To determine whether 5-HT3 receptor function affects opioid withdrawal, the effect of a selective 5-HT3 receptor antagonist (ondansetron) on withdrawal-associated jumping was assessed. Administration of ondansetron before measurement of naloxone-induced jumping significantly reduced this response in morphine-dependent C57BL/6J mice in a dose-dependent manner (Fig. 3a). In addition, simultaneous administration of ondansetron with each morphine dose during the 4-day protocol for establishing dependence diminished the naloxone-precipitated withdrawal response (Fig. 3b). The latter effect was unlikely to be because of the presence of residual ondansetron at the time of the dependence measurement as a 1-mg/kg dose was not able to effectively inhibit withdrawal when given acutely, and approximately 5 half-lives of the drug had passed in the time between the last dose of ondansetron and the naloxone-precipitated withdrawal procedure. We next investigated whether 5-HT3 receptors expressed within the CNS were capable of altering the severity of withdrawal. In these experiments, ondansetron (or saline) was injected i.c.v. before naloxone was administered to morphine-dependent C57BL/6J mice. The i.c.v. administration of ondansetron profoundly blocked the naloxone-precipitated jumping behavior in a dose-dependent manner (Fig. 3c).
