Intersection of Pain and Ethanol-Seeking Mechanisms in Ethanol Dependence

描述（由申请人提供）：这个K99/R00职业发展奖提案（乙醇依赖中的疼痛和寻求酒精机制的交集）包含了我过去研究过的神经元机制相关的主题，包括体内细胞内信号传导和强迫性药物服用和寻求药物行为的调节，使用大鼠药物依赖模型。这些研究是在NRSA个人奖学金的支持下进行的，包括博士前和博士后水平。本提案的目的是结合神经化学（体内微透析）和伤害性行为技术的新训练，并整合比较物种（小鼠）的使用，以补充和丰富这一背景。我觉得，将这种新技术（在K99阶段学到的）应用于疼痛和酒精寻求行为的调查，将为酒精依赖提供有价值的见解，并且，当与博士提供的个性化指导相结合时。在斯克里普斯研究所这样丰富的环境中，帕森斯和库布将极大地促进我在00阶段向独立研究事业的过渡。研究发展计划是根据TSRI博士后办公室的个人发展计划（IDP）计划进行的，包括与资助、有效的科学交流和道德等主题相关的短期和长期目标的专业培训要素。本研究的主要目的是探讨中枢伤害感觉和寻求乙醇的生物行为在促进和/或维持乙醇依赖状态中的趋同机制。基于先前来自疼痛和乙醇相关领域的数据，我假设内源性大麻素活性的增加和前扣带皮层中相关MAP激酶信号的增强在介导这种交叉中起着特定的作用，并进一步假设慢性疼痛状态通过这种机制促进了从乙醇使用到依赖的转变。我提出了一种创新的实验策略，将高度相关的行为技术与神经递质水平和从细胞外空间到细胞核的细胞内信号传导的比较体内测量相结合，包括突触前和突触后蛋白质磷酸化的测量。在R00阶段进行的实验将建立在K99阶段的工作基础上，并为我未来对酒精依赖的生物行为机制的研究提供坚实的基础。更好地了解慢性酒精暴露、伤害感觉改变和强迫性酒精寻求之间的关系，将进一步深入了解从娱乐性酒精使用到酒精中毒转变的机制，并揭示新的治疗机会。

DESCRIPTION (provided by applicant): This K99/R00 career development award proposal (Intersection of Pain and Ethanol-Seeking Mechanisms in Ethanol Dependence) incorporates themes related to neuronal mechanisms I have investigated in the past, including the regulation of in vivo intracellular signaling and compulsive drug taking and drug-seeking behaviors, using models of drug dependence in rats. These studies were conducted with the support of individual NRSA awards at both pre- and postdoctoral levels. The aim of this proposal is to incorporate new training in neurochemistry (in vivo microdialysis) and nociceptive behavioral techniques, and to integrate the use of a comparative species (mice), to complement and enrich this background. I feel that this combination of new techniques (learned during the K99 phase) applied to the investigation of pain and ethanol-seeking behaviors will provide valuable insight into alcohol dependence, and, when combined with the personalized mentoring provided by Drs. Parsons and Koob within an environment as rich as The Scripps Research Institute, will greatly facilitate my transition to an independent research career during the R00 phase. The research development plan is conducted in accordance with the TSRI postdoctoral office's Individual Development Plan (IDP) program, and includes specialized training elements serving both immediate and long-term goals related to such topics as grantsmanship, effective scientific communication, and ethics. The main research objective of the current proposal is to investigate the convergence of central nociceptive and ethanol-seeking biobehavioral mechanisms in promoting and/or maintaining the ethanol-dependent state. Based on previous data from both pain- and ethanol-related fields, I hypothesize a specific role for increased endogenous cannabinoid activity and associated MAP kinase signaling potentiation in the anterior cingulate cortex in mediating this intersection, and further hypothesize that chronic pain states facilitate the transition from ethanol use to dependence via this mechanism. I propose an innovative experimental strategy that combines highly relevant behavioral techniques with comparative in vivo measures of neurotransmitter levels and intracellular signaling spanning from the extracellular space to the nucleus, including measures of both pre- and postsynaptic protein phosphorylation. Experiments conducted during the R00 phase will build on K99 phase work, and should provide a substantial base for my future investigations into the biobehavioral mechanisms of alcohol dependence. A better understanding of the relationship between chronic ethanol exposure, altered nociception, and compulsive ethanol seeking will provide further insight into mechanisms underlying the transition from recreational alcohol use to alcoholism, as well as reveal new treatment opportunities. PUBLIC HEALTH RELEVANCE: Individuals suffering from chronic pain may be more vulnerable to develop alcohol dependence and use alcohol to treat pain symptoms. This project will examine overlapping brain biochemical mechanisms of pain and alcoholism that contribute to the worsening and potential interdependence of these two disorders, with the ultimate goal of developing better therapeutic strategies for these devastating conditions.