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Analgetic actions of intrathecal opiates in cat and primate
Brain Research, 153 (1978) 205-210 ,t) Elsevier/North-Holland Biomedical Press
205
Analgetic actions of intrathecal opiates in cat and primate
TONY L. YAKSH Mayo Clinic' aml Foundation, Rochester, Mhm. 55901 (U.S.A.)
(Accepted April 13th, 1978)
It has been shown that the injection of opiates into the spinal subarachnoid space of the unanesthetized rat and rabbit will produce a behaviorally defined analgesiag,16,17. The pharmacological properties of this local action appears indistinguishable from the depression of spinal nociceptive neurons produced by the systemic administration of opiates in the spinal cat2,a,5,6,n, 12 or of the analgesia observed in the intact animal. Thus, opiates acting on the spinal cord produce effects which are dose dependent, stereospecific, antagonized by naloxone in a quantitative fashion, dependent upon the relative potency of the agonist and show tolerance with repeated administration la-1:. In the present experiments, the phenomena of a behaviorally defined analgesia produced by a pharmacologically specific action of intrathecally administered opiates has been extended to the cat and primate. To permit the reliable and atraumatic intrathecal injection of drugs in the unanesthetized cat and primate, polyethylene catheters (pe 10) were chronically inserted into the spinal subarachnoid space under aseptic conditions through the atlantooccipital membrane. The catheter extended 30 cm down the cord, a length determined by presurgical radiograms to correspond approximately with L-5/L-6 vertebrae in both cat and primate. The catheter was externalized at the top of the skull and protected by a plastic pedestal affixed with screws and cranioplast cement. Twelve cats (2.8-3.6 kg) and one rhesus monkey (7.8 kg) were implanted in this or signs of discomfort. To evoke a clearly defined nociceptive response in the cats, a heat probe with a tip surface (1 sq.cm) maintained at 70 °C was placed lightly, for a maximum of 15 sec, on one of several previously depilated body areas. This strong stimulus commonly produced a local reflex (skin twitch or tail flick) followed by an agitation-escape response. After a two week recovery period, each cat received an intrathecal injection of 0.3 ml of sterile Ringer solution. In no instance did the injection of the vehicle produce any sign of agitation or alter the response of the cat to the 70 °C heat probe. Three or four days later, the cats were injected intrathecally either with 40 #g or 80/,g of mor-
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Fig. 1. The latency of the escape response of a cat to a 70 °C heat probe applied to the regions shown in
the cat figurine as a function of time after the intrathecal injection of morphine sulfate in doses Of40 #g (top) or 80/~g (bottom). Naloxone (0J mg/kg) was administered systemically at the second line. The volume of the intrathecal injection was 0.3 ml of drug followed by 0.1 ml of vehicle. phine in 0.3 ml of vehicle followed by 0.l ml of vehicle to clear the catheter. Seven days later, each cat received the other dose o f morphine. Fig. 1 presents the data taken from one cat in this series o f experiments. As demonstrated, within 5-10 min after the injection, there was a clear elevation in the escape response latency of the cat. During these periods, there was an associated increase in the latency o f the local skin twitch and tail flick reflexes. Significantly, the time course o f the analgesia in all animals following the intrathecal injection revealed a somatotopically limited effect with the cord dermatome regions closest to the catheter tip showing the earliest and m o s t predominant analgesia. T h o u g h the analgesia sometimes extended as far rostral as the shoulders, in no case was a change noted in the response to stimuli applied to the head and upper neck. The long duration o f the intrathecal drug effect, shown in Fig. 1 for this animal was typical o f the time course observed in the cats as well.
