Intermediate efficacy mu opioids: examination of their morphine-like stimulus effects and response rate-decreasing effects in morphine-tolerant rats.
The present study examined the effects of morphine, the intermediate efficacy mu opioids (-)-pentazocine, (-)-metazocine, proxorphan, levallorphan, (-)-NANMY (N-allylnormetazocine) and (-)-cyclazocine, and the mu antagonist naloxone 1) in rats responding under a FR (fixed-ratio) 30 schedule before, during and after a chronic morphine regimen, and 2) in rats trained to discriminate 10.0 [10-MS (morphine sulfate)] or 3.0 mg/kg (3-MS) of morphine from saline. Under the FR30 schedule, chronic administration of morphine produced tolerance to morphine's rate-decreasing effects and conferred cross-tolerance to (-)-metazocine, proxorphan and (-)-pentazocine. However, the effects of these intermediate efficacy mu opioids could be differentiated from those of morphine on the basis of their 1) shallow dose-effect curves, and 2) large differences in the degree to which tolerance developed in individual rats. In the drug discrimination procedure, (-)-metazocine, proxorphan and (-)-pentazocine produced high levels of substitution for the 3-MS stimulus and intermediate levels for the 10-MS stimulus. In contrast to the pattern of substitution observed with morphine in the 10-MS group, the effects of these drugs were characterized by 1) shallow dose-effect curves, 2) large individual differences in the lowest dose of each drug that substituted completely for the 10-MS stimulus and 3) the failure to obtain complete substitution for the 10-MS stimulus in all of the rats tested. The behavioral profile obtained with the intermediate efficacy mu opioids (-)-NANM, levallorphan and (-)-cyclazocine was indicative of opioids with intrinsic efficacy lower than that of (-)-pentazocine, (-)-metazocine and proxorphan. Under the FR30 schedule, chronic administration of morphine produced an enhanced sensitivity to the rate-decreasing effects of (-)-NANM and levallorphan but not (-)-cyclazocine. In the drug discrimination procedure, (-)-NANM, levallorphan and (-)-cyclazocine produced high levels of substitution for the 3-MS stimulus and low levels for the 10-MS stimulus. Like naloxone, these drugs produced a dose-related attenuation of the 10-MS stimulus. The results of the present study suggest that the relative order of intrinsic efficacy among the opioids tested is: morphine > (-)-metazocine = (-)-pentazocine = proxorphan > (-)-cyclazocine = levallorphan = (-)-NANM > naloxone.
Picker
M J
MJ
Department of Psychology, University of North Carolina, Chapel Hill.
Craft
R M
RM
Negus
S S
SS
Powell
K R
KR
Mattox
S R
SR
Jones
S R
SR
Hargrove
B K
BK
Dykstra
L A
LA
D000818:Animals; D004193:Discrimination Learning; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005502:Food; D008297:Male; D009019:Morphinans / Q000494:pharmacology; D009020:Morphine / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology*; D010423:Pentazocine / Q000494:pharmacology; D051381:Rats; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000187:drug effects
D009019:Morphinans; D017450:Receptors, Opioid, mu; D009270:Naloxone; D009020:Morphine; D010423:Pentazocine; C047238:metazocine