Lxfe Sciences, Vol. Prlnted in the USA
51, pp.
2009-2018
Pergamon
Press
MINIREVIEW ROLE OF OPIOIDS IN PERIPHERAL ANALGESIA J.L. Junien and J.G. Wettstein Insmut de Recherche Jouveinal B P 100, 94265 Fresnes Cedex, France (Recelved
in f~nal
form October
5, 1992)
Summary Several pharmacological, neurophysiological and immunohistological studies indicate that exogenous or endogenous opioids can have antmociceptive effects by acting at peripheral sites Although modulation of mu, delta and kappa receptors can mediate these effects, the nature of the noxtous stimulus and the underlying pathological condition may affect the types of opioid receptors involved. Thus, it would be appropriate to develop peripherally-acting opioid analgesics that do not have the untoward central side effects often associated with conventional analgesic drugs This paper reviews the evidence supportwe of a peripheral mechanism of action for op~oids Pain can occur following acute noxious stimuli yet climcal pain can be elicited by what normally would be an innocuous stimulus. The duration of pain may outlast the stimulus and its amplitude may be exaggerated (hyperalgesla). Also, there can be a spread of pathological sensitivity to normal tissue (secondary hyperalgesia) The changes in the threshold, responsweness and spatial properhes of pain are the consequences of modifcations within the nervous system (neuroplastic~ty). Neuronal modification can occur through peripheral sensitization whereby high threshold nociceptors develop a diminished threshold after exposure to a variety of chemical compounds. Central sensitization due to a change in the responsiveness of dorsal horn neurons can be triggered by repetitive nociceptor afferent activity. The nociceptors induce slow synaptic potentials in dorsal neurons that can summate to produce a cumulative Increase in depolarization and a progresswe increase in action potential discharge The depolarization which, in part, is glutamate- and tachykinin-medlated is accompamed by profound changes at the second messenger and gene levels Such changes can lead to alterations in membrane excitability, input recruitment, receptive field properties and expansion in receptive field size.
Corresponding author • J.L. Junien, B.P 100, 94265 Fresnes, France
Copyrlght
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reserved.
2010
Opxolds and Perxpheral Analgesia
Vol. 51, No. 26, 1992
Among the drugs available for the treatment of pain, opioid analgesics acting m the brain and spinal cord are very effective. The major drawbacks of such drugs, however, include respiratory depression and dependence liability. The untoward effects are, in general, due to actions in the central nervous system. In addition, opioids may likely exert antlnoclceptxve effects via peripheral mechanisms The purpose of this essay is to focus on the peripheral mechanism of pare and of opioid analgesia Activation and sensitization of peripheral sensory neurons
C-fibers are stimulated by the action of noxious stimuli on peripheral nocIceptors This results in a release of fast transmitters (e g , glutamate) and sensory peptides (e g , substance P, calcltonln gene-related peptlde (CGRP)) in the dorsal horn and also at peripheral sites where these substances act on the epithehum, smooth muscle and vasculature Noclceptive pathways can be influenced by many elements including neurotrophlc factors, the appearance of immune cells, products of tissue injury, and the sympathetic nervous system
Neurotrophtc factors Among the neurotrophic factors having different cell-type specificity are NGF (nerve growth factor), neurotrophlns 3, 4 and 5 (NT3, NT4, NT5), BDNF (brain-derived growth factor), and CNTF (ciliary neurotrophlc factor) These products are necessary for the development of sensory neurons and exert a neuromodulatory action on mature cells For example, selected neurotrophlc factors can regulate the mRNA synthesis for substance P, and CGRP and can modulate mast cell, basophll and lymphocyte activity
Inflammatton and the tmmune response During inflammatory states, cells can produce factors that cause hyperalgesia. For example, prostaglandms increase levels of cAMP, hydroxy acids activate protein hnase C, and leukotrlenes snmulate immune cell function, peptlde release and gene expression changes Hyperalgesia may be provoked in the rat paw by local injection of PGI2, PGE2, 15-HPETE or Interleukln-lB (I, 2, 3). Recently, Nakamura-Craig demonstrated that repeated subplantar injections of PGE2 for 4 days induced a sustained hyperalgesla that had a duration of at least 10 days (4). Endogenous sensory peptldes play an important role in this response since the hyperalgesic state was inhibited parnally by pretreatment with capsaicin
Vascular factors and products of ttssue injury Vascular factors (e.g, amines, klnlns, endothehum-derived relaxing factor, nitric oxide) and other products of tissue injury (e g , histamine, serotonin, bradyhnln, protons) are involved in the development of pain and hyperalgesia (5, 6, 7)
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Sympathenc nervous system.
Expelamental evidence has led to the suggestion that the peripheral sympathetic nervous system is involved in the generation or maintenance of pain sensation. This view comes in part from clinical observations whereby patients with tissue or nerve injury have prompt pain relief following sympatholytic therapy. Levine et al. have reported that regional sympathetic blockade with guanethidine decreases pain in patients suffering from rheumatoid arthritis (8) There is uncertainty about the site at which catecholammes act to produce pain although evidence suggests that terminals of nociceptwe afferents are the primary targets (9). Several studies have reported that hyperalgesia m animal models of inflammatory pain such as carrageenan edema (10), Freund adjuvant arthritis (11) and intracutaneous injection of bradyklnin (12) depend on the presence of post-ganghonlc sympathetic fibers. Rats rendered hyperalgesic by topical chloroform show a significantly reduced threshold after the injection of noradrenaline that is reversed by local administration of the alpha2-selectlve antagonist yohlmbine (12) It has been proposed that noradrenaline acts on postganglionic fibers to release substances other than noradrenaline that can sensitize nociceptors (12) Noradrenahne and bradykinm may induce prostaglandln release from sympathetic nerve endings that activate putatwe cellular transduction mechanisms such as inositol phosphate 3, diacyglycerol or cAMP formation at noclceptlve endings (13, 14).
