ERK SIGNALING AND ACUTE OPIOID TOLERANCE

描述（申请人摘要）： 这是一个申请小额赠款的优先类别 经验不足的新调查员 阿片类药物是最重要的 用于治疗疼痛的药物。 然而，除了理想的止痛药外， 阿片类药物具有不良的副作用，例如 耐受性、身体依赖性和成瘾风险。 我们建议 耐受性发展涉及一系列分层事件， 复杂的临床表现 人们对这种信号知之甚少 急性耐受性和交叉耐受性形成的机制 阿片类药物或这些适应的时间顺序。 长期 这项研究的目标是了解信号机制负责 对于发展耐受性，交叉耐受性，和物理 对鸦片的依赖 该提案的短期目标是 表征细胞外信号相关激酶（ERK）在 急性耐受性和交叉耐受性的发展，并确定 这些发现与动物行为的相关性。 我们将实现这些目标 通过使用分子和行为技术来测试以下目标 假设： A）阿片样物质耐受性可能由细胞外信号介导。 调节激酶（ERK）级联。 B）ERK应答的脱敏可能是导致 交叉耐受性的发展。 为了验证这些假设，我们提出了以下具体的研究 目的： 目的1：将μ阿片受体激动剂激活ERK与其受体相关 结合亲和力、功效或体外效力。 目的2：研究急性μ阿片类药物对ERK的影响 通过后续剂量的激动剂激活或潜在的交叉耐受 剂. 目的3：评估ERK级联抑制剂对发育的影响。 急性阿片类药物耐受性的证据。 总之，这些研究将ERK激活与其他 激动剂功效和效力的指标，并评估ERK在 急性阿片类药物耐受的发展。 这些实验可能会导致 确定新的治疗靶点， 医生维持阿片类镇痛药的有效性， 从而减少它们的不良副作用和成瘾潜力。

DESCRIPTION (Applicant's Abstract): This is an application for a Small Grant Award under the priority category of newer, less experienced investigators. Opioids are the most important drugs used in pain treatment. However, in addition to desirable analgesic properties, opioids have undesirable side effects such as the development of tolerance, physical dependence and the risk of addicition. We propose that tolerance development involves a series of layered events that result in a complex clinical picture. Very little is known about the signaling mechanisms underlying the development of acute tolerance and cross tolerance to opioids or the temporal sequence of these adaptations. The long term goals of this research are to understand signaling mechanisms responsible for the development of tolerance to, cross tolerance to, and physical dependence on opioids. The short term goals of this proposal are to characterize the role of extracellular signal related kinase (ERK) in the development of acute tolerance and cross tolerance, and to determine the relevance of these findings in behaving animals. We shall achieve these goals by using molecular and behavioral techniques to test the following hypotheses: A) Opioid tolerance may be mediated by the extracellular signal regulated kinase (ERK) cascade. B) Desensitization of ERK responses may be responsible for the development of cross-tolerance. To test these hypotheses, we propose studies with the following specific aims: Aim 1: To correlate ERK activation by mu opioid agonists to their receptor binding affinity, efficacy, or in vitro potency. Aim 2: To characterize trhe effects of acut mu opioid administration on ERK activation by subsequent doses of agonists or potential cross-tolerating agents. Aim 3: To assess the effects of ERK cascade inhibitors on the development of acute opioid tolerance in behaving animals. Taken together, these studies will correlate ERK activation with other indices of agonist efficacy and potency, and assess the role of ERK in the development of acute opioid tolerance. These experiments could lead to the identification of novel therapeutic targets that may eventually enable physicians to sustain the effectiveness of opioid analgesics while diminishing their undesirable side effects and addictive potential.