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Fig. 2. Shock tination records taken from 4 separat eexperiments in a single rhesus monkey. The ordinate is shock level in mA while the abscissa is time in hours after the intrathecal injection of either vehicle (sp Cont), 40/~g morphine sulfate (sp 40 pg), 160/tg morphine sulfate (sp 160/~g) or after the intramuscular injection of morphine sulfate (ira 4 mg/kg). Naloxone (0.1 mg/kg) was given intramuscularly at the second dotted line in each experiment. The volume of the intrathecal injection was always 0.3 mt of drug followed by 0.1 ml of vehicle. Note that the ordinate amplitude for the top two experiments is half that used in the bottom two experiments. To d e m o n s t r a t e t h a t the effect was n o t due to a non-specific action resulting from the injection o f the drug, n a l o x o n e (0.1 mg/kg) was shown to p r o d u c e an a l m o s t complete a n t a g o n i s m o f the elevated t h e r m a l t h r e s h o l d s p r o d u c e d by intrathecal m o r p h i n e As the half-life o f systemically a d m i n i s t e r e d naloxone is short v ( a r o u n d 30 min), it is n o t surprising to note t h a t the elevated nociceptive thresholds began to return shortly after the systemic a d m i n i s t r a t i o n of the opiate antagonist. To d e m o n s t r a t e t h a t the effects p r o d u c e d were not limited to an a c t i o n of morphine, the intrathecal effect o f L-methadone was tested in two animals. Based on earlier w o r k which indicated t h a t m e t h a d o n e was a b o u t 1/6 to 1/Sth as active as m o r p h i n e when a d m i n i s t e r e d intrathecally in the rat iv, a dose of 300/~g was injected. A n elevation in the nociceptive t h r e s h o l d c o m p a r a b l e in m a g n i t u d e to t h a t p r o d u c e d by intrathecal m o r p h i n e was observed. This dose o f m e t h a d o n e , however, a p p e a r e d to be effective
208 only for a period of 5-7 h, in contrast to the overnight action of morphine. The difference in duration is likely due to the relative rate of clearance from the intrathecat space and spinal tissue, with the more lipid soluble material (methadone) being removed before the more water soluble material (morphine) (cf. ref. 19). The single female primate which was implanted had previously been trained on the discrete trials shock titration task. This procedure has been described in detail elsewhere is. Fig. 2 (upper tracing) shows the titration threshold response to a control injection of 0.3 ml sterile Ringer. During the 6 h period, the animal maintained the shock at a stable level. As reported previously is, naloxone (0,1 mg/kg, i.m.) failed to have any detectable effect on the control titration threshold. In contrast, after morphine (40 #g/0.2 ml), the animal's shock threshold rose from around 0.3 mA to 2 mA. After the effect had plateaued, naloxone (0.1 mg/kg) was administered intramuscularly. The dramatic reversal of the effect at this low dose of naloxone suggests clearly t hat the effect was associated with a direct action upon opiate receptors. As with the experiments carried out in the cats, the intrathecal effect was dose dependent. In the third record, morphine sulfate (160 pg/0.2 ml) was injected at the arrow. In this experiment, the range of the titration unit was 4 mA (i.e. double that used in the experiments depicted in the top two records). As can be seen, this 4-fold increase in dose produced an approximate doubling in the levels of shock tolerated by the animal (as compared to the lower dose of opiate). As in the cats, the effect has an extremely long duration. In two experiments, the animal was injected with the opiate (160 #g) and tested on the titration schedule at intervals of every 3 h for 1 h. In these experiments the animal demonstrated a return to baseline levels of shock threshold after 12 and 18 h, respectively. As with the cats, the apparent level of analgesia does not extend to the upper neck or face. In the bottom record, the same animal was given morphine (4 mg/kg, i.m.). It can be seen that this systemic dose produces about the same maximum effect as the 160 ltg dose administered intrathecally. Close observation of the cat and primate during the intrathecally induced analgesia revealed no detectable change in the behavioral characteristics of the animals. There was no change in respiration or heart rate. Pupil size and reflexes were normal. Monitoring of urine output during the course of the 8-18 h experiments with the primate revealed that during the analgesia, there was no change as compared to control. This is in marked contrast to the spinal block produced by local anesthetics wherein bladder emptying is impaired. Even the highest dose of morphine or methadone failed to have any detectable effects upon the animal's posture, or motor responsiveness and coordination. For example, during analgesia, the cat remained clearly able to right itself and land lithely upon all 4 paws after being dropped inverted from a height of 3-4 ft. During the longterm experiments with both the cat and the primate, food and water were available and normal feeding and drinking were noted. At no time did the animals show any signs of discomfort following the intrathecal injection. Likewise, the cats did not display any signs of the 'manic behavior' observed following the injection of opiate systemically. Perhaps most striking is the observation that during the periods following the intratheeal injection when the primate was tolerating high levels of shock, there was