Peripheral analgesic effects of opioids Using acetic acid as a nocicept~ve stimulus, Bentley et al. utilized a modification of the abdominal constriction test in mice to study the antinociceptive effects of morphine and related drugs (15). Instead of pretreating ammals with analgesic drugs, the drugs were administered 1.p when the abdominal constrictmn response had reached a maximum. These authors found that morphine was very potent in this procedure, having an EDso of 1 5/~g/kg Met- and leu-enkephahn (i.p.) also were active albeit for a short duration A prototype kappa opiold, ketocyclazocine, was found to be the most actwe of the compounds tested, having an EDso of 0.036 #g/kg. All the drugs tested by Bentley et al produced maximal effects within 2 min of administration (15). Pretreatment with naloxone (0.5 - 10 mg/kg, s c.) produced a dose-dependent shift to the right of the dose-response curve for morphine but not for ketocyclazoclne. When morphine was admimstered 1.v., higher doses of naloxone (0.5 mg/kg) were necessary to block the writhing response at 2 min; the antagonist effect then diminished rapidly. Intravenous doses of met-enkephalln greater than 10 mg/kg were necessary to obtain a partml reduction of abdominal constriction. Bentley and co-workers proposed that morphine and its congeners have antlnociceptive effects by acting through one or more types of opiold receptors situated on sensory endings within the mouse peritoneum (15) Smith et al. (16) compared the effects of morphine and its quaternary analogue N-methyl-morphine in two models of pain in mice, the hot plate and acetic acid-induced writhing tests. Unlike morphine, N-methyl-morphine poorly crosses the blood brain barrier because of its increased polarity and low lipophilicity. In
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comparison to the experiments of Bentley et al. (15, see above), test drugs were administered s.c before the noxious stimulus. As expected, morphine had strong antmociceptive effects in both the hot plate and acetic acid writhing tests (EDso'S, 0.8 and 2 8 mg/kg, respectively). In comparison, N-methyl morphine, up to 100 mg/kg, was inactive in the hot plate test; it did, however, inhibit acetic acid-induced writhing with an EDso of 24 mg/kg. The effects of both drugs in the writhing test were effectively antagonized by naloxone (8 mg/kg, i.p ). N-methyl-nalorphme (16 mg/kg, 1 p ), the quaternary analogue of nalorphine, inhibited the antinociceptive effects of N-methyl-morphine but not those of morphine. Using 14C-labelled compound, Smith et al also measured the amounts of morphine and N-methyl-morphine m the brain and confirmed N-methyl-morphine's poor penetration (16) From these experiments, Smith et al concluded that the analgesic effect of N-methyl-morphine, in contrast to morphine, was medmted solely by peripheral oploid receptors (16). Further evidence for the peripheral analgesic effects of opiold drugs has been obtained in inflammatory and hyperalgeslc models of pain. A number of groups using different procedures have provided results showing that various opioid ligands have local analgesic effects in inflammatory pain states (17, 18, 19, 20) Carrageenan has been used to induce inflammation and hyperalgesla in hindpaws of rats (18). The kappa and mu agonists, ethylketocyclazoclne (EKC, 100/zg) and levorphanol (40 #g), respectively, injected into the inflamed paw (mtraplantar, 1 pl ) produced a significant level of analgesia restricted to the site of injection as compared to saline injected into the contralateral inflamed paw, the analgesic effects lasted at least 2 hr (18). The effects of mu, delta and kappa opioid agonists were compared in an unilateral paw inflammation procedure reduced by Freund's complete adjuvant injection (19). Four to six days after moculaUon, oplold agomsts were administered i pl DAGO (1 /zg, mu-selective), DPDPE (40/~g, delta-selectwe) and U-50488H (50/~g, kappa-selective) produced marked antlnoc~cepttve effects m the inflamed paw dunng the first 30 mm post-injection At these doses, the three drugs had no effect on pain threshold in the non-inflamed control paw. Equivalent doses apphed systemically, either s.c. or 1 v , were inactive The effects of morphine (10 - 100/zg, 1 pl ) were dose-dependent and stereospecific Moreover, Lpl (-)naloxone but not (+)naloxone antagonized the effects of DAGO, DPDPE and U-50488H m a dose-dependent manner. Selective mu (CTP), delta (ICI 174,864) and kappa (norblnaltorphimine) antagonists reversed the effects of DAGO, DPDPE and U-50488H, respectively, suggesting that the agonists interacted with the three heterogeneous op~old receptor populations (19) It has been reported (20) that the hyperalgeslc effects of increasing doses of PGE2 injected intradermally in the paws of rats are antagonized by low doses (10 ng - l0 /zg) of morphine, morphiceptin and DAGO. These drugs did not alter the nociceptwe threshold of normal skin. Complete reversal of the hyperalgesia induced by 1 #g of PGE 2 was obtained with 10 #g of morphine Again, naloxone dose-dependently inhibited the effect of morphine. Additionally, intradermal pertussis toxin rejection prevented the protective effect of morphine on PGE2-induced hyperalgesia It was further shown that DPDPE and DSLET (both delta agonists) and U-50488H, all up to l0 #g, faded to reverse PGEz_-mduced hyperalgesla (20) Lastly,
