po!ymorphic nature of pain sensation a n d b y the absence of limits of pain appreciation, but are also due to the special characteristics of pain sensation: (a) while it is true that the sensation of pain may always be increased by augmenting the stimulus intensity, it may also be modified by anxiety [13,17,47] or by the degree of motivation of the subjects with regard to the stimulus [5--7]; (b) the form of energy activating the pain receptors is not specific [27]; (c) the somatic and autonomic reflex mechanisms may also be initiated by other phenomena, independent of pain, ~uch as fear or surprise [ 8]. (2) Techniques for measuring pain in man may vary according to the adequate s¢imulus used by different authors, for instance: thermal [14] mechanical [ 36], chemical [ 25] or electrical cutaneous stimulations [ 17,31], or chemical stimulation of the peritoneum [27]. In this study, the threshold of painful sensation was measured during stimulation of nerve fibers from an area of the skin innervated by the sural nerve, which, it appears, transmit preferentially messages originating froni pain receptors. (3) Electrical stimulation of the sural nerve, a cutaneot~s nerve of the lower limb, evokes in man a two component reflex response in the lower limb flexor muscles [20,26]. The first (RII), short latency component, is initiated by the acti~ration of myelinated cutaneous fibers of large diameter and low threshold. The second response (RIII), of longer latency, appears at higher stimulus intensities, where smaller diameter fibers are also activated. Many authors have shown, in animals [1,24,29,50] and in man [11,15, 16] that the c:.~taneous fibers of large diameter (Lloyd's group AII [28]) convey tactile message:; triggerec', by light touch or pressure, while pain sensation is transmitted l)y smaller fibers, especially by group III afferents. According to some auti~ors [ 21,48], there is a close re!ationship between the RII reflex and tactile :~ensation and between the RIH ._ ~ -- and the sensation of pain. The existence of these relationships present a certain interest in establishing me~;hods f,)r measttring pain, since they allow the comparative study of threshold and intensh;y of pain sensation a~d of the nat(Ire and amplitude of the afferent volley responsible for this s-2nsation. This was the method used in the first part of this study. However, being based on direct electrical stimulation of a peripheral nerve, it did not allow the cutaneous receptors, which are the origin of pain reception, to be tested. For this reason, in later experiments, electrical stimulation of the skin was employed. The skin is innervated by cutaneous nerves which run with blood vessels through the subcutaneous tissues. These nerves branch and penetrate the dermis, forming a double pJexus lying parallel to the skin surface. The first description of these structures was put forward by Ruffini [35], who described a deep dermal plexus from which fibers branched at irregular intervals towards a second, more superficial, dermo-epiderrr, al plexus. According to
71 Winkelmann [49], the fibers of the deeper plexus are larger in diameter (AII) than those of the more superficial plexus (AIII and IV). Moreover, this author observed that these small nerve filaments ~.~fgroup AIII and IV may also enter the epidermis. It is t h o u g b t that the fibers o f this superficial plexus, terminating in open complex loops or ?xound the superficial blood capillaries, act here as adequat~ pain receptors [ 27,43--45]. The experimental approach described here differs from others in that an attempt was made to activate the small branches of the supe:fficial plexus selectively. An electromyographical record of the reflex responses of a flexor muscle of the lower limb was made, together with a study of somatic sensation, in particular the threshold of pain, under two experimental conditions: (1) electrical stimulation of the sural nerve; (2) electrical stimulation of the skin within the distal cutaneous field of this nerve. METHODS
The experiments were carried out on 15 subjects (10 males, 5 females), young adults, medical students or physiologists ha~¢ing alreaay pm~icipated in experiments of this kind and thus already familiar with the experimental atmosphere and with the pain inducing stimuli. The experimer~tal procedure was explained previously to the subjects in order to avoid any element of surprise. During the sessions, the subjects were comfortably iastalled in an armchair specially designed to obtain a good muscular relaxaiion.
