5-HT 2A receptor inverse agonist attenuates morphine withdrawal syndrome and its aversiveness in rats.

This study explored a potential role for the 5-hydroxytryptamine 2A (5-HT 2A ) serotonin receptor in opiate physical dependence. Rats were rendered opiate-dependent by 7 days of continuous subcutaneous (s.c.) morphine sulfate infusion. Pimavanserin is a selective 5-HT 2A receptor inverse agonist in current medical use. A day after termination of drug infusion, rats were injected s.c. with 0.3 or 1.0 mg/kg pimavanserin or saline alone. A nondependent control group was infused with saline alone and injected with saline. One hour after injections, all rats were observed under blind conditions for somatically expressed spontaneous withdrawal signs. While both pimavanserin doses significantly reduced withdrawal signs in the dependent rats, the higher dose reduced those signs to the level exhibited by the nondependent group. In a second experiment, utilizing only nondependent, saline-infused rats, pimavanserin had no significant effect vs. saline injection on overall signs. A third experiment extended these findings to naloxone-precipitated morphine withdrawal. Relative to saline injection, pimavanserin, 1.3 mg/kg s.c., significantly reduced withdrawal signs precipitated by 0.3 mg/kg naloxone 1 h later. This effect was reconfirmed in a separate experiment. The pimavanserin injection also significantly attenuated the aversiveness of morphine withdrawal, as indicated by reduced conditioned avoidance of the chamber where precipitated withdrawal had occurred. These results indicate a major role for the 5-HT 2A receptor in opiate physical dependence and withdrawal syndrome, suggesting this receptor as a potential therapeutic target.