Cellular Mechanisms of Opioid Tolerance

阿片类药物耐受的细胞机制

• 批准号: 7649234
• 负责人: MICHAEL M MORGAN
• 金额: $ 33.1万
• 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 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7649234
• 关键词: Agonist; Analgesics; Applications Grants; Binding; Brain; Cell Culture Techniques; Cell Line; Data; Development; Effectiveness; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Fentanyl; Grant; In Vitro; Knockout Mice; Knowledge; Label; Link; Mediating; Medical; Microinjections; Morphine; Neurons; Nociception; Opioid; Opioid Receptor; Pain; Patients; Persistent pain; Pharmaceutical Preparations; Physiological; Preparation; Process; Rattus; Receptor Signaling; Resistance; Role; Slice; Testing; behavior measurement; beta-arrestin; chronic pain; dermorphin; desensitization; midbrain central gray substance; mu opioid receptors; neuromechanism; prevent; receptor internalization; research study

Opioids such as morphine are the most powerful treatment for pain. Unfortunately, the analgesic effects of morphine decrease with repeated administration because of tolerance. Many mechanisms have been proposed to underlie the development of tolerance. Recent studies suggest that opioid binding at the mu-opioid receptor may be a key step in this process. Administration of high efficacy mu-opioid receptor agonists produce maximal receptor signaling, rapid desensitization of the mu-opioid receptor, and receptor internalization, but relatively little tolerance. In contrast, morphine produces minimal desensitization and receptor internalization, but tolerance is rapid and pronounced. Although these findings suggest that agonist efficacy and mu-opioid receptor internalization are important factors in tolerance to opioids, most of these data are derived from in vitro studies using brain slices or cultured cells lines. The objective of the proposed studies is to determine whether the knowledge gathered using these reduced preparations apply to tolerance mediated by the periaqueductal gray (PAG) in intact rats. In particular, the proposed studies will test the hypothesis that changes in mu-opioid receptor signaling in the PAG causes tolerance to the anti nociceptive effects of opioids. This hypotheSis will be tested by determining whether mu-opioid receptor internalization contributes to tolerance to morphine microinjections into the PAG. The strength of these studies lies in correlating physiological and anatomical changes in PAG neurons and behavioral measures of tolerance to the anti nociceptive effects of morphine. An understanding of the mechanisms underlying tolerance in intact rats will allow the development of better treatments for chronic pain patients who are tolerant to the analgesic effects of opioids.

吗啡等阿片类药物是治疗疼痛最有效的药物。不幸的是，由于耐受性，吗啡的镇痛效果会随着重复给药而降低。已经提出了许多机制来支持耐受性的发展。最近的研究表明，阿片类药物与 mu-阿片受体的结合可能是这一过程的关键步骤。施用高效μ-阿片受体激动剂可产生最大的受体信号传导、μ-阿片受体的快速脱敏和受体内化，但耐受性相对较小。相比之下，吗啡产生的脱敏和受体内化作用最小，但耐受性快速且明显。尽管这些发现表明激动剂功效和μ阿片受体内化是阿片类药物耐受性的重要因素，但这些数据大部分来自使用脑切片或培养细胞系的体外研究。拟议研究的目的是确定使用这些减少的制剂收集的知识是否适用于完整大鼠中导水管周围灰质（PAG）介导的耐受性。特别是，拟议的研究将检验以下假设：PAG 中 mu-阿片受体信号传导的变化会导致对阿片类药物的抗伤害作用产生耐受。该假设将通过确定 mu-阿片受体内化是否有助于对 PAG 中吗啡微注射的耐受性进行检验。这些研究的优势在于将 PAG 神经元的生理和解剖学变化与吗啡抗伤害作用耐受性的行为测量相关联。了解完整大鼠的耐受机制将有助于为耐受阿片类药物镇痛作用的慢性疼痛患者开发更好的治疗方法。