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hyperalgesia induced by 8-bromo-cAMP was not attenuated by morphine given intradermally. Based on these data, it was concluded that the peripheral analgesic effects of opioids on primary afferent nociceptors are mediated by actions at a naloxone-reversible binding site with the characteristics of a mu opioid receptor; furthermore, the effects occur by Gi protein inhibition of the cAMP second messenger system in primary afferent noclceptors (20) Nakamura-Craig communicated recently that the peripheral op~oid agonlst BW-443C, a mu-acting enkephalin derivative, effectively attenuated the hyperalgesla produced by PGE2 injected i.pl. in rats (21). To assess the possible role of peripheral oplold receptors in nociception of inflamed tissue, Russell et al. recorded the spontaneous discharges in afferent units from inflamed knee joints of anesthetized cats (22). Afferent discharge activity was more frequent in single units from inflamed than from normal joints. These authors suggested that the increased level of ongoing resting activity was the afferent base of pare sensation in the inflamed joint. An inhibitory effect by oploids on unit discharge from inflamed joints would thus reflect a peripheral mechanism of action. Inflammation was established by intraarticular rejection of both kaohn and carrageenan at least 2 hours before recording (22). Morphine (1 - 5 mg/kg), DAGO (0.5 - 5 mg/kg), EKC (0.5 - 4 mg/kg) and U-50488H (1 10 mg/kg) were injected intraarterially (i.a.) close to the joint Most of the small diameter type IV afferents considered noclceptive were inhibited by these opioid agonists. More units responded to selective (U-50488H) or non-selective (EKC) kappa agonists. The effects of morphine, DAGO and U-50488H, but not EKC, were antagonized by i a naloxone (1 mg/kg) (22). Abbott (23) has used both the formahn and the tail immersion tests in rats to compare the local and central effects of morphine and EKC. Formahn injection i.pl. produces minor tissue injury whereas tad immersion represents thermal nociception. In these experiments, drugs were given either s.c. or i.c.v, before the tests (23) After s.c. administration, EKC was approximately 50 times more actave than morphine in the formalin test but only 10 times more active in the tail immersion test; morphine was equally effective in both tests. Naloxone methylbromide (10 mg/kg, i.p.), a peripherally-acting opiold antagonist, partially antagonized the effects of EKC in the formalin test. Specifically, only the upper portion of the EKC dose-response function was shifted rightward (23). This suggests that the analgesia produced by low doses of EKC are mediated by a central mechanism while the higher dose effects act at peripheral sites Naloxone methylbromide did not alter the effects of morphine in either procedure or the effects of EKC in the tail ~mmersion test. Abbott further reported that i.c v. EKC produced only partial analgesia in the formalin test despite application of twice the dose reqmred for a 50% decrease in nociceptwe scores when EKC was given s.c. Moreover, analgesia produced by central injection of EKC was not antagonized by systemic injection of naloxone methylbromlde Also, i.c.v. naloxone (5 - 25/zg) only partially reduced the effect of a near maximal s.c dose of EKC (23). Taken together, these data suggest that the analgesic effect of EKC in the formalin test is a result of the summatmn of action at central and peripheral kappa opio~d receptors. In comparison, the effects of morphine in both procedures and EKC
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in the tail immersion test are bkely due to central mechanisms. Findings such as these emphastze a role for kappa receptors in the periphery particularly when tissue mjury or inflammation is present. Recently, the function and peripheral location of the receptors mediating the effects of kappa drugs in the formalm test have been identified in the toes of the rat hmd paw by recording the activity of single dorsal horn noctceptive neurons (24) The admimstratton of formalin into the center of the receptive fields (in the toes) provokes two peaks of activity tn the neurons that correspond to the time course of the early (acute) and late (tonic) phases of flmchmg and paw hcking (25) Administration of U-50488H (25 - 100 pg) directly into the site where formalin was injected resulted m a marked dose-related reductton of both the early and the late response peaks (25) The mhibitton of formalin-evoked activity appeared to be the result of a local action of U-50488H since administration of the high dose (100 pg) mto the contralateral, non-Inflamed paw prior to formalin had no Influence on the subsequent formalm response (25) It should be noted that U-50488H was able to inhibit the first peak that occurs prior the generation of inflammation. Neither morphme nor the delta agonist DSTBLET (both at 100 pg) administered under the same conditions reduced neuronal firing Naloxone (100 pg) injected directly into the plantar region of the paw two min before U-50488H antagonized the effects on both response peaks. Naloxone mjected i p. (10 mg/kg) twenty mm before U-50488H only parttally reversed the effects of this drug Electrically evoked A@- and C-fiber responses of the neurons were not inhibited by mjection of 100 pg of U-50488H mto the receptive field desptte having a profound mhibitory effect on the formalm response In addition, the systemic dose required to Inhibit electrically-evoked C-fiber responses was about 10 times the peripheral dose admmlstered (25) Important evidence showing that opioids have antinociceptive effects through direct peripheral modulation of afferent fibers comes m part from experiments showing that the mhibition of the tail fhck reflex produced by 1 p morphme (10 mg/kg) is attenuated by total subdiaphragmatic vagotomy (26) Also, 1 v D-ala-met-enkephalmamide, a synthetic opioid peptide that poorly crosses the blood bram barrier, produced vagally-mediated mhibttion of both the nociceptive tail flick reflex and the responses of lumbar spinal dorsal horn neurons to noxious heating of the foot in rats (27) In addmon, Randich et al have studied the vagal afferent-mediated effects of morphine on the tail flick reflex, artenal blood pressure and heart rate in pentobarbital-anesthetized rats (28). The hypotensive effect and heart rate decrease induced by morphine faded rapidly following drug injection, in contrast, the effect of morphine on the tail flick reflex was sustained. Bilateral cervical vagotomy mhibited the antmociceptive effects of low doses of morphme (0 1 - 1 mg/kg, i.v.) and attenuated, with a delayed onset, the analgesia produced by a high dose of morphine (2.5 mg/kg) (28) Naloxone methylbromide also prevented the effect of morphme on the tail flick reflex with a pattern similar to that recorded after bilateral cervical vagotomy. Sino-aortic denervation had little or no effect on the antinociceptive and cardiovascular responses produced by morphine (28) Subdiaphragmatic vagotomy was only slightly effective in preventing morphine analgesia whereas vagotomy delayed the
