Temporal factors affecting cocaine-opioid interactions: a cocaine drug discrimination study in rats

Rationale: Increasing concomitant abuse of cocaine and morphine-like opioid s has prompted a number of studies aimed at understanding how these drugs i nteract. Objective: The present study was designed to determine if variatio ns in opioid pretreatment time would affect how mu opioid agonists interact with cocaine. Methods: Rats were trained to discriminate 10 mg/kg cocaine from saline. One group of subjects (n=6) received morphine (5.6 mg/kg) 0.5 h, 1 h or 4 h prior to cumulative doses of cocaine (0.1-17.8 mg/kg). These pretreatment times were selected to overlap with states of acute opioid tol erance (similar to1 h) or acute opioid dependence (similar to4 h) as demons trated by previous studies. A second group (n=6) was administered naloxone (0.3 mg/kg) 5 min prior to cumulative cocaine doses, with or without a 4-h morphine (5.6 mg kg) or methadone (3.0 mg/kg) pretreatment. In a third proc edure, the same subjects used in the second experiment were also tested for time-dependent changes in the analgesic effect of morphine using a hot-pla te assay. Results: Morphine pretreatment 1 h prior to assessment of the coc aine dose-response function significantly enhanced the discriminative stimu lus effects of cocaine. However, neither 0.5-h or 4-h morphine pretreatment had any effect. In contrast, when naloxone was administered 4 h following either morphine or methadone and 5 min prior to assessment of the cocaine d ose-response curve, the discriminative stimulus effects of cocaine were sig nificantly attenuated. In assessing morphine-induced analgesia, paw-lick la tency was significantly longer at 1 h and shorter at 4 li following morphin e administration. Conclusions: The results illustrate the importance of tem poral parameters for interactions between cocaine and mu opioid agonists.