Inhibition of morphine withdrawal by lamotrigine: involvement of nitric oxide

We studied the effects of lamotrigine [3,5-diamino-6-(2,3-dichlorophenyl)- 1,2,4-triazine], a new antiepileptic compound, on naloxone-precipitated morphine withdrawal in mice. Pretreatment with lamotrigine (5-100 mg/kg, s.c.) reversed in a dose-dependent way the withdrawal-induced increase in cerebellar Ca(2+)-dependent nitric oxide (NO) synthase activity and reduced the number of escape jumps and other motor symptoms of abstinence, at doses that did not modify locomotor activity (25-50 mg/kg). Pretreatment with the NMDA receptor antagonist MK-801 [(+)-5-methyl-10,11-dihydroxy-5H- dibenzo[a,d]cyclohepten-5,10-imine; dizocilpine] (0.1-0.3 mg/kg, s.c.) also reversed the increase in cerebellar Ca(2+)-dependent NO synthase activity. However, although MK-801 reduced the number of escape jumps and other motor symptoms of abstinence, its effects were not clearly dose-dependent. Furthermore, the highest dose of MK-801 tested (0.3 mg/kg) caused an impairment of the locomotor behaviour in naive mice. Thus, lamotrigine may represent a new and useful agent for the treatment of opiate abstinence.