Paradoxical Impact of Acute and Chronic Alcohol Use on Morphine-Mediated Analgesia

Alcohol use disorder (AUD) and chronic pain frequently co-occur and share overlapping neural substrates that regulate nociception, reward, and stress. Acute ethanol (EtOH) exposure is known to induce antinociception, whereas chronic or repeated alcohol use can induce hyperalgesia; however, how ethanol-induced pain states influence opioid analgesic responsiveness remains unclear. In the present study, the interaction between ethanol exposure and morphine-modulated antinociception is investigated in silico using bioinformatics tool, QIAGEN Ingenuity Pathway Analysis and in vivo using a hot plate assay in C57BL/6J (B6) mouse model. In silico analysis revealed interaction of alcohol use and opioid use through Gamma-aminobutyric Acid (GABA) Receptor Signaling, Neuroinflammation Signaling, Opioid Signaling, G-protein Coupled Receptor Signaling, Dopamine-DARPP32 Feedback in cAMP Signaling, Gαi Signaling, Circadian Rhythm Signaling, cAMP-mediated Signaling, nNOS Signaling in Neurons, Glutamate Receptor Signaling. In vivo study showed that a single cycle of 3-day ethanol treatment significantly enhanced morphine-induced antinociception; while, in contrast, repeated cycles of 3-day binge ethanol exposure produced a pronounced decrease in withdrawal latency, indicative of a pain-like or hyperalgesic state, which was accompanied by diminished opioid analgesic efficacy. Importantly, in the absence of morphine, ethanol exposure alone exhibited a temporal transition from an initial antinociceptive effect to a pain-inducing state following repeated exposure. These findings demonstrate that ethanol-induced nociceptive state plasticity critically governs opioid responsiveness. Our results support a model in which acute ethanol facilitates opioid analgesia, whereas repeated ethanol exposure shifts nociceptive processing toward hyperalgesia, potentially through maladaptive neuroimmune and neuromodulatory mechanisms. This dynamic interaction between alcohol exposure and opioid analgesia may contribute to altered pain management outcomes and increased vulnerability to opioid misuse in individuals with AUD.