Our earlier work showed that morphine-3-glucuronide, a non-opioid morphine metabolite, acts via a toll-like receptor 4 (TLR4) dependent mechanism to enhance pain. We have now studied other classes of glucuronide metabolites and found that glucuronic acid, ethyl glucuronide, and ethanol produce increases in TLR-4 signaling that were blocked by TLR-4 antagonists LPS-RS and (+)-naloxone, a non opioid TLR-4 antagonist. In rats, intrathecal injection of ethyl glucuronide resulted in allodynia that could be blocked by the TLR-4 LPS-RS. Since ethyl glucuronide is a known human metabolite of ethanol our studies suggest that hangover headache and alcohol withdrawal hyperalgesia in humans may involve interaction of ethyl glucuronide with the TLR-4 system. We also characterized a rat model of binge drinking. We studied the effects of three pharmacological agents with different mechanisms of action on the behavior of Sardinian alcohol-preferring (sP) rats drinking either 20% alcohol (Wise procedure) or water. Naltrexone (an opioid antagonist) and SCH 39166 (a dopamine D1 antagonist) both suppressed alcohol drinking while the corticotropin releasing hormone receptor 1 antagonist (CRHR1) R121919 had no effect. The Wise procedure resulted in binge drinking in sP rats that appears to involve the opioid and dopamine systems but not CRHR1 system. These observations may also apply to certain subsets of human alcoholics.
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