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analgesia onset. Randich et al. also showed that cerebral vagotomy had no effect on the depressor response (tail flick) produced by low doses of morphine (0.1 - 1 mg/kg) yet blocked morphine-induced hypotension Naloxone methylbromide blocked completely the depressor and bradycardia effects produced by morphine. The authors then investigated the pathway involved in the vagal afferent-mediated effects of morphine. Spinal cold-block significantly antagonized the antinociception, hypotension and bradycardia produced by a low dose of morphine (0.5 mg/kg); intrathecal administration of naloxone (1.5 - 30 #g at the lumbar enlargement) also antagonized these effects of morphine. Similar doses of naloxone i.v. had no effect. It was concluded that vagal afferents play a functional role in the nociception produced by i.v morphine, mainly at low doses, whereas higher doses of morphine act at spinal and supraspinal levels masking the activation of vagal afferents that engage a spinopetal inhibitory system involving oplotds in the spinal cord (28). Mechanism of action of peripherally-acting opioid drugs It is apparent that mu, delta and kappa agonists can have antinocicept~ve effects by actions at opioid receptors located outside of the central nervous system. This has been demonstrated in models where tissue injury, hyperalgesia or inflammation are present. The mablhty of peripherally administered mu, delta and kappa opioid to alter nociception following acute, non-inflammatory, short duration stimuli such as that produced m the hot plate, tall immersion or paw pressure tests has been reported (16, 19, 20, 23). However, the counterpart to these findings are those showing ~mportant peripheral activity of mu, delta and kappa agonlsts in the acetic acid writhing test, of kappa agonists on the non-Inflammatory acute phase of nooceptlon in the formalin test, and of mu agonists in the tail flick reflex test (15, 24, 28). The precise locahzation and characterization of peripheral opioid receptors is not as yet clear There are opioid receptors on primary afferent neurons in the dorsal root ganghon (29, 30, 31). It also has been reported that peripherally-directed axonal transport of opioid receptors occurs m afferent fibers (32). Furthermore, different types of opiold binding sites have been Identified on primary afferents: Using monoclonal antibodies against opioid receptors and immunohistochemical techniques, Stein et al. were able to visuahze such receptors on peripheral terminals of sensory nerves within the subcutaneous tissue of the paw (33). Oploid agonists can act on afferent terminals to inhibit fiber activation and axon reflex-controlled release of mediators. Activation of kappa receptors has been shown to inhtbxt the influx of calcium into dorsal root ganglion cells via the closure of calcium-conducting channels (34) These mechanisms may operate at peripheral terminals and interfere with the transduction process in peripheral nerve endings. All opioid receptor types appear to be involved in these processes although the effects of kappa agonists may be more consistent than those of other opioids. These findings may be related to the different procedures used or to the individual pharmacokinetic behavior of the various compounds. As discussed prevxously (19), opiold molecules must reach a locus of achon on the peripheral sensory nerve axon or its terminal. In
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order to do so, drugs need to pass connective tissue and lipid membranous barriers in a milieu that can be complex in the case of inflamed tissue where relatively large changes in pH can occur altering molecular behavior and receptor conformation. Different fibers also can express different receptor types under normal as opposed to pathological conditions. It has been suggested that under inflammatory conditions algogemc substances can trigger de novo synthesis and axonat transport of opioid receptors (19) Peripheral op~old receptors on primary afferents likely have a physiological role since pro-dynorphln and pro-enkephahn oploid peptides have been identified lmmunohistochemically on primary sensory neurons (35, 36,). During stressful conditions, nociceptive thresholds can increase, an increase of cwculating endogenous peptides (e.g.,/3-endorphin) could actwate peripheral oplold receptors. It has been shown, for example, that i pl naloxone and/3-endorphin antibodies can reverse the increase of the nociceptive threshold in the inflamed paw of a rat submitted to a concomitant stress (33). In contrast, 1 v B-endorphln did not have a similar effect (37) During inflammatory processes, 13-endorphm, met-enkephahn and dynorphin and their corresponding mRNAs are increased (33). Moreover, immune cells (e.g., lymphocytes, monocytes, macrophages) that infiltrate inflamed t~ssue may contain/3endorphin and related op~oids that are then released, in turn acting on sensory endings (33). Conclusion It appears certain that exogenous and endogenous oploids can have antlnoclceptive effects by acting at peripheral sites The nature of the noxious stimuli and of the pathological conditions may affect the type of opiold receptors involved It would be appropriate, therefore, to have selecUve peripherally-acting opioids Thts can be achieved either by developing drugs that do not penetrate into brain structures after systemic admlmstration or by targeting drugs to act at peripheral sites Local application of oploids can be of therapeutic importance as it has been reported recently that ~ a morphine can reduce pain associated with knee joint inflammation in man (38). In order to develop a better understanding of the opioid processes revolved in peripherally-mediated pain states, it would also be particularly valuable to characterize the kappa opioid receptor subtypes occurring under both normal and pathological conditions in the periphery
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51, pp.
