An experimental therapy for opioid withdrawal syndrome

The ongoing opioid crisis in the United States needs alternative therapeutics. To explore the role of the 5-HT2A serotonin receptor in opioid physical dependence and withdrawal syndrome, morphine dependent rats were treated with pimavanserin, a highly selective 5-HT2A inverse agonist in current medical use. In experiment 1, rats were rendered morphine-dependent after seven days of continuous infusion at 0.6 mg/kg/hr. On the seventh day, morphine infusion ceased, and a day later, rats were injected with either 0.3 or 1.0 mg/kg pimavanserin or saline. A non-morphine dependent saline-infused control group received only saline. One hour post injection, rats were observed under blind conditions for somatically expressed behavioral withdrawal signs utilizing a validated observation checklist. Compared to morphine dependent/saline-injected rats, the non-dependent rats and both morphine-dependent pimavanserin dose groups exhibited significantly reduced withdrawal signs, p < .001, based on Tukey’s HSD test for non-independent pairwise comparisons. The higher pimavanserin dose (1.0 mg/kg) fully reversed the effect of morphine infusion on withdrawal signs, while the lower dose (0.3 mg/kg) largely reversed it. In experiment 2, utilizing only non-dependent/salineinfused rats, pimavanserin showed no significant effect on overall withdrawal signs.

Given pimavanserin’s high selectivity for the 5-HT2A serotonin receptor, these findings indicate that the activity of this receptor plays a role in opioid physical dependence. These results suggest the need for further research on pimavanserin as a novel therapeutic for managing the aversive withdrawal symptoms associated with opioid withdrawal syndrome.