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Development of tolerance to the effects of morphine: association between analgesia and electrical activity in the periaqueductal gray matter
202
Brain Research, 176 (1979) 202-207 © Elsevier/North-Holland Biomedical Press
Development of tolerance to the effects of morphine: association between analgesia and electrical activity in the periaqueductal gray matter
GIDEON URCA, RICHARD L. NAHIN and JOHN C. LIEBESKIND Department of Physiology and Pharmacology, Tel A viv University School of Medicine, Ramat A viv (Israel) and Department of Psychology, University of CaliJbrnia, Los Angeles, Calif. 90024 (U.S.A.)
(Accepted June 28th, 1979)
The existence of a medial brain stem endogenous analgesia substrate employing opioids as neurotransmitters or neuromodulators has gained substantial support from various lines of research 3,4,11,2°. The analgesic action of opiate drugs probably stems from their ability to bind with endogenous opioid receptors in these brain areas. The periaqueductal gray matter (PAG) within the medial brain stem has been implicated as one major site of opiate analgesic action 9,11,2°. Both electrical stimulation of the PAG and microinjections of opiates into this structure produce profound analgesia quite similar to that elicited by systemic injections of opiates3,9,~l,lZ, ~4,2°. It has been suggested that activation of this analgesia substrate leads to the reinforcement of descending controls serving to block pain transmission through nociceptive neurons in the spinal c0rd3,4,9,11-13, 20. Direct evidence for the activating effect of opiates on PAG neurons has been provided by studies showing that intraperitoneal injections of analgesic doses of morphine13,17-1~ or intracerebroventricular injections of morphine or enkephalin 17 produce significant increases of multiple unit activity (MUA) in the PAG which are well-correlated temporally with analgesia. Furthermore, only when analgesia is seen, is a concomitant MUA increase observed 17. If indeed the morphine-induced increase in PAG multiple unit activity seen in previous studies~Z, 17--~9reflects the active role played by this brain area in mechanisms of analgesia, then factors influencing the degree of analgesia should alter the MUA effect correspondingly. The development of tolerance to morphine's analgesic action is a well-documented phenomenon 7. In fact, the analgesic effect of electrically stimulating PAG shows both tolerance and cross-tolerance to morphine analgesia ~0. It has been shown that the development of tolerance to morphine can be attenuated if animals are tested in an environment different from that in which the drug is habitually administered 5,8,16. We therefore sought to determine if the development of tolerance to morphine would be reflected in a parallel tolerance to its MUA-increasing effect in the PAG. In addition, we investigated the question of whether the use of different
203 environmental cues associated with drug administration would affect degree of analgesia and MUA increases in a parallel fashion. Male, Sprague-Dawley, albino rats were implanted chronically with 3 twisted bipolar (175 # diameter) stainless steel electrodes insulated except at the tip. Two electrodes were aimed for the PAG and one for the lateral hypothalamic area. Ten days after surgery, recording and behavioral testing began. Animals were restrained in Plexiglas tubes to allow determination of baseline MUA and responsiveness to noxious heat using the tail-flick method17, is. Baseline tail-flick latencies were noted at 5 min intervals. Fifteen minutes after the beginning of baseline determination, normal saline (0.5 ml, i.p.) was injected. Two tail-flick determinations were then made at 5 min intervals and 15 min later morphine sulfate (10 mg/kg, i.p.) was injected. Tail-flick latency was monitored every 5 min until complete analgesia (as defined by tail-flick latencies exceeding 8 sec) was observed or 50 min had elapsed. MUA was recorded continuously. After this first test day, animals were divided into 2 groups: group 1 (n ---- 5) received 5 additional injections of morphine (10 mg/kg, i.p.) at daily intervals and were tested each day as on day 1. Although complete tolerance to morphine's analgesic effect had not developed by day 6, animals became agitated and made gnawing movements which tended to interfere with MUA recording. For this reason, morphine administration was discontinued. Group 2 (n = 4) also received 5 additional morphine injections, but in this case the drug was administered in the animal's home cage on days 2-5, and no tests were conducted. On day 6, group 2 animals were administered morphine in the test apparatus and analgesia and MUA were measured as on day 1. On the seventh and final test day, all animals were injected with a control solution of physiological saline (0.5 ml) and tail-flick latencies and MUA recordings were taken as before. Tail-flick latencies and MUA levels were virtually identical to baseline values after saline administration. At the end of the experiment, animals were administered an overdose of Nembutal and MUA was validated at each electrode site. Routine histology was performed to locate electrode positions. The magnitude of morphine's analgesic effect was assessed by computing degree of analgesia (DA) scores 1. DA scores were computed from tail-flick trials performed 15, 30 and 45 min after morphine administration. Median MUA changes compared to baseline were assessed from 5 min recording samples begun 12.5, 27.5 and 42.5 min after morphine injection. Thirteen of the electrodes aimed at PAG and eight of those aimed at the lateral hypothalamus yielded valid MUA. Of the 13, 11 sites found histologically to fall within the PAG showed increased MUA following morphine on day 1. Two sites just outside PAG showed pronounced decreases. In both cases, accurate PAG placements in these same animals manifested MUA increases. The remaining 8 electrodes were all found to lie within the lateral hypothalamic area. Seven of these eight sites showed increased MUA after morphine and one showed no MUA change. In group 1 animals, a gradual reduction in morphine analgesia occurred over the last 4 days of morphine administration (Fig. 1). A significant reduction (Sign test, P <
204 I00
<= 8o [ ] Group I I ~ Group 2
~ 6o
g
.
