JD Wherry¹, MR Ross⁴, DV Gil⁴, GE Homanics^1,2,4, SP Farris^1,3,4

Alcohol Use Disorder (AUD) is a highly prevalent disease that causes deterioration of health and a steep socioeconomic cost. Individuals with AUD often report symptoms of chronic pain and many continue consuming alcohol to combat these symptoms, especially during withdrawal. Alcohol has deleterious effects on the neuroimmune system that cause aberrant inflammation and increased sensitivity to painful stimuli. However, the neurobiological connection between AUD and chronic pain remains ill-defined. Microglia are the primary immune cells in the central nervous system and mediate neuroinflammation associated with alcohol consumption and pain responses. We hypothesized that exposure to chronic intermittent ethanol vapor (CIEV) would lead to heightened spontaneous nociception (i.e. grimacing) and changes in microglial morphology indicative of a reactive phenotype. After five weeks of CIEV, PainFace software showed increased grimacing behavior in mice 24 hours into withdrawal compared to air controls, representative of chronic alcohol withdrawal-induced pain (CAWIP). Grimacing behavior was negatively correlated with territory occupied by microglia in the prefrontal cortex (PFC) indicative of increased microglial reactivity. As a positive control, a separate cohort of mice were injected with lipopolysaccharide (LPS; 1.0 mg/kg) to induce innate immune activation, and grimacing behavior was measured 24 hours post-injection. LPS treatment led to increased grimacing behavior and reductions in territory occupied by microglia compared to saline treatment; similar to mice undergoing withdrawal from CIEV. These data indicate an association between spontaneous nociception and microglial reactivity in mice undergoing withdrawal from chronic ethanol exposure and identify microglia as a possible therapeutic target for treating CAWIP.

¹Department of Anesthesiology & Perioperative Medicine, ²Department of Pharmacology & Chemical Biology, ³Department of Biomedical Informatics, ⁴Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA.

Funding Support: Funding Support: NRSA T32 DA057922, NIAAA U01 AA020889, NIAAA R01 AA030257