Cellular Mechanisms of Opioid Tolerance

吗啡等阿片类药物是治疗疼痛的最有效方法。不幸的是，由于耐受性，吗啡的止痛效果会随着反复给药而降低。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，阿片受体上的阿片结合可能是这一过程中的关键步骤。给予高效的Mu-阿片受体激动剂可产生最大的受体信号，使Mu-阿片受体快速脱敏，并使受体内化，但耐受性相对较小。相比之下，吗啡产生的脱敏和受体内化最少，但耐受性很快和明显。尽管这些发现表明激动剂的有效性和u-阿片受体内化是阿片类药物耐受性的重要因素，但这些数据大多来自使用脑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简化的制剂收集的知识是否适用于正常大鼠中脑导水管周围灰质(PAG)介导的耐受。特别是，拟议的研究将检验这样的假设，即PAG中Mu-阿片受体信号的变化导致对阿片类药物的抗伤害性作用的耐受。这一假说将通过确定u-阿片受体内化是否有助于耐受吗啡微量注射到PAG来检验。这些研究的力量在于将PAG神经元的生理和解剖变化以及耐受吗啡抗伤害效应的行为措施联系起来。了解完整大鼠的耐受机制将有助于开发更好的治疗慢性疼痛患者的方法，这些患者对阿片类药物的止痛效果耐受。

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.