2009-2018
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MINIREVIEW ROLE OF OPIOIDS IN PERIPHERAL ANALGESIA J.L. Junien and J.G. Wettstein Insmut de Recherche Jouveinal B P 100, 94265 Fresnes Cedex, France (Recelved
in f~nal
form October
5, 1992)
Summary Several pharmacological, neurophysiological and immunohistological studies indicate that exogenous or endogenous opioids can have antmociceptive effects by acting at peripheral sites Although modulation of mu, delta and kappa receptors can mediate these effects, the nature of the noxtous stimulus and the underlying pathological condition may affect the types of opioid receptors involved. Thus, it would be appropriate to develop peripherally-acting opioid analgesics that do not have the untoward central side effects often associated with conventional analgesic drugs This paper reviews the evidence supportwe of a peripheral mechanism of action for op~oids Pain can occur following acute noxious stimuli yet climcal pain can be elicited by what normally would be an innocuous stimulus. The duration of pain may outlast the stimulus and its amplitude may be exaggerated (hyperalgesla). Also, there can be a spread of pathological sensitivity to normal tissue (secondary hyperalgesia) The changes in the threshold, responsweness and spatial properhes of pain are the consequences of modifcations within the nervous system (neuroplastic~ty). Neuronal modification can occur through peripheral sensitization whereby high threshold nociceptors develop a diminished threshold after exposure to a variety of chemical compounds. Central sensitization due to a change in the responsiveness of dorsal horn neurons can be triggered by repetitive nociceptor afferent activity. The nociceptors induce slow synaptic potentials in dorsal neurons that can summate to produce a cumulative Increase in depolarization and a progresswe increase in action potential discharge The depolarization which, in part, is glutamate- and tachykinin-medlated is accompamed by profound changes at the second messenger and gene levels Such changes can lead to alterations in membrane excitability, input recruitment, receptive field properties and expansion in receptive field size.
Corresponding author • J.L. Junien, B.P 100, 94265 Fresnes, France
Copyrlght
0024-3205/92 $5.00 + .00 © 1992 Pergamon Press Ltd All rlghts
reserved.
2010
Opxolds and Perxpheral Analgesia
Vol. 51, No. 26, 1992
Among the drugs available for the treatment of pain, opioid analgesics acting m the brain and spinal cord are very effective. The major drawbacks of such drugs, however, include respiratory depression and dependence liability. The untoward effects are, in general, due to actions in the central nervous system. In addition, opioids may likely exert antlnoclceptxve effects via peripheral mechanisms The purpose of this essay is to focus on the peripheral mechanism of pare and of opioid analgesia Activation and sensitization of peripheral sensory neurons
C-fibers are stimulated by the action of noxious stimuli on peripheral nocIceptors This results in a release of fast transmitters (e g , glutamate) and sensory peptides (e g , substance P, calcltonln gene-related peptlde (CGRP)) in the dorsal horn and also at peripheral sites where these substances act on the epithehum, smooth muscle and vasculature Noclceptive pathways can be influenced by many elements including neurotrophlc factors, the appearance of immune cells, products of tissue injury, and the sympathetic nervous system
Neurotrophtc factors Among the neurotrophic factors having different cell-type specificity are NGF (nerve growth factor), neurotrophlns 3, 4 and 5 (NT3, NT4, NT5), BDNF (brain-derived growth factor), and CNTF (ciliary neurotrophlc factor) These products are necessary for the development of sensory neurons and exert a neuromodulatory action on mature cells For example, selected neurotrophlc factors can regulate the mRNA synthesis for substance P, and CGRP and can modulate mast cell, basophll and lymphocyte activity
Inflammatton and the tmmune response During inflammatory states, cells can produce factors that cause hyperalgesia. For example, prostaglandms increase levels of cAMP, hydroxy acids activate protein hnase C, and leukotrlenes snmulate immune cell function, peptlde release and gene expression changes Hyperalgesia may be provoked in the rat paw by local injection of PGI2, PGE2, 15-HPETE or Interleukln-lB (I, 2, 3). Recently, Nakamura-Craig demonstrated that repeated subplantar injections of PGE2 for 4 days induced a sustained hyperalgesla that had a duration of at least 10 days (4). Endogenous sensory peptldes play an important role in this response since the hyperalgesic state was inhibited parnally by pretreatment with capsaicin
Vascular factors and products of ttssue injury Vascular factors (e.g, amines, klnlns, endothehum-derived relaxing factor, nitric oxide) and other products of tissue injury (e g , histamine, serotonin, bradyhnln, protons) are involved in the development of pain and hyperalgesia (5, 6, 7)
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Sympathenc nervous system.
Expelamental evidence has led to the suggestion that the peripheral sympathetic nervous system is involved in the generation or maintenance of pain sensation. This view comes in part from clinical observations whereby patients with tissue or nerve injury have prompt pain relief following sympatholytic therapy. Levine et al. have reported that regional sympathetic blockade with guanethidine decreases pain in patients suffering from rheumatoid arthritis (8) There is uncertainty about the site at which catecholammes act to produce pain although evidence suggests that terminals of nociceptwe afferents are the primary targets (9). Several studies have reported that hyperalgesia m animal models of inflammatory pain such as carrageenan edema (10), Freund adjuvant arthritis (11) and intracutaneous injection of bradyklnin (12) depend on the presence of post-ganghonlc sympathetic fibers. Rats rendered hyperalgesic by topical chloroform show a significantly reduced threshold after the injection of noradrenaline that is reversed by local administration of the alpha2-selectlve antagonist yohlmbine (12) It has been proposed that noradrenaline acts on postganglionic fibers to release substances other than noradrenaline that can sensitize nociceptors (12) Noradrenahne and bradykinm may induce prostaglandln release from sympathetic nerve endings that activate putatwe cellular transduction mechanisms such as inositol phosphate 3, diacyglycerol or cAMP formation at noclceptlve endings (13, 14).
