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Effect of morphine on aversive subthalamic stimulation in the cat
EXPERIMENTAL
78, 1-6 (1982)
NEUROLOGY
Effect of Morphine on Aversive Subthalamic Stimulation in the Cat G. F. GEBHART Departments
of Pharmacology Received
October
AND W. W. KAELBER’
and Anatomy, 9, 1981:
University revision
of Iowa,
received
May
Iowa
City,
Iowa
52242
19, 1982
The effect of morphine on the threshold and latency to escape aversive focal electrical stimulation in the subthalamus and pulvinar was evaluated in 16 cats. After training to escape aversive intracranial stimulation by crossing a low barrier in a shuttle box, the effect of morphine (1.5 mg/kg) was compared with that of chlorpromazine (3.0 mg/kg). We found that morphine significantly increased both the threshold and latency to escape stimulation in the subthalamus and pulvinar. The effects of morphine were observed in only one-half of the cats, however, although there were no apparent differences in the electrode placements of cats affected and not affected by morphine. Further, the effects of chlorpromazine were qualitatively similar to those of morphine and, moreover, generally occurred in the cats also affected by morphine. The results are interpreted as examples of nonantinociceptive drug actions against aversive intracranial stimulation.
INTRODUCTION It has been previously demonstrated that cats will learn to escape (6, 8) and avoid (7) aversive focal electrical stimulation in the subthalamic H or Hz fields or Forel. In rats, intracranial stimulation at selected loci has also been reported to be aversive and the effect of morphine on the behavior induced by the intracranial stimulation has been investigated (9, 12- 16). Rosenfeld (14-16) reported a differential effect of morphine on central as opposed to peripheral nociception; morphine is antinociceptive against noxious peripheral stimuli (e.g., hot plate, tail flick, grid shock) but not against aversive intracranial stimulation (e.g., bulbar brain stem, medial thalamus). Others (9, 13), however, reported that morphine is antinociceptive against intracranial stimulation. The dose of morphine in those ’ Please send correspondence to Dr. Kaelber, Department of Anatomy, University of Iowa, Iowa City, IO 52242.
0014-4886/82/100001-06$02.00/0 Copyright 0 1982 by Academic Press, Inc. All rights of reproduction in any form reserved.
2
GEBHART
AND KAELBER
studies was relatively large and it was concluded (9) that the effect of morphine on aversive intracranial stimulation at sites associated with both the neo- and paleospinothalamic systems could have resulted from nonspecific sedative effects. In this communication, the effect of morphine on escape from aversive subthalamic and pulvinar stimulation in the cat was examined and compared with the effect of chlorpromazine. Chlorpromazine has been demonstrated to elevate significantly the threshold of escape to noxious tooth pulp (11, 12) and radial nerve (5) stimulation in the cat and was included in this study as a nonopiate, centrally acting agent. METHODS Bipolar stimulating electrodes (Rhodes Medical Instruments, NE 200) aimed at either the H2 or H fields of Forel, adjacent zona incerta, or the pulvinar were implanted in anesthetized (pentobarbital sodium or Ketamine-HCl), adult cats using standard stereotaxic procedures (6, 7). After 2 weeks and accomodation to the experimental conditions, the cats were trained to escape intracranial stimulation by crossing a lo-cm high barrier in a sound attenuated, illuminated shuttle box ( 120 X 60 X 60 cm). Constant current intracranial stimulation consisted of lOO-Hz biphasic pulse pairs of 0.1 ms/pulse (6, 7). Intracranial stimulation was initiated at 0.25 mA and incremented in 0.25-mA steps every 60 s until the cat crossed the barrier (escaped). After escape from intracranial stimulation, the next level of stimulation was reduced by 0.25 mA following a variable