Effects of benzodiazepines on acute and chronic ethanol-induced nociception in rats

Background: Acute and chronic ethanol produces antinociception, and ethanol withdrawal induces hyperalgesia. Methods: A radiant heat tail-flick assay was used to assess the effects of benzodiazepine ligands on ethanol-induced changes in nociception in rats. A cute activity of cumulative doses of ethanol (0.5-2.0 g/kg) and diazepam (0 .1-10 mg/kg), a benzodiazepine agonist, was tested alone and after pretreat ment with flumazenil (1.0-10 mg/kg), a benzodiazepine antagonist. Chronic e ffects of ethanol were rested in three groups of rats that received a Liqui d diet for 10 days. One group received ethanol alone; one group received et hanol and twice-daily injections of flumazenil (10 mg/kg); and one received a dextrin control diet. Acute withdrawal was tested at 12 hr after removal of the liquid diet. Effects of cumulative doses of diazepam (1.0-10 mg/kg) were tested during withdrawal (12 hr) in the ethanol-alone group. Results: Acute doses of ethanol produced a small but significant degree of antinociception, which was fully suppressed by flumazenil. Acute doses of d iazepam did not produce antinociception. Chronic exposure to ethanol produc ed antinociception on days 2 through 8. Tolerance developed by day 10, and hyperalgesia was seen 12 hr after removal of ethanol. Administration of dia zepam or ethanol during withdrawal reversed the hyperalgesia induced by eth anol withdrawal. However, flumazenil (10-50 mg/kg) failed to reverse the an tihyperalgesic effect of either diazepam or ethanol. No antinociception was seen in either the ethanol/flumazenil or dextrin control groups. Conclusions:These results suggest that the antinociceptive effects of both acute and chronic ethanol are at least partially mediated by GABA receptors , and that diazepam's antihyperalgesic effects may not be mediated by the G ABA acid receptor.