209 no detectable depression of the animal's behavioral responses to the experimenter or the environment. In contrast, during the analgesia produced by 4 mg/kg i.m. of morphine, the animal was behaviorally quite depressed, showing little social responsiveness and virtually no food or fluid consumption. Of principal importance in these experiments is that the opiate effect is directly upon neural tissue within the spinal sac and not upon supraspinal systems which are associated with changes in the nociceptive threshold a9. In 4 cats, which were injected with 0.3 ml of methylene blue dye intrathecally and dissected, it was observed that during the time course with which the analgetic effect occurred, no detectable dye reaches the brain stem via diffusion up the spinal subarachnoid space. The absence of effect upon trigeminal systems, the failure to alter respiration and the rapid onset of the analgesia in the cat following the injection, with the focus of the analgesia being near the dermatome associated with the spinal segments nearest the catheter tip indeed argues that the effect is a local one. In the primate, the relatively long time course of onset may be the result of such a diffusion to other segments or into the cord itself. The small volume, the long (30 cm) distance and the fact that the animal is sitting vertically, facilitating caudad not rostrad fluid circulation argues, however, against the likelihood of the effect being mediated by a supraspinal action. Moreover, it appears unlikely that the effects are mediated by a redistribution via diffusion into plasma as these doses of opiate fail to be active on these tests when administered systemically. In sum, from the combined cat and monkey experiments, it seems clear that the intrathecal action of opiates can produce a profound elevation in the nociceptive thresholds of the animal. The effects do not appear to be associated with alterations in coordinated motor functions or the basic vegetative patterns of the animal such as respiration, heart rate or urination. The preliminary experiments regarding the pharmacology of the effect are in accord with the more extensive experiments carried out previously in the rat and rabbit. Importantly, recent experiments carried out in clinical cancer patients indicate that the intrathecal action of opiates can in fact relieve chronic pain in these cases at doses which, as in the animal studies, have no effect upon motor function or higher mental processes 9. The clinical relevance of these effects are clear. Where within the spinal cord intrathecally administered opiates are acting to produce the observed behavioral effects remains to be determined. The presence of opiate binding in the substantia gelatinosa 1 along with the known modulatory capacity of this region (as evidenced by the effects of stimulating its principal efferent tract, the lateral Lissauer tract 20) makes this region a likely site. On the other hand, Jurna and Grossman 4 have recently reported a direct inhibitory effect of opiates on small peripheral primary afferents. Studies to discern the site of intrathecal action are presently in progress. I would like to thank Dr. F. W. L. Kerr for his helpful comments. This work was supported by the Mayo Foundation.
210 1 Atweh, S. F. and Kuhar, M. J., Autoradiographic localization of opiate receptors in rat brain. 1. Spinal cord and lower medulla, Brain Research, 123 (1977) 53-67. 2 Iwata, N. and Sakai, Y., Effects of fentanyl upon the spinal interneurons activated by A delta afferent fibers of the cutaneous nerve of the cat, Jap. J. Pharmacol., 21 (1971) 413-416. 3 Jurna, I. and Grossman, W., The effect of morphine on the activity evoked in the ventrolateral tract axons of the cat spinal cord, Exp. Brain Res., 24 (1976) 473-484. 4 Jurna, 1. and Grossman, W., The effect of morphine on mammalian nerve fibers, Earop. J. PharmacoL, 44 (1977) 339-348. 5 Kitahata, L. M., Kosaka, Y., Taub, A., Bonikos, C. and Hoffert, M., Lamina specific suppression of dorsal horn unit activity by morphine sulfate, Anesthesiology, 41 (1974) 39-48. 6 LeBars, D., Menetrey, D., Conseiller, C. and Besson, J. M., Depressive effects of morphine upon lamina V cells activities in the dorsal horn of the spinal cat, Brain Research, 98 (t975) 261-277. 7 Misra, A. L., Pontani, R. B., Vadlamani, N. L. and Mule, S. J., Physiological disposition and biotransformation of (allyl-l',3'-laC-naloxone) in the rat and some comparative observations on nalorphine, J. Pharrnacol. exp. Ther., 196 (1976) 257. 8 Wall, P. D. and Yaksh, T. L., The effect of Lissauer tract stimulation on activity in dorsal and ventral roots, Exp. Neurol., (1978) in press. 9 Wang, J. K., Analgesic effect of intrathecally administered morphine, Reg. Anesth., 2 (1977) 3. 10 Wang, J. K.,Solagement de la douleur par administration intratheale de serotonine ou morphine, Abstr., Reunion Nationale Annuelle Journees D'in]brmation Post-universitaire, 1977~ 1t Yaksh, T. L., Inhibition by etorphine of the discharge of dorsal horn neurons: Effects on the neuronal response to both high and low threshold sensory input in the decerebrate spinal cat, Exp. Neurol., 60 (1978) 23-40. 12 Yaksh, T. L., Opiate receptors for behavioral analgesia resemble those related to the depression of spinal nociceptive neurons, Science, 199 (1978) 1231-1233. 