intertrial interval (30 to 120 s). In this fashion, each cat determined its own escape threshold [e.g., see (5)]; 10 trials/day were given and the intracranial stimulation intensity was adjusted (0.25 to 5.0 mA) to produce escape behavior to criteria ( 10 crosses in 10 trials at a latency SlO s for 5 consecutive days). After attainment of stable escape performance, the effects of morphine (1.5 mg/kg as base) and chlorpromazine (3.0 mg/kg as base) on the threshold and latency to escape intracranial stimulation were examined. The effects of the drugs were evaluated 30 and 45 mitt, respectively, after subcutaneous administration. The doses selected were based on previous experience in this laboratory [(5, 11, 72); see also (lo)]. In the cat, 1.5 mg/ kg morphine is antinociceptive yet not overtly excitatory. At the conclusion of the study, anodal electrolytic lesions were produced at the tips of the electrodes for subsequent histological evaluation of electrode placement (6, 7). RESULTS Data were collected from 10 cats with electrode placements subsequently verified to be in the H or H2 fields of Fore1 or adjacent subthalamus, and
MORPHINE
AND
SUBTHALAMIC
3
NOCICEPTION
from six cats with electrodes in or adjacent to the pulvinar (Table 1, Fig. 1). Morphine increased the threshold to escape subthalamic stimulation a mean 153% in six of the 10 cats studied; four cats were unaffected. Morphine also increased the threshold to escape stimulation in the pulvinar region (mean 215%). but in only three of the six cats studied. Chlorpromazine similarly increased the threshold to escape subthalamic stimulation (mean 85%) in five of the same six cats affected by morphine and in two of the same three cats in which morphine affected stimulation in the pulvinar area. TABLE Effects
of Morphine (MOR) Subthalamic
Cat
Electrode placement’
ST 13 ST 14 ST 16 ST 17 ST 20 ST 22 ST 24 ST 25 ST 29 ST 30 PUL 3 PUL7 PUL 8 PUL 10 PUL 11 PUL 12
H-SN junction H-TH ZIG HZ-Z1 junction H2-ZI junction LH-SbN-H2 junction HZ-LH junction HZ-LH H2-H 1 junction H2-ZI-H 1 junction Ventromedial Pm sg PI-Pi junction CTT Dorsomedial Pm Pm-Pi-Sg junction
1
and Chlorpromazine (CPZ) on Escape (ST) and Pulvinar (PUL) Stimulation Escape threshold
(mA) 0.50 0.25 0.50 1.0 1.25 1.75 0.50 1.0 1.50 0.25 0.50 0.25 0.75 2.0 5.0 0.75
Induced
MORb Threshold, 150% T, No A, 100% t, 250% T, 20% T, 100% T, 300% T, No A, No A, No A, No A, 300% T, 300% t, No A, 45% T, No A,
by
CPZb Latency No A 25% 1 75% T No x No A 100% T 75% 1 No A 50% T No A No A No x No x No A No X 175% T
Threshold,
Latency
150% T, No A, 50% T, 25% T, No A, 100% T, 100% T, No A, No A, No A, No A, 300% T,
25% 1 No A No A No A 20% T 150% T 50% 1 No A No A No A No A No x
Nob: 50% T, No A,
No A No X 175% T
u Abbreviations: CTT-central tegmental tract; H-H field of Fore1 (prerubral); H 1 -HI field of Fore1 (thalamic fasciculus); H2-H2 field of Fore1 (lenticular fasciculus); LH-lateral hypothalamus; PUL-pulvinar; Pi-inferior pulvinar nucleus; PI-lateral pulvinar nucleus; Pm-medial pulvinar nucleus; SbN-subthalamic nucleus; Sg-suprageniculate nucleus; TH-tegmentohypothalamic tract; ZI-zona incerta; and ZIc-zona incerta caudalis. ST placements are too widespread to be presented in a single figure; see (6, 7) for detailed histologic examples. Pul placements are portrayed in Fig. 1. b Effects of MOR (1.5 mg/kg as base) and CPZ (3.0 mg/kg as base) on the threshold and latency to escape intracranial stimulation are reported as percent increase (t) or decrease (I) from control. The percent changes were determined by comparing each cat’s control threshold and latency with that following drug administration. In those cases where MOR or CPZ had an effect, there were rarely residual effects on escape threshold and latency, which returned to control values within 1 or 2 days after drug treatment. No A and No X indicate no change and no barrier crosses, respectively; CPZ’s effect in PUL 8 was not evaluated.
