AJ Brandner^1,2,3, C Guerra-Solano^1,2,3, AM Kogos^1,2,3, BK Taylor^1,2,3, SP Farris^1,2,3,4

Alcohol Use Disorder (AUD) is characterized as a chronic medical condition known to be comorbid with pain. Mice experience mechanical and spontaneous pain during alcohol withdrawal, known as chronic alcohol withdrawal-induced pain (CAWIP). We now wanted to characterize a central, brain mechanism that underlies alcohol-induced hypersensitivity during alcohol withdrawal. We hypothesized that the parabrachial nucleus (PBN), a hub for pain and aversion, mediated pain-like responses during alcohol withdrawal. B6J mice were exposed to four weeks of chronic intermittent ethanol vapor (CIEV) or Air (16 hrs ON/8 hrs OFF 4 days/week) to induce pain. During withdrawal, mice underwent 1) immediate early gene (Fos) activation or 2) in vivo fiber photometry experiments to measure PBN neuron activity. To induce Fos expression, mice were anesthetized and their left hind paw was stimulated with either a light brush or a noxious pinch. After 90 minutes, brain tissue was taken for histology. For fiber photometry, stimuli, ranging from innocuous to noxious, were applied to the left hind paw of the mice while calcium activity was recorded in real-time. Both PBN Fos expression and PBN calcium activity were increased by non-painful and painful stimulation in mice treated with CIEV when compared to Air controls. Our studies indicate that PBN neurons are more excitable by innocuous (allodynia) and painful (hyperalgesia) stimuli during alcohol withdrawal. Alcohol-induced sensitization of PBN neurons may underlie the hypersensitivity phenotype we see in our laboratory mice during withdrawal from CIEV. Future studies will focus on PBN neuron inhibition to reduce pain.

Affiliations: Center for Neuroscience¹, Pittsburgh Center for Pain Research², Department of Anesthesiology and Perioperative Medicine³, Department of Biomedical Informatics⁴, Pittsburgh, PA, 15261 USA

Funding Support: NIAAA, NIDA, and NINDS grants AA024836 (SPF), AA020889 (SPF), AA030257 (SPF), DA037621 (BKT), NS045954 (BKT), NS112632 (BKT), AA031431 (AJB), and NS073548 (AJB). We also acknowledge support from Bridging Connections in Addiction Research (BCAR) at the University of Pittsburgh and the Pittsburgh Foundation.