Interactions of Alcohol and Pain in the Context of HIV

摘要 这项NRSA F30奖学金将为申请人成为一名成功的翻译医生做好准备- 科学家。职业发展培训将侧重于高度优先的艾滋病毒/艾滋病共病相关研究， 利用HIV gp120诱导的神经病理性疼痛的临床前啮齿动物模型 艾滋病毒携带者(PLWH)人口。酒精使用障碍(AUD)是一种慢性疾病，与 过度饮酒，经常是艾滋病毒携带者(PLWH)的共病。AUD通常会导致 影响饮酒欲望的负面情绪状态的出现，以及潜在的 导致PLWH患者这些负面情绪状态的重要因素是HIV相关的痛性神经病(HIV- n)。因此，在PLWH饮酒的理由可能源于对疼痛的自我治疗的愿望，这是由于 酒精的止痛特性。重要的是，过量饮酒也会导致痛觉过敏，这是一种情况 这种情况可能会因HIV-N而恶化。以前的工作描述了在动物身上出现的痛觉过敏 对酒精的依赖。对PLWH队列的初步调查也显示出积极的关联 AUDIT(酒精使用障碍识别测试)分数与应激激素循环水平之间的关系 皮质醇。在分子水平上，糖皮质激素受体(GRs)的转录活性受到直接控制 通过磷酸化状态。GR信号的失调可能促进向AUD的转变，并有助于 AUD相关的痛觉过敏，可能在HIV-N的发展中发挥作用。此外，慢性疼痛 可以导致连接伤害性感觉和负面情绪的大脑区域的脊髓上可塑性，例如 扣带回皮质，这也可能有助于AUD的建立或进展。为了支持这一点， 初步数据发现，酒精依赖大鼠扣带回GR磷酸化增加。 为了研究酒精和HIV对HIV-N的贡献，我们利用了一个已建立的临床前啮齿动物模型 使用神经周暴露于HIV包膜蛋白糖蛋白120(Gp120)，它与 在HIV-N的发病机制中。综上所述，我们的初步数据和现有文献支持 假设与艾滋病毒和高风险饮酒相关的疼痛增加是由 糖皮质激素受体活性。拟议的研究将使用一系列广泛的技术来测试两个 假设：(1)GR活性介导与HIV gp120和酒精依赖相关的大鼠痛觉过敏 (2)循环皮质醇水平与PLWH患者的疼痛症状和AUD风险指标相关。 这项研究的发现将促进我们对应激激素信号在相互作用中的作用的理解 艾滋病毒和酒精相关的疼痛之间的关系。在强大的指导团队和NIH P60的支持下 综合酒精-艾滋病毒/艾滋病研究中心(CARC)，完成拟议的研究和培训 该计划将确保申请者为在学术医学领域具有影响力的职业生涯做好准备。

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.