| Popis: |
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 = (-)-NANMnaloxone. |
