u-50488 and Dystonia

The kappa-opioid receptor agonist, U50,488H (trans-(+-)-3,4-dichloro-N-methyl-[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide), has recently been reported to induce dystonia after s.c. administration of 5-10 mg/kg in guinea pigs. The dystonic movements observed in response to U50,488H resembled those previously reported to occur spontaneously or in response to mild environmental stimuli in a mutant hamster model of paroxysmal generalized dystonia. This prompted us to study the effects of opioid receptor antagonists and of U50,488H in the mutant hamster model. Naloxone and naltrexone, 1 and 10 mg/kg i.p., were either ineffective or tended to induce prodystonic effects in the mutant hamsters. In contrast, U50,488H markedly reduced the severity of dystonic movements at doses of 1-10 mg/kg s.c. In non-dystonic hamsters, U50,488H reduced locomotor activity but did not produce dystonic-like symptoms. The data from mutant hamsters demonstrate that stimulation of kappa-opioid receptors is a powerful means of attenuating dystonic movements in a genetic animal model of idiopathic dystonia. The antidystonic effects of U50,488H might relate to interactions between kappa-opioid receptors and dopaminergic and glutamatergic neurotransmission.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Antihypertensive Agents; Cricetinae; Dose-Response Relationship, Drug; Dystonia; Female; Male; Mesocricetus; Models, Biological; Naloxone; Pyrrolidines; Receptors, Opioid, kappa