Modification of morphine tolerance by behavioral variables.

These experiments assessed whether the opportunity to perform a target operant in the presence of morphine would alter the development of behavioral tolerance. Morphine tolerance was assessed in rats responding under a fixed-ratio 30 schedule of food delivery. Separate groups of rats were administered 10 mg/kg of morphine either pre- or postsession for 9 weeks. The degree of drug tolerance was assessed by determining cumulative dose-response functions for morphine before, during and after chronic administration. Three to 4-fold tolerance to the rate-decreasing effects of morphine developed in rats receiving morphine presession, whereas no tolerance developed in rats receiving an equal dose of morphine postsession. Morphine sensitivity returned to initial values 4 weeks after termination of chronic administration. Eight weeks after termination of chronic administration, the drug-daily session relationship was reversed and the rats were re-exposed to 10 mg/kg of morphine for 9 additional weeks. There were fewer differences between groups receiving morphine pre- or postsession during this second chronic administration phase. During chronic administration of morphine, the dose of naloxone required to suppress response rates decreased 100-fold in rats receiving morphine presession, but only 10-fold in rats receiving morphine postsession. In contrast, chronic administration of morphine did not alter the rate-decreasing effects of the nonopioids d-amphetamine, ketamine or pentobarbital. These experiments suggest that reinforcement of an operant response in the presence of morphine promoted the development of pharmacologically specific behavioral tolerance to morphine.