13 Yaksh, T. L., Frederickson, R. C. A., Huang, S. P. and Rudy, T. A., In vivo comparison of the receptor populations acted upon the spinal cord by morphine and pentapeptides in the production of analgesia, Brain Research, (1978) in press. 14 Yaksh, T. L., Huang, S. P., Rudy, T. A. and Frederickson, R. C. A., The direct and specific effect of Met~-enkephalin and analogues on the spinal cord, Neuroscience, 2 (1977) 593-596. 15 Yaksh, T. L., Koll, R. L. and Rudy, T. A., Tolerance and withdrawal in rats receiving morphine in the spinal subarachnoid space, Europ. J. Pharmacol., 42 (1977) 275-284. 16 Yaksh, T. L. and Rudy, T. A., Analgesia mediated by a direct spinal action of narcotics, Science, 192 (1976) 1357-1358. 17 Yaksh, T. L. and Rudy, T. A., Studies on the direct spinal action of narcotics in the production of analgesia in the rat, J. Pharmacol. exp. Ther., 202 (1977) 411428. 18 Yaksh, T. L. and Rudy, T. A., A dose ratio comparison of the interaction between morphine and cyclazocine with naloxone in rhesus monkeys on the shock titration task, Europ. J. Pharmacol., 46 (1977) 83-92. 19 Yaksh, T. L. and Rudy, R. A., Narcotic analgetics: CNS sites and mechanism of action as revealed by intracerebral injection techniques, Pain, 4 (1978) 299-359. 20 Yaksh, T. L. and Wall, P. D., Activation of a local spinal inhibitory system by focal stimulation of the lateral Lissauer tract in spinal decerebrate cats, Fed. Proc., (1978) in press.
205
Analgetic actions of intrathecal opiates in cat and primate
TONY L. YAKSH Mayo Clinic' aml Foundation, Rochester, Mhm. 55901 (U.S.A.)
(Accepted April 13th, 1978)
It has been shown that the injection of opiates into the spinal subarachnoid space of the unanesthetized rat and rabbit will produce a behaviorally defined analgesiag,16,17. The pharmacological properties of this local action appears indistinguishable from the depression of spinal nociceptive neurons produced by the systemic administration of opiates in the spinal cat2,a,5,6,n, 12 or of the analgesia observed in the intact animal. Thus, opiates acting on the spinal cord produce effects which are dose dependent, stereospecific, antagonized by naloxone in a quantitative fashion, dependent upon the relative potency of the agonist and show tolerance with repeated administration la-1:. In the present experiments, the phenomena of a behaviorally defined analgesia produced by a pharmacologically specific action of intrathecally administered opiates has been extended to the cat and primate. To permit the reliable and atraumatic intrathecal injection of drugs in the unanesthetized cat and primate, polyethylene catheters (pe 10) were chronically inserted into the spinal subarachnoid space under aseptic conditions through the atlantooccipital membrane. The catheter extended 30 cm down the cord, a length determined by presurgical radiograms to correspond approximately with L-5/L-6 vertebrae in both cat and primate. The catheter was externalized at the top of the skull and protected by a plastic pedestal affixed with screws and cranioplast cement. Twelve cats (2.8-3.6 kg) and one rhesus monkey (7.8 kg) were implanted in this or signs of discomfort. To evoke a clearly defined nociceptive response in the cats, a heat probe with a tip surface (1 sq.cm) maintained at 70 °C was placed lightly, for a maximum of 15 sec, on one of several previously depilated body areas. This strong stimulus commonly produced a local reflex (skin twitch or tail flick) followed by an agitation-escape response. After a two week recovery period, each cat received an intrathecal injection of 0.3 ml of sterile Ringer solution. In no instance did the injection of the vehicle produce any sign of agitation or alter the response of the cat to the 70 °C heat probe. Three or four days later, the cats were injected intrathecally either with 40 #g or 80/,g of mor-
206
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Fig. 1. The latency of the escape response of a cat to a 70 °C heat probe applied to the regions shown in
the cat figurine as a function of time after the intrathecal injection of morphine sulfate in doses Of40 #g (top) or 80/~g (bottom). Naloxone (0J mg/kg) was administered systemically at the second line. The volume of the intrathecal injection was 0.3 ml of drug followed by 0.1 ml of vehicle. phine in 0.3 ml of vehicle followed by 0.l ml of vehicle to clear the catheter. Seven days later, each cat received the other dose o f morphine. Fig. 1 presents the data taken from one cat in this series o f experiments. As demonstrated, within 5-10 min after the injection, there was a clear elevation in the escape response latency of the cat. During these periods, there was an associated increase in the latency o f the local skin twitch and tail flick reflexes. Significantly, the time course o f the analgesia in all animals following the intrathecal injection revealed a somatotopically limited effect with the cord dermatome regions closest to the catheter tip showing the earliest and m o s t predominant analgesia. T h o u g h the analgesia sometimes extended as far rostral as the shoulders, in no case was a change noted in the response to stimuli applied to the head and upper neck. The long duration o f the intrathecal drug effect, shown in Fig. 1 for this animal was typical o f the time course observed in the cats as well.
