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 ca n acutely potentiate the analgesic effects of morphine in humans, we i nvestigated the effects of fenfluramine on the development of toleranc e to morphine analgesia in rats. Antinociceptive effect, as measured b y the tail-flick latency, was studied over 8 days in rats that receive d 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. Infusi on with morphine alone resulted in a peak analgesia of 100% maximal po ssible effect, which declined with time; full tolerance was reached by day 4. Fenfluramine treatment alone had no effect. Fenfluramine coinf usion attenuated the development of tolerance to morphine; >70% maxima l possible effect was still present on day 4. The effect of fenflurami ne coinfusion occurred in the absence of a significant increase in pla sma or brain morphine concentration, or a decrease in the accumulation of morphine's putative antagonistic metabolite, morphine-3-glucuronid e. in another set of infusion experiments, rats were challenged with a single i.p. dose of morphine to characterize the morphine dose-respon se 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 experime nt was also conducted in naive control rats and in rats receiving a co ncomitant i.p. injection of fenfluramine (2.4 mg/kg). Coinjection of f enfluramine acutely potentiated the antinociceptive potency of morphin e. However, potentiation alone does not fully account for the apparent attenuation of tolerance during morphine i.v. infusion. ED,, of morph ine 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 increase d ED,, to only 3.7 mg/kg. These results demonstrate that fenfluramine significantly attenuates tolerance development to morphine by modulati ng the pharmacological process responsible for tolerance development t o morphine.