Stimulation and recording Stimulation of the sural nerve (n. suralis) was performedl: (1) Percutaneously, using a pair of tinned copper electr6des, each 1 sq. cm, applied to the skin 2 cm apart, over the external retro-malleolar pathway of the sural nerve. The skin had been previously abraded and degreased, and a saline solution ensured electrical conduction such as the inter-electrode resistance (1000--2000 ~ ) did not change significantly during the course of the experiment. ( 2 ) Transcutaneously, by means of a pair of steel needle electrodes, insulated to t h e tip, placed through the skin on the sural nerve, at its external retro-maUeolar pathway, and spaced at about 2 cm. Electrical stimulation of the skin in the distal receptive field of the sural nerve was performed with surface electrodes, using the procedure described previously. In each case, stimulation consisted of a volley of 10, 1 msec rectanCalar pulses delivered over 20 msec (300--400 Hz). This stimulus was delivered using a constant-current stimulator, cathode being placed proximally. Stimulus strength, varying between 1 and 18 mA, was recorded with an intensity probe (Tektronix 134) and CRO displayed. Electromyograms (EMGs) were recorded from the biceps femoris muscle (bicep femoris, capitis brevis, BF) since certain authors [3,20] have shown that this muscle is the earliest reflexly generated activity in the lower limb of normal man. Recordings were made using the technique described by Hugon
72 [21], and the EMGs were displayed on a storage oscilloscope after amplification. Ischemia of the sural nerve, performed on 7 subjects in order to block the large diameter fibers selectively, was obtained by using a pneumatic tourni, quet, placed in the ankle regio~, above the articulation of the foot and the stimulating electrodes. The pneumatic cuff pressure was maintained constant for 15--20 min, at twice the maximal arterial blood pressure. The temperature of the stimulated foot was 33 ± 2 ° C, and remained stable throughout the course of each experiment, except during ischemia where it fell by 3--4°C distal to the cuff. Room temperature was 20 + 2 ° C. The reflex threshold was then defined as the stimulus intensity giving 60--70% of responses. Measurement o f sensations Using a method described by Gybels (personal communication, 1974) modified slightly for the requirement of this study, the quality (tactile and painful) and the intensity of sensation was represented on a linear scale of 10 cm, centered in the middle of a sheet of paper (15 cm X 20 cm). Each subject bad to indicate the type and intensity of sensation by means of a point placed on this {Fig. 1). The left of the: scale represented tactile sensations while the extreme right represented intense and unbearable pain. Somewhere between these two poles was situated ~,he pain threshold. This method of study had the advantage of being able t~) quantitate the sensation more precisely than purely verbal methods. Certair. preliminary precautions were necessary: (1) Preliminary test sessions lasting about 1 0 m i n were made during which stimuli at variou~ intensities (1--18 mA) were given ran(~omly, giving rise to tactile sensation, slight pain o~' extreme pain. At the end of the trial period, each subject presented a stable level of sensation for a st:mulus of given intensity. The pain threshold was then determined usir, g the staircase limits method [38], with 4 serie~ of increasing stimulation and 4 series of decreasing stimulation. (2) In order that the subjects were not influenced by their own results in previous tria~s, the sensation score sheets were replaced every 3 or 4 tests. (3) In order to eliminate interference phenomena "{3 O
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Fig. 1. l~h~s figure gNes an example for one subject of the sensation scale, as a function of intensity ~f stimulation. The left extremity of the line represents tactile sensations, whereas sl:rong and excruciating pain sensations are tocated at the right extremity. The pain thresaold is indicated by the dots draw,~ by the subject for a stimulation at pain threshold.
73 due to the permanent attention and expectation on the part of the subje :g~ test series were begun at random time intervals. Outside test periods, the subject was told to remain calm and relaxed. These precautions were necessary since it is knewn that attention may modify both spinal motoneuron excitability [2,4] and perception of pain [17,47]. Under these conditions, each experimental session lasted an average of 30 min, and the subjects :showed a stable pain threshold throughout the examination and at successive tests repeated at 48 h intervals. Liminal pain was described as a sharp sensation, like a pin-prick localized at the point of stimulation. Each subject was tested at least 3 times. Sensations were measured on the scale and were quantified in arbitrary units (A.U) from 0 to 10.