40
8
i
20
o 0~ Ioo
N 8c Z
,~ 60
la_ o w
,,~ 40 w t21 Z
2O
w
0 2
3
4 DAYS
5
t 6
I
6
Fig. 1. Median degree of analgesia scores and median MUA increases in PAG on days of morphine administration (10 mg/kg) in group 1 and group 2 animals. MUA and analgesia scores are presented for 3 time periods (15, 30 and 45 min following morphine) on each day of testing. Statistical comparisons within each group were made with reference to the corresponding time period on day 1. (*) P < 0.05. 0.05) first appeared in the test period coming 15 min after morphine injection and on subsequent days was also seen in the 30, then 45 min post-morphine tests, indicating a progressive retardation of latency to peak analgesia as well as a reduction in analgesia magnitude (Fig. 1). Tolerance also developed to morphine's excitatory effect on PAG M U A (Fig. 1) although the precise pattern of its development differed somewhat from that seen for the behavioral measure. More careful scrutiny of individual subject data at specific time periods following morphine shows that the correlation between onset latencies to analgesia and to M U A increase seen on day 1 (Spearman rho -- 0.78) disappeared with repeated injections of morphine. Although whenever significant analgesia was evident prominent M U A increases were also seen, nonetheless, variations in analgesia latency were often not accompanied by corresponding M U A latency variations. It appears, therefore, that with the development of tolerance, the temporal correlation between P A G multiple unit increase and behavioral analgesia becomes uncoupled. G r o u p 2 animals also manifested a substantial decrease in analgesia between days 1 and 6 (Fig. 1), although the small number of subjects in this group (n = 4)
205 prohibited statistical evaluation of this change. On the other hand, group 2 animals showed significantly more analgesia (less tolerance) than group 1 animals at each of the 3 test periods on day 6 (Mann-Whitney U-test, P < 0.05), a finding similar to those of earlier studies investigating the effects of environmental cues on the development of tolerance 5,8,1~. Similarly, group 2 rats showed no agitation or gnawing movements on day 6, although such behaviors were routinely seen in group 1 animals. The magnitude of the MUA increases at PAG sites also diminished from day 1 to day 6 in group 2 rats (Fig. 1). However, because there were no significant differences between group 1 and group 2 animals in the day 6 MUA results, no effect of situational cues on P A G M U A can be claimed. The fact that group 2 rats developed significantly less tolerance than group 1 animals to morphine's behavioral effect, but not to its effect on MUA, indicates once again that some degree of uncoupling can occur between PAG M U A and analgesia. Hypothalamic M U A appeared completely unrelated to degree of analgesia after day 1. For example, although various levels of analgesia were achieved by different animals on day 6, on that day none of the 7 hypothalamic sites showing M U A increases to morphine on day 1 showed any increase in MUA. Repeated injections of morphine in the same test environment resulted in tolerance to morphine's analgesic action. The magnitude of the accompanying MUA increase in PAG was also reduced over this same time period. A significant morphineinduced increase in PAG MUA was observed only when analgesia was also seen. In contrast, M U A increases in the lateral hypothalamus showed complete tolerance to morphine's action at a time when partial analgesia was still present. These data support previous findingsla, 17-19 suggesting that increases in PAG MUA reflect, at least in part, morphine's analgesic action. However, two additional findings in this study suggest that an uncoupling occurs during tolerance development between morphine's analgesic action and its effect on PAG M U A : (1) the clear correlation obtained in naive animals between onset latencies to analgesia and MUA increases after