Role for delta opioid receptor in morphine tolerance during chronic pain

描述(由申请者提供)：就受影响的美国人的数量、对医疗保健系统的影响和生产力损失而言，慢性疼痛是最严重的社会负担之一。经典的鸦片类药物，如吗啡，仍然是治疗中重度术后疼痛和癌症疼痛以及治疗慢性非恶性和炎症性疼痛的“黄金标准”。然而，在慢性疼痛的背景下，长期使用MU阿片受体(MOP)激动剂，如吗啡，受到耐受性和身体依赖的发展的限制。阿片类药物耐受性是指药物效力或疗效逐渐丧失，作用时间缩短。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在镇痛中的作用尚不清楚。据报道，在急性疼痛中，给予DOP拮抗剂或在缺乏功能性DOP的小鼠中，吗啡诱导的止痛耐受性降低。因此，MOP-DOP相互作用在吗啡诱导的镇痛耐受中起着重要的调节作用。令人惊讶的是，没有关于DOP或MOP-DOP相互作用在慢性疼痛吗啡诱导的止痛耐受形成中的作用的研究。我们最近报道，用DOP2拮抗剂纳曲本预先阻断吗啡条件性位置偏爱，这种作用与突触DOP二聚体水平的增加有关。此外，我们的初步研究表明，慢性炎症性疼痛时的吗啡耐受与突触DOP表达增加和脊髓背角MOP-DOP异构体水平增加有关。基于这些数据，我们认为，DOP拮抗剂的预处理或MOP-DOP异构体的破坏将导致在慢性疼痛期间反复注射吗啡后形成的止痛耐受性减弱。我们还提出，吗啡诱导的镇痛耐受是通过增加DOP功能和MOP-DOP异构体丰度来介导的，这反过来又减少了MOP对兴奋性传递的抑制。这会导致初级传入、脊髓的阿片类止痛潜能丧失。 脊髓和与阿片类药物控制伤害性感觉有关的脑部位，如中脑导水管周围灰质(PAG)。在具体目标1中，我们将进行行为和生化分析，以探讨MOP-DOP相互作用在慢性炎症性疼痛中减轻吗啡诱导的镇痛耐受中的作用。在特定的目标2中，我们将利用体外记录，表征DOP和MOP-DOP相互作用在慢性炎症性疼痛时吗啡诱导的镇痛耐受过程中控制兴奋性传递的作用。本研究的结果将对阿片受体的生物学和药理学领域产生持续的、强有力的影响，并有望开发出治疗慢性疼痛的新的、更安全、更有效的药物治疗策略。

DESCRIPTION (provided by applicant): 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. 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. Thus, it seems that MOP-DOP interactions play an important role in modulating morphine-induced analgesic tolerance. Surprisingly, there are no studies regarding the role of DOP or MOP-DOP interactions in the development of morphine-induced analgesic tolerance in chronic pain. We have recently reported that pretreatment with the DOP2 antagonist, naltriben, disrupts morphine conditioned place preference and that this effect is associated with an increase in the levels of DOP dimer at the synapse. In addition, our preliminary studies show that morphine tolerance in the presence of chronic inflammatory pain is associated with an increased expression of the DOP at the synapse and with increased levels of the MOP-DOP heteromer in the spinal cord dorsal horn. Based on these data, we propose 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 function and MOP-DOP heteromer abundance, which in turn reduces MOP-mediated inhibition of excitatory transmission. This results in a loss of opiate analgesic potential, at the primary afferent, spinal cord and at brain sites implicated in opioid control of nociception such as the midbrain periaqueductal gray (PAG). In Specific Aim 1 we will conduct behavioral and biochemical analyses to investigate the role of MOP-DOP interactions in the attenuation of morphine-induced analgesic tolerance during chronic inflammatory pain. In Specific Aim 2 using in vitro recordings, we will characterize the role of DOP and MOP-DOP interactions in the control of excitatory transmission during morphine-induced analgesic tolerance in the presence of chronic inflammatory pain. 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.