Analysis o f results Individual and group analysis of the mean and variance of the numerical values of the parameters studied were made for each stimulus intensity. Regression ii~.es were calculated using the method of least squares. The s,:gnificance of variation within and between individuals was determined by means of a complete equilibrated factorial analysis and by a Student t test. RESULTS
(1) Stimulation o f sural nerve As described in the Introducti,,n, electrical stimulation of the sural ne~.we, percutaneously or transcutaneously, evokes two types of reflex activity in the muscle BF (Fig. 2A). The first response (RID has a short latency (40--70 msec) and a low threshold (5 +- 0.6 mA). This response was not feund du~'ing the first recording session for 7 subjects, probably because they were not well relaxed. However, during following sessions, the results were better, and the response RII was observed in all subjects. In every case, the threshold stimulation for the response RII produced a tactile sensation, comparable to that produced by rhythmic percussion of the skin with a reflex testing hammer. The sensation was localized at the point of stimulation and was often accompanied by tingling sensations in the receptive field of the sural ne~-ce. The second response (RIII) had a longer latency (90--130 msec) and a higher threshold (10+ 1 mA). Stimulation at 10 mA provoked a liminal pain sensation of the pin-prick type, localized at the stimulating point.
(2) Stimulation of the skin Electrical stimulation at 10 mA applied to the skin in the distal receptive field of the sural nerve evoked an isolated RIII r~sponse in the muscle, BF (Fig. 2B). This reflex response was of large amt,litude and corresponded clearly to suprathreshold activation of the small diameter myelinated ,:utaneous fibers (AIII). Such a stimulation produced a sensation of intense ,ain, brief and burning, associated with the stimulating electrodes. The response thresholds (RIII and pain) under these conditions ~ere 5 +- 0.5 mA. No P~II response was ever observed in any subject.
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Fig. 2. P o l y s y n a p t i c reflex r e s p o n s e s r e c o r d e d in b i c e p s f e m o r i s m u s c l e ~,t various intens:ities. A: s t i m u l a t i o n to t~le sural nerve. B: s t i m u l a t i o n a p p l i e d on the skin, on the di.~tal receptive field o f t h e nerve. Each trace r e p r e s e n t s a s u p e r i m p o ~ i t i e a o f 5 recordii gs. Note }c~ A the t h r e s h o l d o f R t l i'~:;~ m A a n d t h e RIII r e s p o n s e appears for 10 m A , w h e r e a s in B no F~lI r e s p o n s e is ever observed, w h i l e t h e t h r e s h o l d o f the RI.,'I response is m u c h lower (5 m A ) t h a n it: A.
(3) Measurement of sensations A quantitative study of sensation as a function of the intensity of stiraulation showed a homogeneity of behavior for each subject and ~ s o between ~_ubjects, with respect to the stimulus and the scale of sensation, both for cutaneous and direct .~ur~ nerve stimulation. After 10 rain trah~h~g, each subject established a stable relationship bei, ween the intensity of stimulation, the perceived sensation and its position on the scale. Nc sig~iEicant difference of tactile or pain sensation for a given stimulus int, ensity was noted, either for individual (t = 1.52, df = 28, N.S.) oi betweer, subjects (t = 1.67, df = 428, N.8.) during different recording sessions. Under these conditions there was a very significant relatior, ship h,etweer~ the sensation (tactile or painful) and the iptensity of the stimulation applied to the sural neiwe (r = 0.92, df = 226, P < 0.001) or to the skin ( r - 0 . 9 6 , df = 202, P < 0.001). However, a given stimulus was felt more st~o~gly when it, was applied to the skin, as is shown by the s~ift of the reg~'ession line towards lower intm=sities (Fig. 3). Study of the pain threshold using this basis showed that stimulation of t,he surel ~.e~ie became painful at 10 _+-?~ mA of stimulation intensity, corresponding to 3.5 _+.0.2 A.U on the sensation scale. In contrast, skin stimula. tion became painful at 5,0 ~ 0,6 raA, corresponding to 3,7 + 0.2 A.U on the same sensa6,o.n scale, There is nc significant difference between the sansa-
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STIMULATION (I)
Fig. 3, Regression curves of sensations (S) as a function of stimulation intensity when stimulation is applied on the skin (*) and on the sural nerve (f.r). Hatched area shows the pain ~hreshold zone for alt subjects. Arrows indicate tbe t h r e s h o l d of the RIII reflex for each situation. N o t e t h a t (1) pain occurs precociously it'. ease of skin stimulation, and (2) there is a e!ose relationshio between the pain threshold and the RIIt reflex in b o t h experimental eond,!ions.
