title: Anticonvulsive effects of kappa-opioid receptor modulation in an animal model of ethanol withdrawal.
abstract: Although the neurochemical mechanisms contributing to alcohol withdrawal seizures are poorly understood, withdrawal seizures probably reflect neuronal hyperexcitability resulting from adaptation to chronic alcohol. Altered kappa-Opioid receptor (KOP-R) signaling has been observed in multiple seizure types; however, a role for this system in ethanol withdrawal seizures has not been systematically characterized. We hypothesized that pharmacological manipulations of the KOP-R would alter withdrawal in mice selectively bred for differences in ethanol withdrawal severity. Withdrawal Seizure-Prone (WSP) and Withdrawal Seizure-Resistant (WSR) mice were made physically dependent using chronic ethanol vapor inhalation, and the effects of the KOP-R antagonist nor-binaltorphimine or agonist U-50,488H on withdrawal severity were examined. Pretreatment with nor-binaltorphimine significantly increased handling-induced convulsion (HIC) severity in withdrawing WSR mice, with no observable effects in withdrawing WSP mice. In contrast, U-50,488H significantly decreased HIC severity in WSP mice, with no effects in WSR mice. During extended withdrawal (i.e. hours 12+), a rebound hyperexcitability was observed in WSP mice given agonist. Thus, administration of a KOP-R antagonist increased withdrawal severity in mice normally resistant to withdrawal seizures, while a KOP-R agonist reduced convulsion severity in animals susceptible to withdrawal seizures. These observations are consistent with differences in the KOP-R system observed in these lines at the molecular level, and suggest the KOP-R system may be a promising therapeutic target for management of ethanol withdrawal seizures. Finally, these findings underscore the importance of determining the potential for rebound increases in withdrawal severity during later withdrawal episodes.
authors.affiliation: Department of Behavioral Neuroscience, Oregon Health & Science University Research Service, Portland, OR 97239, USA. bohlinga@ohsu.edu
authors.forename: A S
authors.initials: AS
authors.lastname: Beadles-Bohling
authors.forename: K M
authors.initials: KM
authors.lastname: Wiren
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology* / Q000627:therapeutic use; D020268:Alcohol-Induced Disorders, Nervous System / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology / Q000627:therapeutic use; D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002492:Central Nervous System Depressants / Q000009:adverse effects; D004195:Disease Models, Animal; D004347:Drug Interactions / Q000502:physiology; D004357:Drug Synergism; D000431:Ethanol / Q000009:adverse effects; D008297:Male; D009271:Naltrexone / Q000009:adverse effects / Q000031:analogs & derivatives; D017473:Receptors, Opioid, kappa / Q000187:drug effects* / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D013045:Species Specificity; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D016896:Treatment Outcome
chemical_list: D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D000927:Anticonvulsants; D002492:Central Nervous System Depressants; D017473:Receptors, Opioid, kappa; C051844:norbinaltorphimine; D000431:Ethanol; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer