Effects of 5-HT3 receptor antagonists on behavioural measures of naloxone-precipitated opioid withdrawal

The effect of the selective 5-HT3 receptor antagonists, ondansetron and MDL 72,222, against various behaviours elicited by naloxone-precipitated morphine withdrawal were examined. Rats made dependent upon morphine by the subcutaneous implantation of a 75 mg pellet, when challenged with naloxone (0.5 mg/kg SC), 3 or 4 days later exhibited a wide range of behaviours including wet dog shakes, paw shakes, salivation and a marked weight loss. Pre-treatment with ondansetron (0.01-1 mg/kg SC) or MDL 72,222 (1-3 mg/kg SC) failed to affect the incidence of these responses except weight loss, which was attenuated by both treatments. At doses similar to and below those required to elicit the withdrawal syndrome, naloxone produced a single-trial place aversion in morphine dependent rats. The place aversion produced by naloxone (0.05 mg/kg SC) was antagonized by pre-treatment of ondansetron (0.1-1 mg/kg SC) and MDL 72,222 (1 mg/kg SC) prior to conditioning. Chlordiazepoxide (10 mg/kg IP) but not gepirone (3-10 mg/kg SC) was similarly effective. It is concluded that 5-HT3 antagonists may attenuate some but not all behavioural signs associated with morphine withdrawal. Reasons for this apparent selectivity are discussed.