tions of pain threshold evoked by ~ne two methods. This suggests that the liminal sensations are identical in the two cases• These r~sults .~how the existence of a close relationship betwee,.~ the threshold of the reflex response R[II and the threshold of pain sens~iAon, whether stimulation is applied directly to the nerve or on the skin• However, the threshoId ¢4iraulus intensity of the reflex response and of pain perception were clearly lower for cutaneous stimulation (5 mA) than for direct stimulatim,, of the he;re trunk (10 mA). This discrepancy is associated with the fact that the reflex RII was absent, when the skin was stimulated. This suggests that the large diameter fibers of the sural nerve could have m~ inhibitory action on both the nocieeptive reflex acti~,ity and on the pain apprecation mechanis~s. In order to verify this hypothesis, an isehemic block of the large diameter fibers of the sural nerve was periormed on 7 subjects during test stimulation of the sural nerve at i 0 mA intensity. Towards tho 6th--gth min of ischemi~, the RI! response was redu.cud while the g ! I I response was increased. At the same time, pain sensation, which had been at threshold be~'ore t b.e ischemic block, became more acute and intense. After 12--t.5 rain of isehemia, the response l~II was completely abolished while the R!!! re@on.~e was stii! further increased in amplitude, decreased in latency and was clearly suprathreshold (Fig. 4). in paral!el, pain sensation was intense and identical f,o
76 RII
Rill
Fig. 4. Polysynaptic reflex re~ponses recorded in BF, elicited by a 10 m A sural nerve stimulation, during a selective block (ischemia) of the large diameter fibers (AII) of this nerve. A: control responses (before ischemia). B. reaponses obtained after 6--8 min of ischemia. C: responses obtained afi:er 12--15 rain of ischemia. Note that RII decreases in B and is absent i~, C, whereas RIII increases progressN ely with ischemia.
that provoked by cutaneous stimulation at 10 mA. Subsequent study of the threshold of ~he l~:III response and of pain sensation showed t h a t t h e y were now significantly ~:educed to 5--6 mA. DISCUSSION
Stimulation o f sural nerve, reflex activity and sensations Stimulation of the sural n e ~ e evoked in the BF muscle a tactile and a nociceptb,e reflex response: the threshold of the nociceptive reflex response wa~ identical with that of the p a n sensation. These results confirm those of others [ 21,22]. In case of the response Rll, many arguments are in favor of a tactile origin, h~ the cat~, light stimulation of the fur in the sural nerve sensory field evokes a poty~:ynaptic reflex of short latency in the tenuissimus musch: [23]; in man, the ~ole and s~.des of the toot are regions where a tactile stimulation (slight pres:mre)evokes at thresir~ld a flexion reflex in the BF muscle [142]. However, the RIII reflex res:~onse, initiated by stimulation of group AIII cutaneous fiber~ is a nociceptiv~: reflex response. Its threshold corresponds to
77 the pa;.n threshold. This response is Identified with the general flexion reflex described by Snerrin~on [37]. Furthermore, it has also been shown that the activation of ~ o u p AIiI fibers is painful in map. and in animals [9,15]. Similarly, it has been shown that in the posterior femoris nerve of the cat, there are fibei~s which conduct at 10--3~, m/sec which respond to sharp, painful pinching of the skin [32]. This confirms the participatmn of the group AIII tilers in painful sensation. In the experimental conditions desqrihed here, the stimulation intensities w~re probably not adequate for activation of g~oup IV fibers since it is known that the threshold of these fibers is 4 5 times higher than that of AIII fibers [15], and in order to recruit them, it would thus be necessary t.:., stimulate at 40--50 mA. Moreover, actiw~tion of the grouj~ iV fibers i~ chiefly initiated by cutaneous stimulations of bui'ning type or by the action of acid substances on tke skin [50~51]. On the other hand, a very late ~:eflex response (2000 msee) ascribable to group IV fibc~'s has been obse~wed in paraplegic man, which may be selectively evoked by cutaneous burning. Thus, it seems unlikely that the group IV fiber~ participate either in g~e reflex activity or in pain sensatior~ of these experimental conditions.