GEBHART
AND KAELBER
FIG. 1. Composite drawing of dorsal thalamus and rostra1 mesencephalon indicating stimulation sites in the pulvinar complex (v). Abbreviations: CG-central gray; CTT-central tegmental tract, D-nucleus of Darkschewitsch; Gl-lateral geniculate nucleus; Glv-lateral geniculate nucleus, pars ventralis; Gm-medial geniculate nucleus; Gmm-medial’geniculate nucleus, pars magnocellularis; Li-nucleus limitans; NPC-nucleus of posterior commissure; PC-posterior commissure; Pi-inferior pulvinar nucleus; PI-lateral pulvinar nucleus; Pmmedial pulvinar nucleus; Prt-pretectal area; Rt-reticular nucleus; Sg-suprageniculate nucleus; To-optic tract; Vpm-nucleus ventralis posteromedialis.
The effects of these drugs on the latency to escape intracranial stimulation was likewise mixed. Morphine increased the latency to escape subthalamic stimulation in three and decreased it in two cats; one cat (ST 17) would not cross the barrier while under the influence of morphine and the stimulation was terminated as it became aversive. Chlorpromazine increased the latency to escape subthalamic stimulation in two cats and decreased it in two cats. Morphine exerted a significant influence on the latency to escape regional pulvinar stimulation; three of the four cats affected would not cross the barrier and stimulation was terminated as it became aversive. Chlorpromazine had a similar effect in three of the same cats (PUL 7, 11, and 12). DISCUSSION This laboratory previously established that intracranial stimulation in the rostra1 pontine tegmentum, the mesencephalic tegmentum, and subthalamus is aversive and cats will rapidly learn to escape by crossing a low barrier in a shuttle box (6-8). We also demonstrated that electrolytic lesions in the subthalamus or significant degeneration in the H2 field of Fore1 will block escape induced by subthalamic stimulation (6-8). That subthalamic stimulation and lesions are specific for nociception was established by the failure of lesions in the subthalamus to affect tone-signaled
MORPHINE
AND SUBTHALAMIC
NOCICEPTION
5
avoidance of subthalamic stimulation learned prior to introduction of the lesions (7). These data are consistent with other data [cf. ( 1,4)], including those acquired in man [cf. (2, 3)], that pathways other than the lateral (neo-) spinothalamic and ventral trigeminal tracts convey nociceptive information. The major projections of the alternative pathway(s) include the H2 field and zona incerta of the subthalamus, the intralaminar thalamic nuclei, and the pulvinar [cf. (6)]. This report confirms that stimulation in the subthalamus and pulvinar zone is aversive. The findings do not, however, provide evidence for an opiate-selective antinociception against aversive intracranial stimulation. Morphine was observed to increase significantly the threshold to escape stimulation in the subthalamus as well as pulvinar. The effect was not apparent in all cats, however; only approximately 50% of the cats exhibited this response to morphine. Histological examination of the placement of the intracranial stimulating electrodes revealed no differences among the cats affected by morphine and those which were not. Further, chlorpromazine produced a similar effect on escape thresholds and did so in the same cats affected by morphine. The effects of these two drugs on the latency to escape intracranial stimulation were mixed, but morphine and chlorpromazine generally produced effects in the same direction and in the same cats. The data suggest that the drug effects represent nonantinociceptive actions against aversive intracranial stimulation. The results are generally supportive of those reported by Rosenfeld ( 1416) regarding the effects of morphine on aversive intracranial simulation in the rat. He reported that although morphine was reliably antinociceptive against peripherally induced nociception, it was without influence on intracranial stimulation in loci of the neospinothalamic, paleospinothalamic, or spinoreticular afferent nociceptive input. As in the cat (7) Rosenfeld also confirmed his results with an avoidance paradigm (16). He also established that the lack of morphine’s effect was not related to the frequency of intracranial stimulation (16), thus addressing a similar concern regarding the data reported herein. Kiser and German (9) stimulated in regions of the rat brain receiving afferent input from neo- and paleospinothalmic systems and observed that morphine significantly reduced bar pressing to escape aversive intracranial stimulation at all loci. However, inasmuch as morphine failed to selectively influence aversive intracranial stimuli in regions receiving paleospinothalmic afferent fibers and was also administered in a relatively high dose (15 mg/kg), they concluded that the effect of morphine was likely due to nonspecific cataleptic or sedative effects. The inclusion of chlorpromazine in our study and the similarity of its effects to morphine support their conclusion of nonspecific drug effects. In summary, our study failed to demonstrate an opiate-selective antinociceptive effect against aversive intracranial stimulation in the cat.