207
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Fig. 2. Shock tination records taken from 4 separat eexperiments in a single rhesus monkey. The ordinate is shock level in mA while the abscissa is time in hours after the intrathecal injection of either vehicle (sp Cont), 40/~g morphine sulfate (sp 40 pg), 160/tg morphine sulfate (sp 160/~g) or after the intramuscular injection of morphine sulfate (ira 4 mg/kg). Naloxone (0.1 mg/kg) was given intramuscularly at the second dotted line in each experiment. The volume of the intrathecal injection was always 0.3 mt of drug followed by 0.1 ml of vehicle. Note that the ordinate amplitude for the top two experiments is half that used in the bottom two experiments. To d e m o n s t r a t e t h a t the effect was n o t due to a non-specific action resulting from the injection o f the drug, n a l o x o n e (0.1 mg/kg) was shown to p r o d u c e an a l m o s t complete a n t a g o n i s m o f the elevated t h e r m a l t h r e s h o l d s p r o d u c e d by intrathecal m o r p h i n e As the half-life o f systemically a d m i n i s t e r e d naloxone is short v ( a r o u n d 30 min), it is n o t surprising to note t h a t the elevated nociceptive thresholds began to return shortly after the systemic a d m i n i s t r a t i o n of the opiate antagonist. To d e m o n s t r a t e t h a t the effects p r o d u c e d were not limited to an a c t i o n of morphine, the intrathecal effect o f L-methadone was tested in two animals. Based on earlier w o r k which indicated t h a t m e t h a d o n e was a b o u t 1/6 to 1/Sth as active as m o r p h i n e when a d m i n i s t e r e d intrathecally in the rat iv, a dose of 300/~g was injected. A n elevation in the nociceptive t h r e s h o l d c o m p a r a b l e in m a g n i t u d e to t h a t p r o d u c e d by intrathecal m o r p h i n e was observed. This dose o f m e t h a d o n e , however, a p p e a r e d to be effective
208 only for a period of 5-7 h, in contrast to the overnight action of morphine. The difference in duration is likely due to the relative rate of clearance from the intrathecat space and spinal tissue, with the more lipid soluble material (methadone) being removed before the more water soluble material (morphine) (cf. ref. 19). The single female primate which was implanted had previously been trained on the discrete trials shock titration task. This procedure has been described in detail elsewhere is. Fig. 2 (upper tracing) shows the titration threshold response to a control injection of 0.3 ml sterile Ringer. During the 6 h period, the animal maintained the shock at a stable level. As reported previously is, naloxone (0,1 mg/kg, i.m.) failed to have any detectable effect on the control titration threshold. In contrast, after morphine (40 #g/0.2 ml), the animal's shock threshold rose from around 0.3 mA to 2 mA. After the effect had plateaued, naloxone (0.1 mg/kg) was administered intramuscularly. The dramatic reversal of the effect at this low dose of naloxone suggests clearly t hat the effect was associated with a direct action upon opiate receptors. As with the experiments carried out in the cats, the intrathecal effect was dose dependent. In the third record, morphine sulfate (160 pg/0.2 ml) was injected at the arrow. In this experiment, the range of the titration unit was 4 mA (i.e. double that used in the experiments depicted in the top two records). As can be seen, this 4-fold increase in dose produced an approximate doubling in the levels of shock tolerated by the animal (as compared to the lower dose of opiate). As in the cats, the effect has an extremely long duration. In two experiments, the animal was injected with the opiate (160 #g) and tested on the titration schedule at intervals of every 3 h for 1 h. In these experiments the animal demonstrated a return to baseline levels of shock threshold after 12 and 18 h, respectively. As with the cats, the apparent level of analgesia does not extend to the upper neck or face. In the bottom record, the same animal was given morphine (4 mg/kg, i.m.). It can be seen that this systemic dose produces about the same maximum effect as the 160 ltg dose administered intrathecally. Close observation of the cat and primate during the intrathecally induced analgesia revealed no detectable change in the behavioral characteristics of the animals. There was no change in respiration or heart rate. Pupil size and reflexes were