morphine administration was partially disrupted by continued morphine injections; (2) a similar disruption occurred in group 2 animals, those given morphine on days 2-5 in an environment different from the test apparatus. They manifested significantly less tolerance to morphine's analgesic action than did group 1 animals, yet M U A increases to morphine on the final test day did not differ between these groups. Two explanations may be suggested for this uncoupling between PAG activity and the behavioral index of analgesia. The first is that brain areas other than PAG may more sensitively index morphine analgesia or that they come to do so with repeated opiate administration. The second relies on the assumption that behavioral manifestations of tolerance to morphine's analgesic action depend upon environmental determinants in addition to drug action per se. The present finding that a novel test environment caused a decrease in the manifestation of tolerance to morphine's analgesic action is, in fact, consistent with several earlier reportsS,S, 18. However, Bardo and Hughes 2 and Sherman et al. 15 have reported that a novel test environment also increases morphine analgesia in drug-naive rats. Moreover, Bardo and Hughes find
206 that novelty alone can induce analgesia in drug-free animals, a n effect which was n o t reversed by naloxone a n d hence appears unrelated to e n d o g e n o u s opioid mechanisms 2. This p h e n o m e n o n would appear to be an example of stress-induced analgesia which, at least u n d e r certain test conditions, is also unaffected by naloxone 6. We suggest that the a p p a r e n t lack o f analgesic tolerance in group 2 rats in our study reflects the occurrence of novelty-induced analgesia. The fact that P A G M U A fails to manifest this novelty effect suggests, moreover, that this b r a i n area is not involved in mediating the opiate unrelated p h e n o m e n o n of novelty analgesia. This interpretation is consistent with a recent finding from our l a b o r a t o r y that even very large P A G lesions in the rat do n o t reduce stress analgesia in this species (J. T. C a n n o n a n d S. M. R y a n , in preparation). The authors wish to express their appreciation to Dr. J. E. S h e r m a n for his helpful c o m m e n t s in preparing this manuscript. This research was supported by N I H G r a n t NS07628.
1 Akil, H. and Liebeskind, J. C., Monoaminergic mechanisms of stimulation-produced analgesia, Brain Research, 94 (1975) 279-296. 2 Bardo, M. T. and Hughes, R. T., Exposure to a nonfunctional hot plate as a factor in the assessment of morphine-induced analgesia and analgesic tolerance in rats, Pharmacol., Biochem., Behav. 10 (1979) 481-485. 3 Cannon, J. T., Liebeskind, J. C. and Frenk, H., Neural and neurochemical mechanisms of pain inhibition. In R. A. Sternbach (Ed.), The Psychology of Pain, Raven Press, New York, 1978, pp. 27-47. 4 Fields, H. L. and Basbaum, A. I., Brainstem control of spinal pain-transmission neurons, Ann. Rev. Physiol., 40 (1978) 217-248. 5 Gebhart, G. F. and Mitchell, C. L., Further studies on the development of tolerance to the analgesic effect of morphine: the role played by the cylinder in the hot plate testing procedure, Arch. int. Pharmacodyn., 191 (1971) 96-103. 6 Hayes, R. L., Bennett, G. J., Newlon, P. G. and Mayer, D. J., Behavioral and physiological studies of non-narcotic analgesia in the rat elicited by certain environmental stimuli, Brain Research, 155 (1978) 69-90. 7 Jaffe, J. H., Narcotic analgesics. In L. S. Goodman and A. Gilman (Eds.), The Pharmacological Basis of Therapeutics, MacMillan, London, 1970, pp. 237 275. 8 Kayan, S., Woods, L. A. and Mitchell, C. L., Experience as a factor in the development of tolerance to the analgesic effect of morphine, Europ. J. Pharmaeol., 6 (1969) 333-339. 9 Liebeskind, J. C., Giesler, G. J., Jr. and Urca, G., Evidence pertaining to an endogenous mechanism of pain inhibition in the central nervous system. In Y. Zotterman (Ed.), Sensory Functions of the Skin in Primates, Pergamon Press, Oxford, 1976, pp. 561-573. 