6
GEBHART
AND
KAELBER
Rather, the effects of morphine were observed to be similar to those of chlorpromazine on both the threshold and latency to escape. Moreover, morphine’s effects were apparent in only some subjects despite similar placements of stimulating electrodes. On the basis of his data, Rosenfeld (14) suggested that opiates exert their antinociceptive action primarily by influencing descending systems or by a direct action at or distal to the primary afferent terminal. These data, taken together with the antinociception produced by morphine in a similar paradigm using noxious radial nerve stimulation (5), are consistent with previous reports (14-16). REFERENCES 1. ANDERSON, F. D., AND C. M. BERRY. 1959. Degeneration studies of long ascending fiber systems in the cat brainstem. J. Camp. Neural. 111: 195-230. 2. CASSINARI, V., AND C. A. PAGNI. 1969. Central Pain: A Neurosurgical Survey. Harvard Univ. Press, Cambridge, Mass. 3. COOPER, I. S., M. RILAN, ANDP. RAKIC, Eds. 1974. The Pulvinar-LP Complex. Thomas, Springfield, Ill. 4. GEBHART, G. 1982. Opiate and opioid peptide effects on brainstem neurons: relevance to nociception and antinociceptive mechanisms. Pain 12: 93-140. 5. GEBHART, G. F., AND J. R. TOLEIKIS. 1978. An examination of stimulation-produced analgesia in the cat. Exp. Neural. 62: 570-579. 6. KAELBER, W. W. 1977. Subthalamic nociceptive stimulation in the cat: effect of secondary lesions and rostra1 fiber projections. Exp. Neurol. 56: 574-597. 7. KAELBER, W. W. 1981. Escape from and avoidance of nociception elicited by intracranial stimulation of the cat subthalamus. Exp. Neural. 73: 397-420. 8. KAELBER, W. W., AND C. L. MITCHELL. 1975. Alteration in escape responding in the cat: a lesion and degeneration comparison following stimulation studies. Brain Behav, Evol. 12: 137-150. 9. KISER, R. S., AND D. C. GERMAN. 1978. Opiate effects on aversive midbrain stimulation in rats. Neurosci. Lett. 10: 197-202. 10. MCKENZIE, J. S., AND N. R. BEECHEY. 1962. The effects of morphine and pethidine on somatic evoked responses in the midbrain of the cat, and their relevance to analgesia. Electroenceph. Clin. Neurophysiol. 14: 501-519. 11. MITCHELL, C. L. 1964. A comparison of drug effects upon the jaw jerk response to electrical stimulation of the tooth pulp in dogs and cats. J. Pharmacol. Exp. Ther. 146: l-6. 12.
13. 14.
15. 16.
MITCHELL, C. L. 1966. Effect of morphine and chlorpromazine alone and in combination on the reaction to noxious stimuli. Arch. Int. Pharmacodyn. 163: 387-392. PERT, A. 1975. Effects of opiates on electrical stimulation of the mesencephalon of the rat. Sot. Neurosci. Abstr. 1: 280. ROSENFELD, J. P., AND B. S. HOLZMAN. 1978. Effects of morphine on medial thalamic and medial bulboreticular aversive stimulation thresholds. Brain Res. 150: 436-440. ROSENFELD, J. P., AND R. KOWATCH. 1975. Differential effect of morphine on central versus peripheral nociception. Brain Res. 88: 181-185. ROSENFELD, J. P., AND J. L. VICKERY. 1976. Differential effect of morphine on trigeminal nucleus versus reticular aversive stimulation: independence of negative effects from stimulation parameters. Pain 2: 405-5 16.
