Cellular Mechanisms of Opioid Tolerance

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，吗啡的镇痛作用随着反复给药而减弱。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，阿片在mu-阿片受体上的结合可能是这一过程的关键步骤。施用高效的阿片受体激动剂可产生最大的受体信号，快速脱敏和受体内化，但耐受性相对较低。相比之下，吗啡产生最小的脱敏和受体内化，但耐受性是迅速和明显的。虽然这些发现表明，激动剂的功效和阿片受体内化是阿片耐受性的重要因素，但这些数据大多来自体外研究，使用脑切片或培养细胞系。拟议研究的目的是确定使用这些还原制剂收集的知识是否适用于完整大鼠的导水管周围灰质（PAG）介导的耐受性。特别是，拟议的研究将验证PAG中mu-阿片样物质受体信号的变化导致阿片样物质抗伤害作用耐受性的假设。这一假设将通过确定mu-阿片受体内化是否有助于对PAG微量注射吗啡的耐受性来验证。这些研究的优势在于将PAG神经元的生理和解剖变化与吗啡抗伤害效应耐受的行为措施联系起来。了解完整大鼠的耐受性机制将有助于开发对阿片类药物镇痛作用耐受的慢性疼痛患者的更好治疗方法。

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.