Interactions of Alcohol and Pain in the Context of HIV

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Abstract This NRSA F30 fellowship will prepare the applicant for a successful career as a translational physician- scientist. Career development training will focus on High Priority HIV/AIDS comorbidity-related research, utilizing a preclinical rodent model of HIV gp120-induced neuropathic pain alongside investigation of a clinical population of people living with HIV (PLWH). Alcohol use disorder (AUD) is a chronic disease associated with excessive drinking and is frequently comorbid in people living with HIV (PLWH). AUD often results in the emergence of negative emotional states that influence the desire to consume alcohol, and one potentially important contributor to these negative affective states in PLWH is HIV-associated painful neuropathies (HIV- N). Thus, the rationale for drinking in PLWH may stem from a desire for self-medication of pain due to the analgesic properties of alcohol. Importantly, excessive alcohol use can also result in hyperalgesia, a condition that may be worsened by HIV-N. Previous work has described the emergence of hyperalgesia in animals made dependent on alcohol. Preliminary investigation in a cohort of PLWH has also revealed positive associations between AUDIT (Alcohol Use Disorders Identification Test) scores and circulating levels of the stress hormone cortisol. At the molecular level, the transcriptional activity of glucocorticoid receptors (GRs) is directly controlled via phosphorylation status. Dysregulation of GR signaling may facilitate the transition to AUD and contribute to AUD-associated hyperalgesia, potentially playing a role in development of HIV-N. Furthermore, chronic pain can result in supraspinal plasticity in brain areas linking nociception and negative emotion, such as the cingulate cortex, which may also contribute to the establishment or progression of AUD. In support of this, preliminary data has discovered increases in GR phosphorylation in the cingulate of alcohol-dependent rats. To study the contributions of alcohol and HIV to HIV-N, we’ve utilized an established preclinical rodent model employing perineural exposure to the HIV envelope protein, glycoprotein 120 (gp120), which is closely involved in the pathogenesis of HIV-N. Taken together, our preliminary data and the existing literature support the hypothesis that increased pain associated with HIV and at-risk alcohol use is driven by heightened glucocorticoid receptor (GR) activity. The proposed study will employ a wide array of techniques to test two hypotheses: (1) GR activity mediates hyperalgesia associated with HIV gp120 and alcohol dependence in rats and (2) circulating cortisol levels are associated with pain symptoms and AUD risk measures in PLWH. Findings from this study will advance our understanding of the role of stress hormone signaling in the interplay between HIV- and alcohol-associated pain. With the support of a strong mentoring team and the NIH P60 Comprehensive Alcohol-HIV/AIDS Research Center (CARC), completion of the proposed research and training plan will ensure that the applicant is prepared for an impactful career in academic medicine.