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

• 批准号: 9063186
• 负责人: Susan M Carlton
• 金额: $ 1.19万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9063186
• 关键词: Absence of pain sensation; Acute Pain; Adverse effects; Affect; Afferent Neurons; Agonist; American; Analgesics; Animals; Behavioral; Biochemical; Biochemistry; Biology; Brain; Caring; Cells; Chronic; Chronic inflammatory pain; Clinical Management; Complex; Cutaneous; Data; Dependence; Development; Disease; Dose; Exploratory/Developmental Grant; Fiber; Goals; Gold; Health; Healthcare Systems; In Vitro; Inflammatory; Injection of therapeutic agent; Investigation; Ligands; Low Back Pain; Mediating; Midbrain structure; Modeling; Molecular; Morphine; Mus; Nociception; Non-Malignant; Opiates; Opioid; Opioid Receptor; Outcome; Pain; Patients; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Pharmacology; Physical Dependence; Play; Postherpetic neuralgia; Postoperative Period; Productivity; Property; Receptor Activation; Reporting; Rewards; Role; Site; Spinal Cord; Spinal cord posterior horn; Symptoms; Synapses; Synaptic Transmission; attenuation; base; cancer pain; chronic pain; delta opioid receptor; dimer; improved; inflammatory pain; midbrain central gray substance; mu opioid receptors; novel; novel strategies; opiate tolerance; patch clamp; postsynaptic; preference; prevent; theories; transmission process; treatment strategy

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.

描述（由申请人提供）：就受影响的美国人数量、其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治疗慢性非恶性疼痛和炎性疼痛的“黄金标准”。然而，在慢性疼痛的情况下，长期使用μ阿片受体（MOP）激动剂如吗啡受到耐受性和身体依赖性的发展的限制。阿片类药物耐受性是药物效力或效力的逐渐丧失，以及作用持续时间的缩短。阿片受体亚家族包括μ、δ和κ阿片受体（MOP、DOP和KOP）。虽然很明显吗啡诱导的镇痛是由MOP激活介导的，但DOP在镇痛中的作用仍不清楚。据报道，在急性疼痛中，吗啡诱导的镇痛耐受性在施用DOP拮抗剂后和在缺乏功能性DOP的小鼠中降低。因此，看来MOP-DOP相互作用在调节吗啡诱导的镇痛耐受中起重要作用。令人惊讶的是，没有关于DOP或MOP-DOP相互作用在慢性疼痛中吗啡诱导的镇痛耐受的发展中的作用的研究。我们最近报道，预处理与DOP 2拮抗剂，纳曲本，破坏吗啡条件性位置偏爱，这种效果与增加的DOP二聚体在突触的水平。此外，我们的初步研究表明，在慢性炎性疼痛的存在下，吗啡耐受性与突触处DOP的表达增加和脊髓背角中MOP-DOP异聚体的水平增加相关。基于这些数据，我们提出，用DOP拮抗剂预处理或破坏MOP-DOP异聚体将导致在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性介导的DOP功能和MOP-DOP异源聚体丰度增加，这反过来又减少了MOP介导的抑制兴奋性传递。这导致在初级传入神经、脊髓神经和脊髓神经节中阿片镇痛潜力的丧失。 脊髓和涉及阿片样物质控制伤害感受的脑部位，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，以研究MOP-DOP相互作用在慢性炎性疼痛期间吗啡诱导的镇痛耐受减弱中的作用。在具体目标2中，使用体外记录，我们将描述的作用，DOP和MOP-DOP相互作用的兴奋性传输控制在吗啡诱导的镇痛耐受在慢性炎性疼痛的存在。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，强大的影响，并有望为治疗慢性疼痛提供新的，更安全，更有效的药理学策略。