78, 1-6 (1982)
NEUROLOGY
Effect of Morphine on Aversive Subthalamic Stimulation in the Cat G. F. GEBHART Departments
of Pharmacology Received
October
AND W. W. KAELBER’
and Anatomy, 9, 1981:
University revision
of Iowa,
received
May
Iowa
City,
Iowa
52242
19, 1982
The effect of morphine on the threshold and latency to escape aversive focal electrical stimulation in the subthalamus and pulvinar was evaluated in 16 cats. After training to escape aversive intracranial stimulation by crossing a low barrier in a shuttle box, the effect of morphine (1.5 mg/kg) was compared with that of chlorpromazine (3.0 mg/kg). We found that morphine significantly increased both the threshold and latency to escape stimulation in the subthalamus and pulvinar. The effects of morphine were observed in only one-half of the cats, however, although there were no apparent differences in the electrode placements of cats affected and not affected by morphine. Further, the effects of chlorpromazine were qualitatively similar to those of morphine and, moreover, generally occurred in the cats also affected by morphine. The results are interpreted as examples of nonantinociceptive drug actions against aversive intracranial stimulation.
INTRODUCTION It has been previously demonstrated that cats will learn to escape (6, 8) and avoid (7) aversive focal electrical stimulation in the subthalamic H or Hz fields or Forel. In rats, intracranial stimulation at selected loci has also been reported to be aversive and the effect of morphine on the behavior induced by the intracranial stimulation has been investigated (9, 12- 16). Rosenfeld (14-16) reported a differential effect of morphine on central as opposed to peripheral nociception; morphine is antinociceptive against noxious peripheral stimuli (e.g., hot plate, tail flick, grid shock) but not against aversive intracranial stimulation (e.g., bulbar brain stem, medial thalamus). Others (9, 13), however, reported that morphine is antinociceptive against intracranial stimulation. The dose of morphine in those ’ Please send correspondence to Dr. Kaelber, Department of Anatomy, University of Iowa, Iowa City, IO 52242.
0014-4886/82/100001-06$02.00/0 Copyright 0 1982 by Academic Press, Inc. All rights of reproduction in any form reserved.
2
GEBHART
AND KAELBER
studies was relatively large and it was concluded (9) that the effect of morphine on aversive intracranial stimulation at sites associated with both the neo- and paleospinothalamic systems could have resulted from nonspecific sedative effects. In this communication, the effect of morphine on escape from aversive subthalamic and pulvinar stimulation in the cat was examined and compared with the effect of chlorpromazine. Chlorpromazine has been demonstrated to elevate significantly the threshold of escape to noxious tooth pulp (11, 12) and radial nerve (5) stimulation in the cat and was included in this study as a nonopiate, centrally acting agent. METHODS Bipolar stimulating electrodes (Rhodes Medical Instruments, NE 200) aimed at either the H2 or H fields of Forel, adjacent zona incerta, or the pulvinar were implanted in anesthetized (pentobarbital sodium or Ketamine-HCl), adult cats using standard stereotaxic procedures (6, 7). After 2 weeks and accomodation to the experimental conditions, the cats were trained to escape intracranial stimulation by crossing a lo-cm high barrier in a sound attenuated, illuminated shuttle box ( 120 X 60 X 60 cm). Constant current intracranial stimulation consisted of lOO-Hz biphasic pulse pairs of 0.1 ms/pulse (6, 7). Intracranial stimulation was initiated at 0.25 mA and incremented in 0.25-mA steps every 60 s until the cat crossed the barrier (escaped). After escape from intracranial stimulation, the next level of stimulation was reduced by 0.25 mA following a variable intertrial interval (30 to 120 s). In this fashion, each cat determined