Is antagonism of α3β4 nicotinic receptors a strategy to reduce morphine dependence?

Abstract

18-Methoxycoronaridine, a synthetic iboga alkaloid congener, has been previously shown to attenuate several signs of morphine withdrawal in rats. The recently discovered action of 18-methoxycoronaridine to block α3β4 nicotinic receptors may be responsible for this effect. To test this hypothesis the effects of non-selective α3β4 receptor antagonists, dextromethorphan, mecamylamine, bupropion, and their combinations, were assessed on of acute naltrexone-precipitated (1 mg/kg i.p.) morphine withdrawal in rats. Dextromethorphan (5–40 mg/kg, s.c.), mecamylamine (0.25–4 mg/kg, i.p.) and bupropion (10–30 mg/kg, i.p.) alone produced variable effects on signs of withdrawal. However, two low-dose combinations, i.e., dextromethorphan (5 mg/kg, s.c.) and mecamylamine (0.25 mg/kg, i.p.), mecamylamine (0.25 mg/kg, i.p.) and bupropion (10 mg/kg, i.p.) as well as the three-drug combination significantly attenuated diarrhea and weight loss; none of the agents administered alone had these effects. The results of the present study provide evidence that α3β4 nicotinic receptors are involved in the expression of at least two signs of opioid withdrawal.