Sex-specific mechanisms underlying the effects of pain on opioid seeking

在任何给定时间，高达20%的美国人口都会经历疼痛。阿片类止痛药很有效 止痛药通常用于治疗疼痛症状，但阿片类药物的滥用对疼痛有很大的限制 管理越来越多的人支持疼痛患者中阿片类药物滥用的性别差异。不过， 男性和女性之间处方阿片类药物滥用的患病率通常相似， 这一发现与男性虐待发生率一直高于女性形成鲜明对比。比如说， 接受阿片类药物治疗的男性疼痛患者更有可能增加阿片类药物的摄入量， 处方药过量而死然而，关于长期使用避孕药的性别特异性趋势知之甚少。 处方阿片类药物治疗疼痛性别差异似乎在阿片类药物滥用中起着重要作用， 关于疼痛或阿片类药物既往摄入史如何导致阿片类药物滥用倾向性别差异的临床前数据 是有限的。我们实验室的初步发现概括了临床数据中发现的性别依赖趋势 使用临床前模型。我们的数据显示，雄性大鼠自我管理芬太尼的量高于雌性大鼠。 此外，我们发现，持续性炎性疼痛增加芬太尼摄入量的男性相对于女性。 这表明，炎症性疼痛条件导致更高的滥用倾向选择性的男性。在这 项目，我们建议调查疼痛如何改变神经适应过程中长期使用阿片类药物， 性别特异性方式以及这些功能变化是否预示着芬太尼的适应不良模式 摄入中脑边缘系统是整合疼痛和奖励的关键网络节点。DA传输在 中脑边缘系统，通过腹侧被盖区（VTA）到延髓核（NAc），长期以来一直是 它在奖励处理和动机行为中的作用得到认可。然而，目前尚不清楚性- 疼痛对阿片类药物使用的依赖性作用是由腹侧被盖区DA活性模式的性别差异介导的。我们 初步数据显示，持续性炎性疼痛通过增加腹侧被盖区DA神经元的兴奋性， 抑制驱动VTA DA神经元从GABA能输入的头内侧被盖核（RMTg）。 这表明，在疼痛的条件下，较高的阿片类药物剂量是必要的，以触发水平的腹侧被盖区DA 释放与非疼痛条件下产生的释放相当。然而，目前尚不清楚是否类似 阿片类药物滥用模式的性别差异的机制。根据初步调查结果，我们 假设疼痛加剧了RMTg介导的雄性VTA DA细胞活性抑制，而不是雌性 阿片类药物自我给药后。本项目旨在通过调查来解决我们理解中的这一差距 疼痛和长期使用阿片类药物在RMTg VTA通路内的性别特异性功能后果。

Pain is experienced by up to 20% of the US population at any given time. Opioid pain medications are potent analgesics commonly used to treat pain symptoms, but the misuse of opioids presents a major limitation for pain management. There is increasing support for sex differences for opioid misuse among pain patients. Although, prevalence rates for prescription opioid misuse between men and women are often found to be similar, this finding contrasts with the consistently higher prevalence of abuse in men compared to women. For example, male pain patients treated with opioids are more likely to increase intake of their opioid doses, misuse prescriptions, and die from overdose. However, little is known about sex-specific trends in long-term use of prescribed opioids for pain conditions. Sexual differences appear to play an important role in opioid misuse, but preclinical data on how pain or prior history of opioid intake contributes to sex differences in opioid abuse liability are limited. Preliminary findings from our lab have recapitulated the sex-dependent trends found in clinical data using a preclinical model. Our data show that male rats self-administer higher amounts of fentanyl than females. In addition, we found that persistent inflammatory pain increases fentanyl intake in males relative to females. This suggests that inflammatory pain conditions lead to a higher misuse liability selectively in males. In this project, we propose to investigate how pain alters neuroadaptative processes during long-term opioid use in a sex-specific manner and whether these functional changes are predictive of maladaptive patterns of fentanyl intake. The mesolimbic system is a key network node that integrates pain and reward. DA transmission in the mesolimbic system, via the ventral tegmental area (VTA) to the nucleus accumbens (NAc), has long been recognized for its role in reward processing and motivated behaviors. However, it remains unclear whether sex- dependent effects of pain on opioid use are mediated by sex differences in the patterns of VTA DA activity. Our preliminary data shows that persistent inflammatory pain reduces VTA DA neuron excitability by increasing the inhibitory drive onto VTA DA neurons from the GABAergic inputs of the rostromedial tegmental nucleus (RMTg). This suggests that under conditions of pain, higher opioid doses are necessary to trigger levels of VTA DA release comparable to those produced in non-pain conditions. However, it is unknown whether similar mechanisms underlie sex differences in the patterns of opioid misuse. Based on our preliminary findings, we hypothesize that pain exacerbates RMTg-mediated inhibition of VTA DA cell activity in males, but not females following opioid self-administration. This project aims to address this gap in our understanding by investigating the sex-specific functional consequences of pain and long-term opioid use within the RMTgVTA pathway.