10 Mayer, D. J. and Hayes, R. L., Stimulation-produced analgesia: development of tolerance and cross-tolerance to morphine, Science, 188 (1975) 941-943. 11 Mayer, D. J. and Price, D. D., Central nervous system mechanisms of analgesia, Pain, 2 (1976) 379-404. 12 Mayer, D. J., Wolfle, T. L., Akil, H., Carder, B. and Liebeskind, J. C., Analgesia from electrical stimulation of the brainstem of the rat, Science, 174 (1971) 1351-1354. 13 Oleson, T. D., Twombly, D. A. and Liebeskind, J. C., Effects of pain-attenuating brain stimulation and morphine on electrical activity in the raphe nuclei of the awake rat, Pain, 4 (1978) 211-230. 14 Reynolds, D. V., Surgery in the rat during electrical analgesia induced by focal brain stimulation, Science, 164 (1969) 444-445. 15 Sherman, J. E., Lewis, J. and Liebeskind, J. C., Differential effects of extinction on conditioned hyperthermia and analgesic tolerance to morphine, Proc. West. Pharmacol. Soe., in press.
207 16 Siegel, S., Morphine analgesic tolerance: its situation specificity supports a Pavlovian conditioning model, Science, 193 (1976) 323-325. 17 Urca, G., Frenk, H., Liebeskind, J. C. and Taylor, A. N., Morphine and enkephalin: analgesic and epileptic properties, Science, 197 (1977) 83-86. 18 Urca, G. and Liebeskind, J. C., Electrophysiological indices of opiate action in awake and anesthetized rats, Brain Research, 161 (1979) 162-166. 19 Urca, G. and Nahin, R. L., Morphine-induced multiple unit changes in analgesic and rewarding brain sites, Pain Abstr., 1 (1978) 261. 20 Yaksh, T. L. and Rudy, T. A., Narcotic analgetics : CNS sites and mechanisms of action as revealed by intracerebral injection techniques, Pain, 4 (1978) 299-359.
Brain Research, 176 (1979) 202-207 © Elsevier/North-Holland Biomedical Press
Development of tolerance to the effects of morphine: association between analgesia and electrical activity in the periaqueductal gray matter
GIDEON URCA, RICHARD L. NAHIN and JOHN C. LIEBESKIND Department of Physiology and Pharmacology, Tel A viv University School of Medicine, Ramat A viv (Israel) and Department of Psychology, University of CaliJbrnia, Los Angeles, Calif. 90024 (U.S.A.)
(Accepted June 28th, 1979)
The existence of a medial brain stem endogenous analgesia substrate employing opioids as neurotransmitters or neuromodulators has gained substantial support from various lines of research 3,4,11,2°. The analgesic action of opiate drugs probably stems from their ability to bind with endogenous opioid receptors in these brain areas. The periaqueductal gray matter (PAG) within the medial brain stem has been implicated as one major site of opiate analgesic action 9,11,2°. Both electrical stimulation of the PAG and microinjections of opiates into this structure produce profound analgesia quite similar to that elicited by systemic injections of opiates3,9,~l,lZ, ~4,2°. It has been suggested that activation of this analgesia substrate leads to the reinforcement of descending controls serving to block pain transmission through nociceptive neurons in the spinal c0rd3,4,9,11-13, 20. Direct evidence for the activating effect of opiates on PAG neurons has been provided by studies showing that intraperitoneal injections of analgesic doses of morphine13,17-1~ or intracerebroventricular injections of morphine or enkephalin 17 produce significant increases of multiple unit activity (MUA) in the PAG which are well-correlated temporally with analgesia. Furthermore, only when analgesia is seen, is a concomitant MUA increase observed 17. If indeed the morphine-induced increase in PAG multiple unit activity seen in previous studies~Z, 17--~9reflects the active role played by this brain area in mechanisms of analgesia, then factors influencing the degree of analgesia should alter the MUA effect correspondingly. The development of tolerance to morphine's analgesic action is a well-documented phenomenon 7. In fact, the analgesic effect of electrically stimulating PAG shows both tolerance and cross-tolerance to morphine analgesia ~0. It has been shown that the development of tolerance to morphine can be attenuated if animals are tested in an environment different from that in which the drug is habitually administered 5,8,16. We therefore sought to determine if the development of tolerance to morphine would be reflected in a parallel tolerance to its MUA-increasing effect in the PAG. In addition, we investigated the question of whether the use of different