Peripheral analgesic effects of opioids Using acetic acid as a nocicept~ve stimulus, Bentley et al. utilized a modification of the abdominal constriction test in mice to study the antinociceptive effects of morphine and related drugs (15). Instead of pretreating ammals with analgesic drugs, the drugs were administered 1.p when the abdominal constrictmn response had reached a maximum. These authors found that morphine was very potent in this procedure, having an EDso of 1 5/~g/kg Met- and leu-enkephahn (i.p.) also were active albeit for a short duration A prototype kappa opiold, ketocyclazocine, was found to be the most actwe of the compounds tested, having an EDso of 0.036 #g/kg. All the drugs tested by Bentley et al produced maximal effects within 2 min of administration (15). Pretreatment with naloxone (0.5 - 10 mg/kg, s c.) produced a dose-dependent shift to the right of the dose-response curve for morphine but not for ketocyclazoclne. When morphine was admimstered 1.v., higher doses of naloxone (0.5 mg/kg) were necessary to block the writhing response at 2 min; the antagonist effect then diminished rapidly. Intravenous doses of met-enkephalln greater than 10 mg/kg were necessary to obtain a partml reduction of abdominal constriction. Bentley and co-workers proposed that morphine and its congeners have antlnociceptive effects by acting through one or more types of opiold receptors situated on sensory endings within the mouse peritoneum (15) Smith et al. (16) compared the effects of morphine and its quaternary analogue N-methyl-morphine in two models of pain in mice, the hot plate and acetic acid-induced writhing tests. Unlike morphine, N-methyl-morphine poorly crosses the blood brain barrier because of its increased polarity and low lipophilicity. In
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comparison to the experiments of Bentley et al. (15, see above), test drugs were administered s.c before the noxious stimulus. As expected, morphine had strong antmociceptive effects in both the hot plate and acetic acid writhing tests (EDso'S, 0.8 and 2 8 mg/kg, respectively). In comparison, N-methyl morphine, up to 100 mg/kg, was inactive in the hot plate test; it did, however, inhibit acetic acid-induced writhing with an EDso of 24 mg/kg. The effects of both drugs in the writhing test were effectively antagonized by naloxone (8 mg/kg, i.p ). N-methyl-nalorphme (16 mg/kg, 1 p ), the quaternary analogue of nalorphine, inhibited the antinociceptive effects of N-methyl-morphine but not those of morphine. Using 14C-labelled compound, Smith et al also measured the amounts of morphine and N-methyl-morphine m the brain and confirmed N-methyl-morphine's poor penetration (16) From these experiments, Smith et al concluded that the analgesic effect of N-methyl-morphine, in contrast to morphine, was medmted solely by peripheral oploid receptors (16). Further evidence for the peripheral analgesic effects of opiold drugs has been obtained in inflammatory and hyperalgeslc models of pain. A number of groups using different procedures have provided results showing that various opioid ligands have local analgesic effects in inflammatory pain states (17, 18, 19, 20) Carrageenan has been used to induce inflammation and hyperalgesla in hindpaws of rats (18). The kappa and mu agonists, ethylketocyclazoclne (EKC, 100/zg) and levorphanol (40 #g), respectively, injected into the inflamed paw (mtraplantar, 1 pl ) produced a significant level of analgesia restricted to the site of injection as compared to saline injected into the contralateral inflamed paw, the analgesic effects lasted at least 2 hr (18). The effects of mu, delta and kappa opioid agonists were compared in an unilateral paw inflammation procedure reduced by Freund's complete adjuvant injection (19). Four to six days after moculaUon, oplold agomsts were administered i pl DAGO (1 /zg, mu-selective), DPDPE (40/~g, delta-selectwe) and U-50488H (50/~g, kappa-selective) produced marked antlnoc~cepttve effects m the inflamed paw dunng the first 30 mm post-injection At these doses, the three drugs had no effect on pain threshold in the non-inflamed control paw. Equivalent doses apphed systemically, either s.c. or 1 v , were inactive The effects of morphine (10 - 100/zg, 1 pl ) were dose-dependent and stereospecific Moreover, Lpl (-)naloxone but not (+)naloxone antagonized the effects of DAGO, DPDPE and U-50488H m a dose-dependent manner. Selective mu (CTP), delta (ICI 174,864) and kappa (norblnaltorphimine) antagonists reversed the effects of DAGO, DPDPE and U-50488H, respectively, suggesting that the agonists interacted with the three heterogeneous op~old receptor populations (19) It has been reported (20) that the hyperalgeslc effects of increasing doses of PGE2 injected intradermally in the paws of rats are antagonized by low doses (10 ng - l0 /zg) of morphine, morphiceptin and DAGO. These drugs did not alter the nociceptwe threshold of normal skin. Complete reversal of the hyperalgesia induced by 1 #g of PGE 2 was obtained with 10 #g of morphine Again, naloxone dose-dependently inhibited the effect of morphine. Additionally, intradermal pertussis toxin rejection prevented the protective effect of morphine on PGE2-induced hyperalgesia It was further shown that DPDPE and DSLET (both delta agonists) and U-50488H, all up to l0 #g, faded to reverse PGEz_-mduced hyperalgesla (20) Lastly,
