The kappa-opioid receptor agonist, U50,488H, exerts antidystonic activity in a mutant hamster model of generalized 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.
Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
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Richter
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Löscher
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004421:Dystonia / Q000139:chemically induced / Q000188:drug therapy*; D005260:Female; D008297:Male; D008647:Mesocricetus; D008954:Models, Biological; D009270:Naloxone / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000187:drug effects
D000959:Antihypertensive Agents; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D009270:Naloxone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer