Differential cross-tolerance to opioid agonists in morphine-tolerant squirrel monkeys responding under a schedule of food presentation.
The effects of various mu and kappa opioid agonists were evaluated in three squirrel monkeys responding under a fixed-ratio 30 schedule of food presentation before, during and after a regimen of chronic morphine administration. Initially, dose-effect curves for the mu opioid agonists morphine and l-methadone, the kappa opioid agonists U50,488 and tifluadom, the mixed mu/kappa opioid agonist ethylketocyclazocine, and the non-opioid compound pentobarbital were determined in non-tolerant squirrel monkeys. Subsequently, monkeys were administered up to 3.0 mg/kg of morphine twice daily for 8-9 weeks, which resulted in a 1/2 to 3/4 log unit shift to the right of the morphine dose-effect curve relative to its prechronic position. During the chronic morphine regimen, the l-methadone dose-effect curve shifted to the right approximately 3/4 log unit, while the U50,488 and pentobarbital dose-effect curves did not change. In contrast, the ethylketocyclazocine and tifluadom dose-effect curves shifted to the left approximately 1/4 and 3/4 log unit, respectively. The lack of cross-tolerance between mu and kappa agonists in morphine-tolerant squirrel monkeys observed in the present study provides further support for the differentiation of mu and kappa agonists. The occurrence of leftward shifts in the dose-effect curves of some opioid compounds with kappa agonist activity during the regimen of chronic morphine administration suggests that morphine tolerance modulates their
Doty
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P
Department of Psychology, University of North Carolina, Chapel Hill 27599-3270.
Picker
M J
MJ
Dykstra
L A
LA
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects*; D003496:Cyclazocine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D016314:Ethylketocyclazocine; D005502:Food; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D010424:Pentobarbital / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D011957:Receptors, Opioid / Q000502:physiology; D017450:Receptors, Opioid, mu; D012055:Reinforcement Schedule; D012453:Saimiri
D009294:Narcotics; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D001569:Benzodiazepines; D016314:Ethylketocyclazocine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine; D010424:Pentobarbital; D003496:Cyclazocine; C035470:tifluadom