Intersection of Pain and Ethanol-Seeking Mechanisms in Ethanol Dependence

描述（由申请人提供）：这个K99/R 00职业发展奖提案（乙醇依赖中疼痛和乙醇寻求机制的交叉点）包含了与我过去研究的神经元机制相关的主题，包括体内细胞内信号传导的调节和强迫性药物服用和药物寻求行为，使用大鼠药物依赖模型。这些研究是在博士前和博士后水平的NRSA个人奖项的支持下进行的。该提案的目的是纳入神经化学（体内微透析）和伤害性行为技术的新培训，并整合使用比较物种（小鼠），以补充和丰富这一背景。我觉得这种新技术的结合（在K99阶段学到的）应用于疼痛和乙醇寻求行为的调查，将为酒精依赖提供有价值的见解，并且，当与帕森斯博士和Koob博士在斯克里普斯研究所这样丰富的环境中提供的个性化指导相结合时，将大大促进我在R 00阶段过渡到独立的研究生涯。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granitary，有效的科学交流和道德等主题相关的近期和长期目标的专业培训元素。目前的建议的主要研究目标是调查中枢伤害性和乙醇寻求的生物行为机制在促进和/或维持乙醇依赖性状态的收敛。基于以往的数据从疼痛和乙醇相关领域，我假设一个特定的作用，增加内源性大麻素的活性和相关的MAP激酶信号增强在前扣带皮层在介导这个交叉点，并进一步假设慢性疼痛状态促进过渡，通过这种机制从乙醇的使用依赖。我提出了一个创新的实验策略，结合高度相关的行为技术与比较在体内的神经递质水平和细胞内信号转导的措施，从细胞外空间到细胞核，包括突触前和突触后蛋白磷酸化的措施。在R 00阶段进行的实验将建立在K99阶段的工作，并应提供一个坚实的基础，为我未来的研究酒精依赖的生物行为机制。更好地了解慢性乙醇暴露，改变伤害感受和强迫性乙醇寻求之间的关系，将提供进一步深入了解从娱乐性酒精使用到酒精中毒的过渡机制，以及揭示新的治疗机会。 公共卫生相关性：患有慢性疼痛的人可能更容易产生酒精依赖，并使用酒精来治疗疼痛症状。该项目将研究疼痛和酗酒的重叠脑生化机制，这些机制导致这两种疾病的恶化和潜在的相互依赖性，最终目标是为这些毁灭性的疾病开发更好的治疗策略。

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.