Phenothiazine-type antipsychotics may attenuate naloxone-precipitated withdrawal jumping in morphine-dependent mice

Abstract

ObjectivesWithdrawal of opioids is usually associated with intolerable aversive symptoms. Our objective was to evaluate the efficacy of phenothiazine-type antipsychotics for reducing withdrawal symptoms during morphine abstinence. MethodsAdult NRL mice were rendered physically dependent on morphine by escalating the doses of subcutaneous morphine for 3 days. Withdrawal jumping was precipitated by a subcutaneous injection of naloxone (50 mg/kg) on day 4. In study I, on an equimolar basis, we compared the efficacy of six phenothiazine antipsychotics in saline on reducing morphine withdrawal symptoms. One hour before naloxone injection, the mice were assigned to receive intramuscular (i.m.) saline or one of the six phenothiazine-type antipsychotics (0.3 μmol/kg). After naloxone injection, the tested mouse was immediately placed in a transparent acrylic cylinder, and the severity of withdrawal symptoms was assessed, via a computer connected to the floor of the cylinder, by counting the number of the withdrawal jumps over a 30-minute interval. In study II, we performed a dose–response test in these six phenothiazine antipsychotics (0.03, 0.3, and 3 μmol/kg, i.m., for each test drug) on the inhibition of naloxone-precipitated morphine withdrawal jumping. ResultsWe found that all six phenothiazine-type antipsychotics attenuated the morphine withdrawal jumps, as compared with saline (p < 0.05). The effect is dose-dependent, with the potency ranking order as follows: fluphenazine ＝ triflupromazine > chlorpromazine ＝ perphenazine > promazine ＝ thioridazine (p < 0.05). ConclusionsAll six phenothiazine-type antipsychotics could attenuate morphine withdrawal symptoms; in particular, fluphenazine and triflupromazine may potentially be the more appropriate candidates for the treatment of morphine withdrawal symptoms.