Role for delta opioid receptor in morphine tolerance during chronic pain

描述（由申请人提供）：就受影响的美国人数量、对医疗保健系统的影响和生产力损失而言，慢性疼痛是最重要的社会负担之一。吗啡等经典阿片类药物仍然是治疗中度至重度术后疼痛和癌症疼痛以及慢性非恶性疼痛和炎症性疼痛的“金标准”。然而，长期使用阿片受体（MOP）激动剂如吗啡，在慢性疼痛的情况下，受到耐受性和身体依赖性的发展限制。阿片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）。虽然吗啡诱导的镇痛是由MOP激活介导的，但DOP在镇痛中的作用尚不清楚。据报道，吗啡诱导的急性疼痛镇痛耐受性在给予DOP拮抗剂和缺乏功能性DOP的小鼠中降低。因此，mopp - dop相互作用似乎在吗啡诱导的镇痛耐受调节中起重要作用。令人惊讶的是，目前还没有关于DOP或mopp -DOP相互作用在慢性疼痛中吗啡诱导的镇痛耐受发展中的作用的研究。我们最近报道了DOP2拮抗剂钠三苯预处理会破坏吗啡条件下的位置偏好，并且这种影响与突触中DOP2二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中DOP的表达增加以及脊髓背角中mopp -DOP异构体的水平增加有关。基于这些数据，我们建议使用DOP拮抗剂预处理或破坏mopp -DOP异构体将导致慢性疼痛期间反复注射吗啡后产生的镇痛耐受性减弱。我们还提出吗啡诱导的镇痛耐受是通过增加DOP功能和mopp -DOP异构体丰富度介导的，这反过来又降低了mopp介导的兴奋传递抑制。这导致阿片类镇痛电位的丧失，在初级传入，脊柱

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.