Anticonvulsive effects of κ-Opioid receptor modulation in an animal model of ethanol withdrawal

A. S. Beadles-Bohling, K. M. Wiren

Research output: Contribution to journalArticle

20 Scopus citations

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 κ-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.

Original languageEnglish (US)
Pages (from-to)483-496
Number of pages14
JournalGenes, Brain and Behavior
Volume5
Issue number6
DOIs
StatePublished - Aug 2006

Keywords

  • 488H
  • Alcohol withdrawal-induced seizure
  • Musmusculus
  • Nor-binaltorphimine
  • Prodynorphin
  • U-50
  • κ-Opioid receptor

ASJC Scopus subject areas

  • Genetics
  • Neurology
  • Behavioral Neuroscience

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