Temporal factors affecting cocaine-opioid interactions: a cocaine drug discrimination study in rats.
BACKGROUND
Increasing concomitant abuse of cocaine and morphine-like opioids has prompted a number of studies aimed at understanding how these drugs interact.


OBJECTIVE
The present study was designed to determine if variations 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 tolerance (approximately 1 h) or acute opioid dependence (approximately 4 h) as demonstrated 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 procedure, the same subjects used in the second experiment were also tested for time-dependent changes in the analgesic effect of morphine using a hot-plate assay.


RESULTS
Morphine pretreatment 1 h prior to assessment of the cocaine dose-response function significantly enhanced the discriminative stimulus 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 dose-response curve, the discriminative stimulus effects of cocaine were significantly attenuated. In assessing morphine-induced analgesia, paw-lick latency was significantly longer at 1 h and shorter at 4 h following morphine administration.


CONCLUSIONS
The results illustrate the importance of temporal parameters for interactions between cocaine and mu opioid agonists.
Green-Jordan
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K
Laboratory of Behavioral Neuroscience, Department of Psychology, Boston University, Boston, MA 02215, USA. Kristen.Jordan@targacept.com
Warren
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Kantak
K M
KM
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D004192:Discrimination, Psychological / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000819:agonists
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D009270:Naloxone; D009020:Morphine; D003042:Cocaine