Stimulation of the skin, reflex activity and sensations Electrical stimulation applied to the skin in the distal receptive field of the sural nerve activates in particular the nerve filaments forming the superficial plexus and the free terminals consisting of myelinated fibers of small dian~eter (AIII) and non-m~ elinated fibers (iV), since the deep plexus, consisting mainly of group AH fibers which supply encapsulated receptors: is no';~ very sensitive to electrical stimulation, responding mainly to specific s~h~quiation of these receptors [12,49]. These facts sdggest that the cutaneous stimulation used in this wo'.."k activated the group A!! fibers very little, if at aii, and this expIain~ why the RII reflex could not be obtained. Only the r~ociceptive response (RIII) was recc, rded in the BF muscle, and the threshold of this reflex corresponde,il to tha~, of paiuhfl sensation, as in case of stim~dation of sural nerve. ~T,owever, the threshold of these responses (P~III and pain) was clearly lower in case of cutaneous stimulation (5 mA) than during sthnulatien of the sural ne~-ve (10 mA).
Interaction of afferent t'olleys The data described here clearly show a~ interaction between the tactile and nociceptive afferents iuputs. It is tempting to explain this interaction by the existence of an inhibition exe~;ed at the spinal level by the tactile messages conveyed via the AiI fibers with the pain messages conveyeu by the smaller fibers and with the nociceptive reflex. An argument in favor ef this hypothesis is supplied by the results obtained with ischemic block of All fibers during sural nerve s~:Jmulatiol.~ at threshold (10 mA) for pain sensation and RIII reflex. When onliy the AII fibers were blocked, the tactile reflex response (RII) was abolished, while, the ~!ociceptive response (RI!I) and pa!n sellsation became c!ear~,y s~iprathresho}d. These results confirm the obselwa-
'78 tions of many authors [21,22,41], and may support the hypothesis of Melzack and Wall [ 30] stating that the activation of the large diameter cutaneous fibers provokes an inhibition of the pain messages carried by the smaller fibers. They are also similar to those of Hugon [21] who no~ed tha~ a tactile stimulus precedin~ a very painful stimulation applied to the:sural nerve had the effect of reducing the RIII reflex activity and of diminishing the sensation of pa~n initially described. Inversely, if the preceding stimulus was painful, there was a cumulative facilitation of the R~II response as well as a progressive at~gmentation in pain sensation. Many arguments are ia favor of the action of the AII fibers'on the group AIII fibers being due to a q inhibitory mechanism which is b o t h pre- and postsynaptic. The facilitation of the nociceptive reflex i:1 the absence of AII fiber activation may be {,xplained by a reduction in the level of presynaptic inhibition [30] or perh~ps by a facilitation of interneurons situated in the nociceptive pathway [ 4 ; ] . Many authors have shown that the cells of the layers V and I of Rexed [34] are very easily excited by sensory messages transmitted by small diameter fibers [10,18,33,39,40]. However, postsynaptic inhibition of the cells of layers IV and V has been observed following activation of large diameter, low threshold cutaneous fibers [19]. It is difficult to evaluate the importance and respective role of each of these inhibitory mechanisms in the control of pain sensation and in the modulation of the nociceptive reflex. ACKNOWLEDGEMENTS
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