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hyperalgesia induced by 8-bromo-cAMP was not attenuated by morphine given intradermally. Based on these data, it was concluded that the peripheral analgesic effects of opioids on primary afferent nociceptors are mediated by actions at a naloxone-reversible binding site with the characteristics of a mu opioid receptor; furthermore, the effects occur by Gi protein inhibition of the cAMP second messenger system in primary afferent noclceptors (20) Nakamura-Craig communicated recently that the peripheral op~oid agonlst BW-443C, a mu-acting enkephalin derivative, effectively attenuated the hyperalgesla produced by PGE2 injected i.pl. in rats (21). To assess the possible role of peripheral oplold receptors in nociception of inflamed tissue, Russell et al. recorded the spontaneous discharges in afferent units from inflamed knee joints of anesthetized cats (22). Afferent discharge activity was more frequent in single units from inflamed than from normal joints. These authors suggested that the increased level of ongoing resting activity was the afferent base of pare sensation in the inflamed joint. An inhibitory effect by oploids on unit discharge from inflamed joints would thus reflect a peripheral mechanism of action. Inflammation was established by intraarticular rejection of both kaohn and carrageenan at least 2 hours before recording (22). Morphine (1 - 5 mg/kg), DAGO (0.5 - 5 mg/kg), EKC (0.5 - 4 mg/kg) and U-50488H (1 10 mg/kg) were injected intraarterially (i.a.) close to the joint Most of the small diameter type IV afferents considered noclceptive were inhibited by these opioid agonists. More units responded to selective (U-50488H) or non-selective (EKC) kappa agonists. The effects of morphine, DAGO and U-50488H, but not EKC, were antagonized by i a naloxone (1 mg/kg) (22). Abbott (23) has used both the formahn and the tail immersion tests in rats to compare the local and central effects of morphine and EKC. Formahn injection i.pl. produces minor tissue injury whereas tad immersion represents thermal nociception. In these experiments, drugs were given either s.c. or i.c.v, before the tests (23) After s.c. administration, EKC was approximately 50 times more actave than morphine in the formalin test but only 10 times more active in the tail immersion test; morphine was equally effective in both tests. Naloxone methylbromide (10 mg/kg, i.p.), a peripherally-acting opiold antagonist, partially antagonized the effects of EKC in the formalin test. Specifically, only the upper portion of the EKC dose-response function was shifted rightward (23). This suggests that the analgesia produced by low doses of EKC are mediated by a central mechanism while the higher dose effects act at peripheral sites Naloxone methylbromide did not alter the effects of morphine in either procedure or the effects of EKC in the tail ~mmersion test. Abbott further reported that i.c v. EKC produced only partial analgesia in the formalin test despite application of twice the dose reqmred for a 50% decrease in nociceptwe scores when EKC was given s.c. Moreover, analgesia produced by central injection of EKC was not antagonized by systemic injection of naloxone methylbromlde Also, i.c.v. naloxone (5 - 25/zg) only partially reduced the effect of a near maximal s.c dose of EKC (23). Taken together, these data suggest that the analgesic effect of EKC in the formalin test is a result of the summatmn of action at central and peripheral kappa opio~d receptors. In comparison, the effects of morphine in both procedures and EKC
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in the tail immersion test are bkely due to central mechanisms. Findings such as these emphastze a role for kappa receptors in the periphery particularly when tissue mjury or inflammation is present. Recently, the function and peripheral location of the receptors mediating the effects of kappa drugs in the formalm test have been identified in the toes of the rat hmd paw by recording the activity of single dorsal horn noctceptive neurons (24) The admimstratton of formalin into the center of the receptive fields (in the toes) provokes two peaks of activity tn the neurons that correspond to the time course of the early (acute) and late (tonic) phases of flmchmg and paw hcking (25) Administration of U-50488H (25 - 100 pg) directly into the site where formalin was injected resulted m a marked dose-related reductton of both the early and the late response peaks (25) The mhibitton of formalin-evoked activity appeared to be the result of a local action of U-50488H since administration of the high dose (100 pg) mto the contralateral, non-Inflamed paw prior to formalin had no Influence on the subsequent formalm response (25) It should be noted that U-50488H was able to inhibit the first peak that occurs prior the generation of inflammation. Neither morphme nor the delta agonist DSTBLET (both at 100 pg) administered under the same conditions reduced neuronal firing Naloxone (100 pg) injected directly into the plantar region of the paw two min before U-50488H antagonized the effects on both response peaks. Naloxone mjected i p. (10 mg/kg) twenty mm before U-50488H only parttally reversed the effects of this drug Electrically evoked A@- and C-fiber responses of the neurons were not inhibited by mjection of 100 pg of U-50488H mto the receptive field desptte having a profound mhibitory effect on the formalm response In addition, the systemic dose required to Inhibit electrically-evoked C-fiber responses was about 10 times the peripheral dose admmlstered (25) Important evidence showing that opioids have antinociceptive effects through direct peripheral modulation of afferent fibers comes m part from experiments showing that the mhibition of the tail fhck reflex produced by 1 p morphme (10 mg/kg) is attenuated by total subdiaphragmatic vagotomy (26) Also, 1 v D-ala-met-enkephalmamide, a synthetic opioid peptide that poorly crosses the blood bram barrier, produced vagally-mediated mhibttion of both the nociceptive tail flick reflex and the responses of lumbar spinal dorsal horn neurons to noxious heating of the foot in rats (27) In addmon, Randich et al have studied the vagal afferent-mediated effects of morphine on the tail flick reflex, artenal blood pressure and heart rate in pentobarbital-anesthetized rats (28). The hypotensive effect and heart rate decrease induced by morphine faded rapidly following drug injection, in contrast, the effect of morphine on the tail flick reflex was sustained. Bilateral cervical vagotomy mhibited the antmociceptive effects of low doses of morphme (0 1 - 1 mg/kg, i.v.) and attenuated, with a delayed onset, the analgesia produced by a high dose of morphine (2.5 mg/kg) (28) Naloxone methylbromide also prevented the effect of morphme on the tail flick reflex with a pattern similar to that recorded after bilateral cervical vagotomy. Sino-aortic denervation had little or no effect on the antinociceptive and cardiovascular responses produced by morphine (28) Subdiaphragmatic vagotomy was only slightly effective in preventing morphine analgesia whereas vagotomy delayed the
