Role for delta opioid receptor in morphine tolerance during chronic pain

就美国人的数量而言，慢性疼痛是最严重的社会负担之一 受影响，其对卫生保健系统的影响和生产力损失。传统的鸦片类药物，如吗啡， 仍然是治疗中重度术后疼痛和癌性疼痛的“黄金标准” 以及治疗慢性非恶性和炎症性疼痛。然而，长期使用的亩 阿片受体激动剂，如吗啡，在慢性疼痛的背景下，受到发展的限制。 容忍和身体依赖。阿片耐受性是指药物效力或疗效的逐渐丧失，以及 缩短了行动持续时间。耐受性常常伴随着身体依赖，在某些情况下 因为上瘾。阿片受体亚家族包括Mu、Delta和Kappa阿片受体(MOP、DOP和 KOP)。虽然很明显，吗啡的镇痛作用是通过激活MOP介导的，但DOP在脑内的作用 止痛作用仍不清楚。据报道，吗啡诱导的镇痛耐受在急性疼痛中是 在给予DOP拮抗剂和缺乏功能性DOP的小鼠中减少。令人惊讶的是，没有 关于DOP在慢性疼痛吗啡镇痛耐受形成中的作用的研究。 我们认为同时靶向MOP和DOP将降低慢性吗啡诱导的镇痛耐受性。 疼痛。MOP和DOP之间的功能和物理相互作用在 慢性疼痛过程中吗啡诱导的镇痛耐受的发展提供了一个新的靶点 哪种MOP-DOP相互作用的调节可以改善吗啡和其他MOP的副作用 配基。拟议的实验将检验这样的假设，即用DOP拮抗剂或 破坏MOP-DOP异构体将导致形成的止痛耐受性的减弱 在慢性疼痛期间反复注射吗啡后。我们还提出了吗啡诱导的镇痛剂 耐受性是由DOP表达和功能增加以及MOP-DOP增加所介导的 初级传入、脊髓和/或脑区的异构体丰度与阿片类药物控制有关 伤害性感觉，如中脑导水管周围灰质(PAG)。在具体目标1中，我们将进行生化 和行为分析，以调查MOP-DOP相互作用在吗啡减弱中的作用。 在慢性炎症性疼痛模型中使用DOP拮抗剂诱导镇痛耐受。在具体目标2中使用 在体外记录中，我们将表征DOP和MOP在吗啡诱导的减弱中的作用 慢性炎症性疼痛模型中的止痛耐受性。本研究的结果将有一个 阿片受体在生物学和药理学领域的持续、强大的影响与前景 用于治疗慢性疼痛的新的、更安全和更有效的药物治疗策略。事实上, 由于MOP激动剂已广泛应用于临床，改善其不良反应和 增强其止痛作用有可能使慢性疼痛患者迅速受益，

Chronic pain represents one of the most significant societal burdens in terms of the number of Americans affected, its impact on the health care system and lost productivity. Classical opiates, such as morphine, remain the "gold standard" of care for the management of moderate to severe post-operative and cancer pain as well as for the treatment of chronic non-malignant and inflammatory pain. However, the long-term use of mu opioid receptor (MOP) agonists such as morphine, in the setting of chronic pain, is limited by the development of tolerance and physical dependence. Opiate tolerance is the gradual loss of drug potency or efficacy, and reduced duration of action. Tolerance is frequently accompanied by physical dependence and in some cases by addiction. The opioid receptor subfamilies include mu, delta, and kappa opioid receptors (MOP, DOP, and KOP). While it is clear that morphine-induced analgesia is mediated by MOP activation, the role of DOP in analgesia remains unclear. It has been reported that morphine-induced analgesic tolerance in acute pain is reduced upon administration of DOP antagonists and in mice lacking functional DOP. Surprisingly, there are no studies regarding the role of DOP in the development of morphine-induced analgesic tolerance in chronic pain. We propose that targeting both the MOP and DOP will reduce morphine-induced analgesic tolerance in chronic pain. The concept that functional and physical interactions between MOP and DOP play a key role in the development of morphine-induced analgesic tolerance during chronic pain provides a novel target through which modulation of MOP-DOP interactions may improve the side-effect profile of morphine and other MOP ligands. The proposed experiments will test the hypothesis that pretreatment with DOP antagonists or disruption of the MOP-DOP heteromer will result in an attenuation of the analgesic tolerance that develops after repeated morphine injections during chronic pain. We also propose that morphine-induced analgesic tolerance is mediated by increased DOP expression and function as well as by increased MOP-DOP heteromer abundance at the primary afferent, spinal cord and/or at brain areas implicated in opioid control of nociception such as the midbrain periaqueductal gray (PAG). In Specific Aim 1 we will conduct biochemical and behavioral analyses to investigate the role of MOP-DOP interactions in the attenuation of morphine- induced analgesic tolerance by DOP antagonists in a chronic inflammatory pain model. In Specific Aim 2 using in vitro recordings, we will characterize the role of DOP and MOP in the attenuation of morphine-induced analgesic tolerance in a chronic inflammatory pain model. The outcomes of the present studies will have a sustained, powerful impact on the fields of the biology and pharmacology of opioid receptors with the prospects of novel, safer and more effective pharmacotherapeutic strategies for the treatment of chronic pain. In fact, since MOP agonists are already widely used in the clinic, ameliorating their negative side-effects and potentiating their analgesic effects have the potential to rapidly benefit chronic pain patients,