normal. Monitoring of urine output during the course of the 8-18 h experiments with the primate revealed that during the analgesia, there was no change as compared to control. This is in marked contrast to the spinal block produced by local anesthetics wherein bladder emptying is impaired. Even the highest dose of morphine or methadone failed to have any detectable effects upon the animal's posture, or motor responsiveness and coordination. For example, during analgesia, the cat remained clearly able to right itself and land lithely upon all 4 paws after being dropped inverted from a height of 3-4 ft. During the longterm experiments with both the cat and the primate, food and water were available and normal feeding and drinking were noted. At no time did the animals show any signs of discomfort following the intrathecal injection. Likewise, the cats did not display any signs of the 'manic behavior' observed following the injection of opiate systemically. Perhaps most striking is the observation that during the periods following the intratheeal injection when the primate was tolerating high levels of shock, there was
209 no detectable depression of the animal's behavioral responses to the experimenter or the environment. In contrast, during the analgesia produced by 4 mg/kg i.m. of morphine, the animal was behaviorally quite depressed, showing little social responsiveness and virtually no food or fluid consumption. Of principal importance in these experiments is that the opiate effect is directly upon neural tissue within the spinal sac and not upon supraspinal systems which are associated with changes in the nociceptive threshold a9. In 4 cats, which were injected with 0.3 ml of methylene blue dye intrathecally and dissected, it was observed that during the time course with which the analgetic effect occurred, no detectable dye reaches the brain stem via diffusion up the spinal subarachnoid space. The absence of effect upon trigeminal systems, the failure to alter respiration and the rapid onset of the analgesia in the cat following the injection, with the focus of the analgesia being near the dermatome associated with the spinal segments nearest the catheter tip indeed argues that the effect is a local one. In the primate, the relatively long time course of onset may be the result of such a diffusion to other segments or into the cord itself. The small volume, the long (30 cm) distance and the fact that the animal is sitting vertically, facilitating caudad not rostrad fluid circulation argues, however, against the likelihood of the effect being mediated by a supraspinal action. Moreover, it appears unlikely that the effects are mediated by a redistribution via diffusion into plasma as these doses of opiate fail to be active on these tests when administered systemically. In sum, from the combined cat and monkey experiments, it seems clear that the intrathecal action of opiates can produce a profound elevation in the nociceptive thresholds of the animal. The effects do not appear to be associated with alterations in coordinated motor functions or the basic vegetative patterns of the animal such as respiration, heart rate or urination. The preliminary experiments regarding the pharmacology of the effect are in accord with the more extensive experiments carried out previously in the rat and rabbit. Importantly, recent experiments carried out in clinical cancer patients indicate that the intrathecal action of opiates can in fact relieve chronic pain in these cases at doses which, as in the animal studies, have no effect upon motor function or higher mental processes 9. The clinical relevance of these effects are clear. Where within the spinal cord intrathecally administered opiates are acting to produce the observed behavioral effects remains to be determined. The presence of opiate binding in the substantia gelatinosa 1 along with the known modulatory capacity of this region (as evidenced by the effects of stimulating its principal efferent tract, the lateral Lissauer tract 20) makes this region a likely site. On the other hand, Jurna and Grossman 4 have recently reported a direct inhibitory effect of opiates on small peripheral primary afferents. Studies to discern the site of intrathecal action are presently in progress. I would like to thank Dr. F. W. L. Kerr for his helpful comments. This work was supported by the Mayo Foundation.
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