its own escape threshold [e.g., see (5)]; 10 trials/day were given and the intracranial stimulation intensity was adjusted (0.25 to 5.0 mA) to produce escape behavior to criteria ( 10 crosses in 10 trials at a latency SlO s for 5 consecutive days). After attainment of stable escape performance, the effects of morphine (1.5 mg/kg as base) and chlorpromazine (3.0 mg/kg as base) on the threshold and latency to escape intracranial stimulation were examined. The effects of the drugs were evaluated 30 and 45 mitt, respectively, after subcutaneous administration. The doses selected were based on previous experience in this laboratory [(5, 11, 72); see also (lo)]. In the cat, 1.5 mg/ kg morphine is antinociceptive yet not overtly excitatory. At the conclusion of the study, anodal electrolytic lesions were produced at the tips of the electrodes for subsequent histological evaluation of electrode placement (6, 7). RESULTS Data were collected from 10 cats with electrode placements subsequently verified to be in the H or H2 fields of Fore1 or adjacent subthalamus, and
MORPHINE
AND
SUBTHALAMIC
3
NOCICEPTION
from six cats with electrodes in or adjacent to the pulvinar (Table 1, Fig. 1). Morphine increased the threshold to escape subthalamic stimulation a mean 153% in six of the 10 cats studied; four cats were unaffected. Morphine also increased the threshold to escape stimulation in the pulvinar region (mean 215%). but in only three of the six cats studied. Chlorpromazine similarly increased the threshold to escape subthalamic stimulation (mean 85%) in five of the same six cats affected by morphine and in two of the same three cats in which morphine affected stimulation in the pulvinar area. TABLE Effects
of Morphine (MOR) Subthalamic
Cat
Electrode placement’
ST 13 ST 14 ST 16 ST 17 ST 20 ST 22 ST 24 ST 25 ST 29 ST 30 PUL 3 PUL7 PUL 8 PUL 10 PUL 11 PUL 12
H-SN junction H-TH ZIG HZ-Z1 junction H2-ZI junction LH-SbN-H2 junction HZ-LH junction HZ-LH H2-H 1 junction H2-ZI-H 1 junction Ventromedial Pm sg PI-Pi junction CTT Dorsomedial Pm Pm-Pi-Sg junction
1
and Chlorpromazine (CPZ) on Escape (ST) and Pulvinar (PUL) Stimulation Escape threshold
(mA) 0.50 0.25 0.50 1.0 1.25 1.75 0.50 1.0 1.50 0.25 0.50 0.25 0.75 2.0 5.0 0.75
Induced
MORb Threshold, 150% T, No A, 100% t, 250% T, 20% T, 100% T, 300% T, No A, No A, No A, No A, 300% T, 300% t, No A, 45% T, No A,
by
CPZb Latency No A 25% 1 75% T No x No A 100% T 75% 1 No A 50% T No A No A No x No x No A No X 175% T
Threshold,
Latency
150% T, No A, 50% T, 25% T, No A, 100% T, 100% T, No A, No A, No A, No A, 300% T,
25% 1 No A No A No A 20% T 150% T 50% 1 No A No A No A No A No x
Nob: 50% T, No A,
No A No X 175% T
u Abbreviations: CTT-central tegmental tract; H-H field of Fore1 (prerubral); H 1 -HI field of Fore1 (thalamic fasciculus); H2-H2 field of Fore1 (lenticular fasciculus); LH-lateral hypothalamus; PUL-pulvinar; Pi-inferior pulvinar nucleus; PI-lateral pulvinar nucleus; Pm-medial pulvinar nucleus; SbN-subthalamic nucleus; Sg-suprageniculate nucleus; TH-tegmentohypothalamic tract; ZI-zona incerta; and ZIc-zona incerta caudalis. ST placements are too widespread to be presented in a single figure; see (6, 7) for detailed histologic examples. Pul placements are portrayed in Fig. 1. b Effects of MOR (1.5 mg/kg as base) and CPZ (3.0 mg/kg as base) on the threshold and latency to escape intracranial stimulation are reported as percent increase (t) or decrease (I) from control. The percent changes were determined by comparing each cat’s control threshold and latency with that following drug administration. In those cases where MOR or CPZ had an effect, there were rarely residual effects on escape threshold and latency, which returned to control values within 1 or 2 days after drug treatment. No A and No X indicate no change and no barrier crosses, respectively; CPZ’s effect in PUL 8 was not evaluated.
