Cellular Mechanisms of Opioid Tolerance

阿片类药物耐受的细胞机制

• 批准号: 6878947
• 负责人: MICHAEL M MORGAN
• 金额: $ 25.69万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6878947
• 关键词: behavior test; drug tolerance; laboratory rat; morphine; neurons; opiate alkaloid; opioid receptor; pain; periaqueductal gray matter; receptor binding; tissue /cell culture; voltage /patch clamp

DESCRIPTION (provided by applicant): Opioids are the most effective treatment for pain. Unfortunately, their efficacy decreases with repeated administration because of the development of tolerance. The broad long-term objective of this research is to understand the underlying neural mechanisms for tolerance so more effective pain treatments can be developed. Many previous studies have examined opioid tolerance. However, these studies show over 30 different mechanisms for tolerance, and it is unlikely that all of these putative mechanisms are directly involved. The proposed studies will focus on tolerance in the ventrolateral periaqueductal gray (PAG) in an attempt to identify causal mechanisms for tolerance. PAG neurons are particularly well suited for studying opioid tolerance because microinjection of morphine into the PAG produces antinociception and repeated microinjections produce tolerance. In addition, the neuronal circuitry and intracellular signaling cascades through which opioids produce antinociception have been described. The proposed studies will take advantage of both intracellular and behavioral measures of tolerance in an attempt to understand the neurochemical basis of tolerance in these neurons. Tolerance could be caused by a change anywhere along the signaling pathway from opioid receptors to feedback circuits. The aims of this project will examine all of the steps along this pathway. Aim 1 will identify the specific PAG neurons that contribute to opioid tolerance. Aim 2 will determine whether receptor internalization contributes to the development of tolerance. Aim 3 will identify the intracellular molecules that contribute to the development of tolerance. And Aim 4 will determine whether feedback to the PAG is necessary for the development of tolerance. A unique feature of this project is that whole cell recordings will be used to link neuronal changes to behavioral measures of tolerance. For example, the intracellular signaling cascades believed to contribute to tolerance will be systematically disrupted to determine the contribution of each step in this signaling cascade to opioid tolerance measured behaviorally. The combined use of in vivo and in vitro techniques provides a powerful approach to understanding the link between molecular changes and behavioral consequences. In the long term, such knowledge will contribute to the development of therapies that improve pain treatment by preventing tolerance to opioids.

描述（由申请人提供）：阿片类药物是治疗疼痛最有效的方法。不幸的是，由于耐受性的产生，它们的功效随着重复给药而降低。这项研究的广泛长期目标是了解耐受性的潜在神经机制，以便开发更有效的疼痛治疗方法。之前的许多研究都检查了阿片类药物的耐受性。然而，这些研究显示了超过 30 种不同的耐受机制，而且所有这些假定的机制不太可能直接参与。拟议的研究将重点关注腹外侧导水管周围灰质（PAG）的耐受性，试图确定耐受性的因果机制。 PAG 神经元特别适合研究阿片类药物耐受性，因为将吗啡微量注射到 PAG 中会产生镇痛作用，并且重复微量注射会产生耐受性。此外，阿片类药物产生镇痛作用的神经元回路和细胞内信号级联也已被描述。拟议的研究将利用细胞内和行为耐受性测量，试图了解这些神经元耐受性的神经化学基础。耐受性可能是由阿片受体到反馈回路的信号通路中任何地方的变化引起的。该项目的目标将检查该路径上的所有步骤。目标 1 将识别有助于阿片类药物耐受的特定 PAG 神经元。目标 2 将确定受体内化是否有助于耐受性的发展。目标 3 将识别有助于耐受性发展的细胞内分子。目标 4 将确定向 PAG 的反馈对于发展耐受性是否是必要的。该项目的一个独特之处在于，全细胞记录将用于将神经元变化与耐受性行为测量联系起来。例如，被认为有助于耐受的细胞内信号级联将被系统地破坏，以确定该信号级联中的每个步骤对行为测量的阿片类药物耐受性的贡献。体内和体外技术的结合使用为理解分子变化和行为后果之间的联系提供了一种强有力的方法。从长远来看，这些知识将有助于开发通过防止阿片类药物耐受来改善疼痛治疗的疗法。