Involvement of kappa-opioids in the mouse cerebellar adenosinergic modulation of ethanol-induced motor incoordination.
Using rotorod performance as the test response, possible modulation and co-modulation of ethanol-induced motor incoordination by the cerebellar kappa-opioid and adenosine A1 receptors was studied. A dose-related accentuation of ethanol-induced motor incoordination was observed after direct cerebellar microinfusion of three kappa-opioid receptor agonists: U-50488, U-62066, and bremazocine. On the contrary, significant and dose-related attenuation of ethanol's motor impairment was produced by intracerebellar nor-binaltorphimine, a kappa-opioid receptor antagonist. Furthermore, the accentuation by kappa-agonists was virtually abolished by kappa-antagonist nor-binaltorphimine. Therefore, the accentuation and attenuation by kappa-opioid receptor agonists/antagonist, respectively, was through specific kappa-opioid receptors. Pretreatment with the intracerebellar adenosine A1-selective agonist, N6-cyclohexyladenosine, further enhanced the ethanol-induced motor incoordination and its accentuation by intracerebellar kappa-opioid receptor agonists. Ethanol-induced motor incoordination was markedly attenuated by intracerebellar pertussis toxin (PTX) pretreatment, suggesting an involvement of PTX-sensitive G protein in the expression of motor incoordinating effect of ethanol. Additionally, the intracerebellar PTX also markedly attenuated the accentuation by kappa-opioid agonists of ethanol-induced motor impairment, suggesting participation of PTX-sensitive GTP-binding G protein (Gi, Go) in the kappa-opioid modulation of ethanol's motor impairment. It also confirms that kappa-opioid receptors are linked to PTX-sensitive G protein. The functional similarity between kappa-opioid and adenosine A1 receptors in increasing ethanol's motor incoordination, together with their anatomical co-localization primarily on the axons and axonal terminals of the cerebellar granule cells, suggests a possible common catalytic unit of adenylate cyclase as the basis of modulation of ethanol-induced motor incoordination by both receptor mechanisms.
Dar
M S
MS
Department of Pharmacology, School of Medicine, East Carolina University, Greenville, North Carolina 27858, USA.
D000435:Alcoholic Intoxication / Q000503:physiopathology*; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology; D001931:Brain Mapping; D002531:Cerebellum / Q000187:drug effects* / Q000503:physiopathology; D000431:Ethanol / Q000633:toxicity*; D019204:GTP-Binding Proteins / Q000502:physiology; D008297:Male; D051379:Mice; D009048:Motor Skills / Q000187:drug effects* / Q000502:physiology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D004856:Postural Balance / Q000187:drug effects / Q000502:physiology; D017473:Receptors, Opioid, kappa / Q000187:drug effects* / Q000502:physiology; D018047:Receptors, Purinergic P1 / Q000187:drug effects* / Q000502:physiology
D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; D018047:Receptors, Purinergic P1; C051844:norbinaltorphimine; D000431:Ethanol; D009271:Naltrexone; D019204:GTP-Binding Proteins