203 environmental cues associated with drug administration would affect degree of analgesia and MUA increases in a parallel fashion. Male, Sprague-Dawley, albino rats were implanted chronically with 3 twisted bipolar (175 # diameter) stainless steel electrodes insulated except at the tip. Two electrodes were aimed for the PAG and one for the lateral hypothalamic area. Ten days after surgery, recording and behavioral testing began. Animals were restrained in Plexiglas tubes to allow determination of baseline MUA and responsiveness to noxious heat using the tail-flick method17, is. Baseline tail-flick latencies were noted at 5 min intervals. Fifteen minutes after the beginning of baseline determination, normal saline (0.5 ml, i.p.) was injected. Two tail-flick determinations were then made at 5 min intervals and 15 min later morphine sulfate (10 mg/kg, i.p.) was injected. Tail-flick latency was monitored every 5 min until complete analgesia (as defined by tail-flick latencies exceeding 8 sec) was observed or 50 min had elapsed. MUA was recorded continuously. After this first test day, animals were divided into 2 groups: group 1 (n ---- 5) received 5 additional injections of morphine (10 mg/kg, i.p.) at daily intervals and were tested each day as on day 1. Although complete tolerance to morphine's analgesic effect had not developed by day 6, animals became agitated and made gnawing movements which tended to interfere with MUA recording. For this reason, morphine administration was discontinued. Group 2 (n = 4) also received 5 additional morphine injections, but in this case the drug was administered in the animal's home cage on days 2-5, and no tests were conducted. On day 6, group 2 animals were administered morphine in the test apparatus and analgesia and MUA were measured as on day 1. On the seventh and final test day, all animals were injected with a control solution of physiological saline (0.5 ml) and tail-flick latencies and MUA recordings were taken as before. Tail-flick latencies and MUA levels were virtually identical to baseline values after saline administration. At the end of the experiment, animals were administered an overdose of Nembutal and MUA was validated at each electrode site. Routine histology was performed to locate electrode positions. The magnitude of morphine's analgesic effect was assessed by computing degree of analgesia (DA) scores 1. DA scores were computed from tail-flick trials performed 15, 30 and 45 min after morphine administration. Median MUA changes compared to baseline were assessed from 5 min recording samples begun 12.5, 27.5 and 42.5 min after morphine injection. Thirteen of the electrodes aimed at PAG and eight of those aimed at the lateral hypothalamus yielded valid MUA. Of the 13, 11 sites found histologically to fall within the PAG showed increased MUA following morphine on day 1. Two sites just outside PAG showed pronounced decreases. In both cases, accurate PAG placements in these same animals manifested MUA increases. The remaining 8 electrodes were all found to lie within the lateral hypothalamic area. Seven of these eight sites showed increased MUA after morphine and one showed no MUA change. In group 1 animals, a gradual reduction in morphine analgesia occurred over the last 4 days of morphine administration (Fig. 1). A significant reduction (Sign test, P <
204 I00
<= 8o [ ] Group I I ~ Group 2
~ 6o
g
.
40
8
i
20
o 0~ Ioo
N 8c Z
,~ 60
la_ o w
,,~ 40 w t21 Z
2O
w
0 2
3
4 DAYS
5
t 6
I
6
Fig. 1. Median degree of analgesia scores and median MUA increases in PAG on days of morphine administration (10 mg/kg) in group 1 and group 2 animals. MUA and analgesia scores are presented for 3 time periods (15, 30 and 45 min following morphine) on each day of testing. Statistical comparisons within each group were made with reference to the corresponding time period on day 1. (*) P < 0.05. 0.05) first appeared in the test period coming 15 min after morphine injection and on subsequent days was also seen in the 30, then 45 min post-morphine tests, indicating a progressive retardation of latency to peak analgesia as well as a reduction in analgesia magnitude (Fig. 1). Tolerance also developed to morphine's excitatory effect on PAG M U A (Fig. 1) although the precise pattern of its development differed somewhat from that seen for the behavioral measure. More careful scrutiny of individual subject data at specific time periods following morphine shows that the correlation between onset latencies to analgesia and to M U A increase seen on day 1 (Spearman rho -- 0.78) disappeared with repeated injections of morphine. Although whenever significant analgesia was evident prominent M U A increases were also seen, nonetheless, variations in analgesia latency were often not accompanied by corresponding M U A latency variations. It appears, therefore, that with the development of tolerance, the temporal correlation between P A G multiple unit increase and behavioral analgesia becomes uncoupled. G r o u p 2 animals also manifested a substantial decrease in analgesia between days 1 and 6 (Fig. 1), although the small number of subjects in this group (n = 4)
205 prohibited statistical evaluation of this change. On the other hand, group 2 animals showed significantly more analgesia (less tolerance) than group 1 animals at each of the 3 test periods on day 6 (Mann-Whitney U-test, P < 0.05), a finding similar to those of earlier studies investigating the effects of environmental cues on the development of tolerance 5,8,1~. Similarly, group 2 rats showed no agitation or gnawing movements on day 6, although such behaviors were routinely seen in group 1 animals. The magnitude of the MUA increases at PAG sites also diminished from day 1 to day 6 in group 2 rats (Fig. 1). However, because there were no significant differences between group 1 and group 2 animals in the day 6 MUA results, no effect of situational cues on P A G M U A can be claimed. The fact that group 2 rats developed significantly less tolerance than group 1 animals to morphine's behavioral effect, but not to its effect on MUA, indicates once again that some degree of uncoupling can occur between PAG M U A and analgesia. Hypothalamic M U A appeared completely unrelated to degree of analgesia after day 1. For example, although various levels of analgesia were achieved by different animals on day 6, on that day none of the 7 hypothalamic sites showing M U A increases to morphine on day 1 showed any increase in MUA. Repeated injections of morphine in the same test environment resulted in tolerance to morphine's analgesic action. The magnitude of the accompanying MUA increase in PAG was also reduced over this same time period. A significant morphineinduced increase in PAG MUA was observed only when analgesia was also seen. In contrast, M U A increases in the lateral hypothalamus showed complete tolerance to morphine's action at a time when partial analgesia was still present. These data support previous findingsla, 17-19 suggesting that increases in PAG MUA reflect, at least in part, morphine's analgesic action. However, two additional findings in this study suggest that an uncoupling occurs during tolerance development between morphine's analgesic action and its effect on PAG M U A : (1) the clear correlation obtained in naive animals between onset latencies to analgesia and MUA increases after morphine administration was partially disrupted by continued morphine injections; (2) a similar disruption occurred in group 2 animals, those given morphine on days 2-5 in an environment different from the test apparatus. They manifested significantly less tolerance to morphine's analgesic action than did group 1 animals, yet M U A increases to morphine on the final test day did not differ between these groups. Two explanations may be suggested for this uncoupling between PAG activity and the behavioral index of analgesia. The first is that brain areas other than PAG may more sensitively index morphine analgesia or that they come to do so with repeated opiate administration. The second relies on the assumption that behavioral manifestations of tolerance to morphine's analgesic action depend upon environmental determinants in addition to drug action per se. The present finding that a novel test environment caused a decrease in the manifestation of tolerance to morphine's analgesic action is, in fact, consistent with several earlier reportsS,S, 18. However, Bardo and Hughes 2 and Sherman et al. 15 have reported that a novel test environment also increases morphine analgesia in drug-naive rats. Moreover, Bardo and Hughes find
206 that novelty alone can induce analgesia in drug-free animals, a n effect which was n o t reversed by naloxone a n d hence appears unrelated to e n d o g e n o u s opioid mechanisms 2. This p h e n o m e n o n would appear to be an example of stress-induced analgesia which, at least u n d e r certain test conditions, is also unaffected by naloxone 6. We suggest that the a p p a r e n t lack o f analgesic tolerance in group 2 rats in our study reflects the occurrence of novelty-induced analgesia. The fact that P A G M U A fails to manifest this novelty effect suggests, moreover, that this b r a i n area is not involved in mediating the opiate unrelated p h e n o m e n o n of novelty analgesia. This interpretation is consistent with a recent finding from our l a b o r a t o r y that even very large P A G lesions in the rat do n o t reduce stress analgesia in this species (J. T. C a n n o n a n d S. M. R y a n , in preparation). The authors wish to express their appreciation to Dr. J. E. S h e r m a n for his helpful c o m m e n t s in preparing this manuscript. This research was supported by N I H G r a n t NS07628.
