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Role for delta opioid receptor in morphine tolerance during chronic pain

δ阿片受体在慢性疼痛期间吗啡耐受中的作用

基本信息

批准号：
9237059
负责人：
Jose A Moron-Concepcion
金额：
$ 11.59万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9237059
关键词：
Role delta opioid receptor morphine

项目摘要

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,

慢性疼痛是美国人最重要的社会负担之一，受影响，其对医疗保健系统的影响和生产力的损失。传统的鸦片制剂，如吗啡，仍然是治疗中度至重度术后疼痛和癌症疼痛的“黄金标准” 以及用于治疗慢性非恶性疼痛和炎性疼痛。然而，长期使用亩阿片受体（MOP）激动剂，如吗啡，在慢性疼痛的设置，是有限的发展，耐受性和身体依赖性。阿片类药物耐受性是药物效力或功效的逐渐丧失，减少行动时间。耐受性往往伴随着身体依赖，在某些情况下，上瘾。阿片样物质受体亚家族包括μ、δ和κ阿片样物质受体（MOP、DOP和Kappa）。 KOP）。虽然很明显吗啡诱导的镇痛是由MOP激活介导的，但DOP在吗啡诱导的镇痛中的作用并不明显。镇痛仍然不清楚。有报道称，吗啡诱导的急性疼痛镇痛耐受性是在施用DOP拮抗剂后以及在缺乏功能性DOP的小鼠中，令人惊讶的是，没有关于DOP在慢性疼痛中吗啡诱导的镇痛耐受性的发展中的作用的研究。我们认为，同时靶向MOP和DOP将减少慢性吗啡依赖患者吗啡诱导的镇痛耐受。痛苦MOP和DOP之间的功能和物理相互作用在这一过程中起着关键作用，慢性疼痛期间吗啡诱导的镇痛耐受的发展提供了一个新的靶点， MOP-DOP相互作用的调节可以改善吗啡和其它MOP的副作用特征配体。所提出的实验将检验用DOP拮抗剂或 MOP-DOP异聚体的破坏将导致镇痛耐受性的减弱，在慢性疼痛期间反复注射吗啡。我们还提出吗啡诱导的镇痛剂耐受性由DOP表达和功能的增加以及MOP-DOP增加介导在初级传入神经、脊髓和/或涉及阿片样物质控制的脑区的异聚体丰度伤害感受，如中脑导水管周围灰质（PAG）。在具体目标1中，我们将进行生物化学和行为分析，以研究MOP-DOP相互作用在吗啡衰减中的作用，在慢性炎性疼痛模型中通过DOP拮抗剂诱导镇痛耐受。在具体目标2中，在体外记录中，我们将描述DOP和MOP在吗啡诱导的衰减中的作用。慢性炎性疼痛模型中的镇痛耐受性。目前的研究结果将有一个对阿片受体的生物学和药理学领域产生了持续、强大的影响，具有广阔的应用前景新的，更安全，更有效的药物治疗策略，用于治疗慢性疼痛。事实上，由于MOP激动剂已经广泛用于临床，改善了它们的负面副作用，增强它们的镇痛作用具有迅速有益于慢性疼痛患者的潜力，