Cotreatment with racemic fenfluramine inhibits the development of tolerance to morphine analgesia in rats.

As a follow-up study to an earlier report that racemic fenfluramine can acutely potentiate the analgesic effects of morphine in humans, we investigated the effects of fenfluramine on the development of tolerance to morphine analgesia in rats. Antinociceptive effect, as measured by the tail-flick latency, was studied over 8 days in rats that received continuous i.v. infusion of 1) 22 mg/kg/day of morphine, 2) 20 mg/kg/day of fenfluramine, 3) both drugs concomitantly or 4) saline. Infusion with morphine alone resulted in a peak analgesia of 100% maximal possible effect, which declined with time; full tolerance was reached by day 4. Fenfluramine treatment alone had no effect. Fenfluramine coinfusion attenuated the development of tolerance to morphine; >70% maximal possible effect was still present on day 4. The effect of fenfluramine coinfusion occurred in the absence of a significant increase in plasma or brain morphine concentration, or a decrease in the accumulation of morphine's putative antagonistic metabolite, morphine-3-glucuronide. In another set of infusion experiments, rats were challenged with a single i.p. dose of morphine to characterize the morphine dose-response curves at 10 hr following 4-day i.v. infusion of 1) 22 mg/kg/day of morphine, 2) 20 mg/kg/day fenfluramine, 3) morphine plus fenfluramine or 4) saline. An acute i. p. morphine challenge dose response experiment was also conducted in naïve control rats and in rats receiving a concomitant i.p. injection of fenfluramine (2.4 mg/kg). Coinjection of fenfluramine acutely potentiated the antinociceptive potency of morphine. However, potentiation alone does not fully account for the apparent attenuation of tolerance during morphine i.v. infusion. ED50 of morphine was elevated to 7.0 mg/kg in the morphine-infused rats compared to 2.4 mg/kg in saline-infused rats. Coinfusion of fenfluramine increased ED50 to only 3.7 mg/kg. These results demonstrate that fenfluramine significantly attenuates tolerance development to morphine by modulating the pharmacological process responsible for tolerance development to morphine.