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analgesia onset. Randich et al. also showed that cerebral vagotomy had no effect on the depressor response (tail flick) produced by low doses of morphine (0.1 - 1 mg/kg) yet blocked morphine-induced hypotension Naloxone methylbromide blocked completely the depressor and bradycardia effects produced by morphine. The authors then investigated the pathway involved in the vagal afferent-mediated effects of morphine. Spinal cold-block significantly antagonized the antinociception, hypotension and bradycardia produced by a low dose of morphine (0.5 mg/kg); intrathecal administration of naloxone (1.5 - 30 #g at the lumbar enlargement) also antagonized these effects of morphine. Similar doses of naloxone i.v. had no effect. It was concluded that vagal afferents play a functional role in the nociception produced by i.v morphine, mainly at low doses, whereas higher doses of morphine act at spinal and supraspinal levels masking the activation of vagal afferents that engage a spinopetal inhibitory system involving oplotds in the spinal cord (28). Mechanism of action of peripherally-acting opioid drugs It is apparent that mu, delta and kappa agonists can have antinocicept~ve effects by actions at opioid receptors located outside of the central nervous system. This has been demonstrated in models where tissue injury, hyperalgesia or inflammation are present. The mablhty of peripherally administered mu, delta and kappa opioid to alter nociception following acute, non-inflammatory, short duration stimuli such as that produced m the hot plate, tall immersion or paw pressure tests has been reported (16, 19, 20, 23). However, the counterpart to these findings are those showing ~mportant peripheral activity of mu, delta and kappa agonlsts in the acetic acid writhing test, of kappa agonists on the non-Inflammatory acute phase of nooceptlon in the formalin test, and of mu agonists in the tail flick reflex test (15, 24, 28). The precise locahzation and characterization of peripheral opioid receptors is not as yet clear There are opioid receptors on primary afferent neurons in the dorsal root ganghon (29, 30, 31). It also has been reported that peripherally-directed axonal transport of opioid receptors occurs m afferent fibers (32). Furthermore, different types of opiold binding sites have been Identified on primary afferents: Using monoclonal antibodies against opioid receptors and immunohistochemical techniques, Stein et al. were able to visuahze such receptors on peripheral terminals of sensory nerves within the subcutaneous tissue of the paw (33). Oploid agonists can act on afferent terminals to inhibit fiber activation and axon reflex-controlled release of mediators. Activation of kappa receptors has been shown to inhtbxt the influx of calcium into dorsal root ganglion cells via the closure of calcium-conducting channels (34) These mechanisms may operate at peripheral terminals and interfere with the transduction process in peripheral nerve endings. All opioid receptor types appear to be involved in these processes although the effects of kappa agonists may be more consistent than those of other opioids. These findings may be related to the different procedures used or to the individual pharmacokinetic behavior of the various compounds. As discussed prevxously (19), opiold molecules must reach a locus of achon on the peripheral sensory nerve axon or its terminal. In
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order to do so, drugs need to pass connective tissue and lipid membranous barriers in a milieu that can be complex in the case of inflamed tissue where relatively large changes in pH can occur altering molecular behavior and receptor conformation. Different fibers also can express different receptor types under normal as opposed to pathological conditions. It has been suggested that under inflammatory conditions algogemc substances can trigger de novo synthesis and axonat transport of opioid receptors (19) Peripheral op~old receptors on primary afferents likely have a physiological role since pro-dynorphln and pro-enkephahn oploid peptides have been identified lmmunohistochemically on primary sensory neurons (35, 36,). During stressful conditions, nociceptive thresholds can increase, an increase of cwculating endogenous peptides (e.g.,/3-endorphin) could actwate peripheral oplold receptors. It has been shown, for example, that i pl naloxone and/3-endorphin antibodies can reverse the increase of the nociceptive threshold in the inflamed paw of a rat submitted to a concomitant stress (33). In contrast, 1 v B-endorphln did not have a similar effect (37) During inflammatory processes, 13-endorphm, met-enkephahn and dynorphin and their corresponding mRNAs are increased (33). Moreover, immune cells (e.g., lymphocytes, monocytes, macrophages) that infiltrate inflamed t~ssue may contain/3endorphin and related op~oids that are then released, in turn acting on sensory endings (33). Conclusion It appears certain that exogenous and endogenous oploids can have antlnoclceptive effects by acting at peripheral sites The nature of the noxious stimuli and of the pathological conditions may affect the type of opiold receptors involved It would be appropriate, therefore, to have selecUve peripherally-acting opioids Thts can be achieved either by developing drugs that do not penetrate into brain structures after systemic admlmstration or by targeting drugs to act at peripheral sites Local application of oploids can be of therapeutic importance as it has been reported recently that ~ a morphine can reduce pain associated with knee joint inflammation in man (38). In order to develop a better understanding of the opioid processes revolved in peripherally-mediated pain states, it would also be particularly valuable to characterize the kappa opioid receptor subtypes occurring under both normal and pathological conditions in the periphery
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