Mechanisms of Opioid Receptor Interactions

阿片受体相互作用的机制

• 批准号: 7061325
• 负责人: George Latimer Wilcox
• 金额: $ 32.63万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7061325
• 关键词: alpha adrenergic receptor; analgesia; analgesics; behavior test; cell surface receptors; chronic pain; confocal scanning microscopy; drug interactions; electron microscopy; electrophysiology; immunocytochemistry; laboratory mouse; neural plasticity; neuropathology; opioid receptor; receptor coupling; receptor expression; single cell analysis; spinal cord

DESCRIPTION (provided by applicant): Opioid and adrenergic agonists produce analgesia synergistically at G protein-coupled receptors (GPCR). Opioid tolerance and neuropathic pain both involve neuronal plasticity that may decrease this synergistic relationship. The proposed research will 1) determine how synergistic interactions occur between opioid receptor (OR) and alpha-2 adrenergic receptor (AR) agonists, 2) compare the mechanisms underlying GPCR-mediated analgesic synergism under normal conditions and in states of neuronal plasticity, and 3) examine the functional relationships between OR and AR transmitters. We will test the following hypotheses: Hypothesis 1A - Synergistically acting receptor pairs sharing localization couple through different intracellular pathways; Hypothesis 1B - Synergistically interacting receptor pairs coupling through the same intracellular pathways reside in different locations; Hypothesis 2 - Persistent alterations in receptor distribution or coupling driven by neural plasticity impact potency or efficacy of analgesic agonists by changing interactions between receptor subtypes. Behavioral studies will examine the mechanism of spinal analgesic synergy under normal, opioid tolerant, and neuropathic conditions. Immunohistochemical localization of OR/AR and quantification of transmitter release from spinal cord slices will define the anatomical substrates for the functional interactions observed. Electrophysiology of dorsal horn neurons will examine the cellular mechanisms of drug action and interaction at the single cell level. The information gained from these studies may identify new therapeutic analgesic combinations and combination receptor targets leading toward reduction of dependence liabilities of analgesic treatments.

描述（由申请人提供）： 阿片类药物和肾上腺素能激动剂在G蛋白偶联受体（GPCR）协同产生镇痛。阿片类药物耐受性和神经性疼痛都涉及神经元可塑性，可能会降低这种协同关系。提出的研究将为1）确定如何在阿片受体（OR）和α-2肾上腺素能受体（AR）激动剂之间发生协同相互作用，2）比较了在正常条件下以及神经元可塑性状态下GPCR介导的镇痛协同作用的机制，以及在神经元可塑性的状态下，以及3）检查或3）。我们将测试以下假设：假设1a-通过不同的细胞内途径共享定位夫妇的合理作用受体对；假设1b-通过相同的细胞内途径耦合的协同相互作用的受体对位于不同位置；假设2-通过改变受体亚型之间的相互作用，神经可塑性影响造成效力或镇痛激动剂的功效所驱动的受体分布或耦合的持续改变。行为研究将检查在正常，阿片类药物耐受和神经性疾病下脊柱镇痛协同作用的机制。 OR/AR的免疫组织化学定位以及从脊髓切片中释放发射机的定量将定义观察到的功能相互作用的解剖底物。背角神经元的电生理学将检查单细胞水平的药物作用和相互作用的细胞机制。从这些研究中获得的信息可以确定新的治疗性镇痛组合和组合受体靶标，导致降低镇痛治疗的依赖性负债。