1 Akil, H. and Liebeskind, J. C., Monoaminergic mechanisms of stimulation-produced analgesia, Brain Research, 94 (1975) 279-296. 2 Bardo, M. T. and Hughes, R. T., Exposure to a nonfunctional hot plate as a factor in the assessment of morphine-induced analgesia and analgesic tolerance in rats, Pharmacol., Biochem., Behav. 10 (1979) 481-485. 3 Cannon, J. T., Liebeskind, J. C. and Frenk, H., Neural and neurochemical mechanisms of pain inhibition. In R. A. Sternbach (Ed.), The Psychology of Pain, Raven Press, New York, 1978, pp. 27-47. 4 Fields, H. L. and Basbaum, A. I., Brainstem control of spinal pain-transmission neurons, Ann. Rev. Physiol., 40 (1978) 217-248. 5 Gebhart, G. F. and Mitchell, C. L., Further studies on the development of tolerance to the analgesic effect of morphine: the role played by the cylinder in the hot plate testing procedure, Arch. int. Pharmacodyn., 191 (1971) 96-103. 6 Hayes, R. L., Bennett, G. J., Newlon, P. G. and Mayer, D. J., Behavioral and physiological studies of non-narcotic analgesia in the rat elicited by certain environmental stimuli, Brain Research, 155 (1978) 69-90. 7 Jaffe, J. H., Narcotic analgesics. In L. S. Goodman and A. Gilman (Eds.), The Pharmacological Basis of Therapeutics, MacMillan, London, 1970, pp. 237 275. 8 Kayan, S., Woods, L. A. and Mitchell, C. L., Experience as a factor in the development of tolerance to the analgesic effect of morphine, Europ. J. Pharmaeol., 6 (1969) 333-339. 9 Liebeskind, J. C., Giesler, G. J., Jr. and Urca, G., Evidence pertaining to an endogenous mechanism of pain inhibition in the central nervous system. In Y. Zotterman (Ed.), Sensory Functions of the Skin in Primates, Pergamon Press, Oxford, 1976, pp. 561-573. 10 Mayer, D. J. and Hayes, R. L., Stimulation-produced analgesia: development of tolerance and cross-tolerance to morphine, Science, 188 (1975) 941-943. 11 Mayer, D. J. and Price, D. D., Central nervous system mechanisms of analgesia, Pain, 2 (1976) 379-404. 12 Mayer, D. J., Wolfle, T. L., Akil, H., Carder, B. and Liebeskind, J. C., Analgesia from electrical stimulation of the brainstem of the rat, Science, 174 (1971) 1351-1354. 13 Oleson, T. D., Twombly, D. A. and Liebeskind, J. C., Effects of pain-attenuating brain stimulation and morphine on electrical activity in the raphe nuclei of the awake rat, Pain, 4 (1978) 211-230. 14 Reynolds, D. V., Surgery in the rat during electrical analgesia induced by focal brain stimulation, Science, 164 (1969) 444-445. 15 Sherman, J. E., Lewis, J. and Liebeskind, J. C., Differential effects of extinction on conditioned hyperthermia and analgesic tolerance to morphine, Proc. West. Pharmacol. Soe., in press.
207 16 Siegel, S., Morphine analgesic tolerance: its situation specificity supports a Pavlovian conditioning model, Science, 193 (1976) 323-325. 17 Urca, G., Frenk, H., Liebeskind, J. C. and Taylor, A. N., Morphine and enkephalin: analgesic and epileptic properties, Science, 197 (1977) 83-86. 18 Urca, G. and Liebeskind, J. C., Electrophysiological indices of opiate action in awake and anesthetized rats, Brain Research, 161 (1979) 162-166. 19 Urca, G. and Nahin, R. L., Morphine-induced multiple unit changes in analgesic and rewarding brain sites, Pain Abstr., 1 (1978) 261. 20 Yaksh, T. L. and Rudy, T. A., Narcotic analgetics : CNS sites and mechanisms of action as revealed by intracerebral injection techniques, Pain, 4 (1978) 299-359.