GEBHART
AND KAELBER
FIG. 1. Composite drawing of dorsal thalamus and rostra1 mesencephalon indicating stimulation sites in the pulvinar complex (v). Abbreviations: CG-central gray; CTT-central tegmental tract, D-nucleus of Darkschewitsch; Gl-lateral geniculate nucleus; Glv-lateral geniculate nucleus, pars ventralis; Gm-medial geniculate nucleus; Gmm-medial’geniculate nucleus, pars magnocellularis; Li-nucleus limitans; NPC-nucleus of posterior commissure; PC-posterior commissure; Pi-inferior pulvinar nucleus; PI-lateral pulvinar nucleus; Pmmedial pulvinar nucleus; Prt-pretectal area; Rt-reticular nucleus; Sg-suprageniculate nucleus; To-optic tract; Vpm-nucleus ventralis posteromedialis.
The effects of these drugs on the latency to escape intracranial stimulation was likewise mixed. Morphine increased the latency to escape subthalamic stimulation in three and decreased it in two cats; one cat (ST 17) would not cross the barrier while under the influence of morphine and the stimulation was terminated as it became aversive. Chlorpromazine increased the latency to escape subthalamic stimulation in two cats and decreased it in two cats. Morphine exerted a significant influence on the latency to escape regional pulvinar stimulation; three of the four cats affected would not cross the barrier and stimulation was terminated as it became aversive. Chlorpromazine had a similar effect in three of the same cats (PUL 7, 11, and 12). DISCUSSION This laboratory previously established that intracranial stimulation in the rostra1 pontine tegmentum, the mesencephalic tegmentum, and subthalamus is aversive and cats will rapidly learn to escape by crossing a low barrier in a shuttle box (6-8). We also demonstrated that electrolytic lesions in the subthalamus or significant degeneration in the H2 field of Fore1 will block escape induced by subthalamic stimulation (6-8). That subthalamic stimulation and lesions are specific for nociception was established by the failure of lesions in the subthalamus to affect tone-signaled
MORPHINE
AND SUBTHALAMIC
NOCICEPTION
5
avoidance of subthalamic stimulation learned prior to introduction of the lesions (7). These data are consistent with other data [cf. ( 1,4)], including those acquired in man [cf. (2, 3)], that pathways other than the lateral (neo-) spinothalamic and ventral trigeminal tracts convey nociceptive information. The major projections of the alternative pathway(s) include the H2 field and zona incerta of the subthalamus, the intralaminar thalamic nuclei, and the pulvinar [cf. (6)]. This report confirms that stimulation in the subthalamus and pulvinar zone is aversive. The findings do not, however, provide evidence for an opiate-selective antinociception against aversive intracranial stimulation. Morphine was observed to increase significantly the threshold to escape stimulation in the subthalamus as well as pulvinar. The effect was not apparent in all cats, however; only approximately 50% of the cats exhibited this response to morphine. Histological examination of the placement of the intracranial stimulating electrodes revealed no differences among the cats affected by morphine and those which were not. Further, chlorpromazine produced a similar effect on escape thresholds and did so in the same cats affected by morphine. The effects of these two drugs on the latency to escape intracranial stimulation were mixed, but morphine and chlorpromazine generally produced effects in the same direction and in the same cats. The data suggest that the drug effects represent nonantinociceptive actions against aversive intracranial stimulation. The results are generally supportive of those reported by Rosenfeld ( 1416) regarding the effects of morphine on aversive intracranial simulation in the rat. He reported that although morphine was reliably antinociceptive against peripherally induced nociception, it was without influence on intracranial stimulation in loci of the neospinothalamic, paleospinothalamic, or spinoreticular afferent nociceptive input. As in the cat (7) Rosenfeld also confirmed his results with an avoidance paradigm (16). He also established that the lack of morphine’s effect was not related to the frequency of intracranial stimulation (16), thus addressing a similar concern regarding the data reported herein. Kiser and German (9) stimulated in regions of the rat brain receiving afferent input from neo- and paleospinothalmic systems and observed that morphine significantly reduced bar pressing to escape aversive intracranial stimulation at all loci. However, inasmuch as morphine failed to selectively influence aversive intracranial stimuli in regions receiving paleospinothalmic afferent fibers and was also administered in a relatively high dose (15 mg/kg), they concluded that the effect of morphine was likely due to nonspecific cataleptic or sedative effects. The inclusion of chlorpromazine in our study and the similarity of its effects to morphine support their conclusion of nonspecific drug effects. In summary, our study failed to demonstrate an opiate-selective antinociceptive effect against aversive intracranial stimulation in the cat.
