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.
Departamento de Farmacología, Universidad Complutense de Madrid, Spain. nlfucm@eucmvx.sim.ucm.es
I
I
Lizasoain
J C
JC
Leza
B
B
Cuéllar
M A
MA
Moro
P
P
Lorenzo
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D000077213:Lamotrigine; D008297:Male; D051379:Mice; D009020:Morphine / Q000009:adverse effects*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy*; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use*
D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D009292:Narcotic Antagonists; D014227:Triazines; D009270:Naloxone; D016291:Dizocilpine Maleate; D009020:Morphine; D019001:Nitric Oxide Synthase; D000077213:Lamotrigine