Antiretroviral Therapy and Chronic Binge Alcohol Alter Nociceptive System Gene Expression in SIV‐infected Rhesus Macaques

Chronic pain affects over half of people living with HIV (PLWH). The underlying pathophysiological mechanism of HIV‐associated pain is not well defined, hindering effective pain management strategies. Alcohol use and pain symptoms have a bidirectional relationship, where people consume alcohol for its analgesic properties, and where chronic alcohol use leads to increased pain sensitivity. Approximately 30% of PLWH self‐report an alcohol use disorder (AUD), which may impact different components of pain signaling pathways in this population. The aim of this study was to examine the effects of chronic binge alcohol (CBA)‐administration and antiretroviral therapy (ART) on neuroadaptations of nociceptive signaling pathways (including endogenous opioid, endocannabinoid (eCB), and tachykinin systems) in SIV‐infected male macaques. We hypothesized that CBA‐administration decreases expression of endogenous opioid and eCB system genes in the frontal cortex (FC) and spinal cord (SC), reflecting a possible dampening of these endogenous analgesic pathways. Adult male macaques (n=3‐6 per group) received 13‐14 g/kg CBA or isocaloric sucrose (SUC) 7 days a week. Peak blood alcohol concentrations averaged 50‐60 mM 2 h after alcohol administration. Three months after initiation of CBA administration, macaques were inoculated with SIV Mac251, and 2.5 months later half were randomized to ART (PMPA 20 mg/kg, FTC, 30 mg/kg). Macaques were euthanized 11 months after SIV infection, and the brains and spinal cords were excised and cryopreserved at ‐80 o C until qPCR analysis to determine relative mRNA expression of selected proteins in the FC and SC. In the FC, CBA increased expression of monoacylglycerol lipase ( MAGL ) (p=0.03). ART significantly increased kappa opioid receptor ( OPRK1 ) in SUC‐administered macaques but decreased it in CBA‐administered macaques (p=0.04). In the SC, CBA significantly increased TRPV1 levels (p=0.03) in ART‐naïve animals. ART significantly reduced tachykinin receptor 1 ( TACR1) levels (p=0.04), regardless of CBA. Our results suggest differential gene expression adaptations in the nociceptive systems in SC and FC. We propose that the CBA‐associated increase in FC MAGL could be indicative of decreased eCB tone, as MAGL is an eCB degradation enzyme. Signaling through TACR1 by its ligand tachykinin increases pain signal transmission in the ascending pain circuits. Thus, we speculate that the ART‐associated reduction in SC TACR1 may reflect a protective role of ART in pain transduction. TRPV1 is a heat‐sensing receptor in peripheral nerves and our data suggest that CBA may increase thermal sensitivity, while ART may be protective. Taken together, our results suggest CBA detrimental effects and potentially protective effects of ART to reduce pain signaling in the spinal cord. Our findings elucidate potential new therapeutic targets for treating pain in PLWH and AUD.