6
GEBHART
AND
KAELBER
Rather, the effects of morphine were observed to be similar to those of chlorpromazine on both the threshold and latency to escape. Moreover, morphine’s effects were apparent in only some subjects despite similar placements of stimulating electrodes. On the basis of his data, Rosenfeld (14) suggested that opiates exert their antinociceptive action primarily by influencing descending systems or by a direct action at or distal to the primary afferent terminal. These data, taken together with the antinociception produced by morphine in a similar paradigm using noxious radial nerve stimulation (5), are consistent with previous reports (14-16). REFERENCES 1. ANDERSON, F. D., AND C. M. BERRY. 1959. Degeneration studies of long ascending fiber systems in the cat brainstem. J. Camp. Neural. 111: 195-230. 2. CASSINARI, V., AND C. A. PAGNI. 1969. Central Pain: A Neurosurgical Survey. Harvard Univ. Press, Cambridge, Mass. 3. COOPER, I. S., M. RILAN, ANDP. RAKIC, Eds. 1974. The Pulvinar-LP Complex. Thomas, Springfield, Ill. 4. GEBHART, G. 1982. Opiate and opioid peptide effects on brainstem neurons: relevance to nociception and antinociceptive mechanisms. Pain 12: 93-140. 5. GEBHART, G. F., AND J. R. TOLEIKIS. 1978. An examination of stimulation-produced analgesia in the cat. Exp. Neural. 62: 570-579. 6. KAELBER, W. W. 1977. Subthalamic nociceptive stimulation in the cat: effect of secondary lesions and rostra1 fiber projections. Exp. Neurol. 56: 574-597. 7. KAELBER, W. W. 1981. Escape from and avoidance of nociception elicited by intracranial stimulation of the cat subthalamus. Exp. Neural. 73: 397-420. 8. KAELBER, W. W., AND C. L. MITCHELL. 1975. Alteration in escape responding in the cat: a lesion and degeneration comparison following stimulation studies. Brain Behav, Evol. 12: 137-150. 9. KISER, R. S., AND D. C. GERMAN. 1978. Opiate effects on aversive midbrain stimulation in rats. Neurosci. Lett. 10: 197-202. 10. MCKENZIE, J. S., AND N. R. BEECHEY. 1962. The effects of morphine and pethidine on somatic evoked responses in the midbrain of the cat, and their relevance to analgesia. Electroenceph. Clin. Neurophysiol. 14: 501-519. 11. MITCHELL, C. L. 1964. A comparison of drug effects upon the jaw jerk response to electrical stimulation of the tooth pulp in dogs and cats. J. Pharmacol. Exp. Ther. 146: l-6. 12.
13. 14.
15. 16.
MITCHELL, C. L. 1966. Effect of morphine and chlorpromazine alone and in combination on the reaction to noxious stimuli. Arch. Int. Pharmacodyn. 163: 387-392. PERT, A. 1975. Effects of opiates on electrical stimulation of the mesencephalon of the rat. Sot. Neurosci. Abstr. 1: 280. ROSENFELD, J. P., AND B. S. HOLZMAN. 1978. Effects of morphine on medial thalamic and medial bulboreticular aversive stimulation thresholds. Brain Res. 150: 436-440. ROSENFELD, J. P., AND R. KOWATCH. 1975. Differential effect of morphine on central versus peripheral nociception. Brain Res. 88: 181-185. ROSENFELD, J. P., AND J. L. VICKERY. 1976. Differential effect of morphine on trigeminal nucleus versus reticular aversive stimulation: independence of negative effects from stimulation parameters. Pain 2: 405-5 16.