The role of RTK signaling in opioid tolerance

RTK 信号在阿片类药物耐受中的作用

• 批准号: 8852587
• 负责人: HOWARD B GUTSTEIN
• 金额: $ 19.46万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8852587
• 关键词: Absence of pain sensation; Adverse effects; American; Analgesics; Anatomy; Blood - brain barrier anatomy; Chronic; Constipation; Delirium; Dose; Drug Formulations; Effectiveness; Epidermal Growth Factor Receptor; Face; Gefitinib; Health; Human; Imatinib; Intractable Pain; Lead; Life; Molecular; Morphine; Narcotics; Opioid; Output; Pain; Patients; Pharmaceutical Preparations; Platelet-Derived Growth Factor Receptor; Platelet-Derived Growth Factor beta Receptor; Quality of life; Recording of previous events; Regulation; Risk; Role; Signal Transduction; Societies; Solutions; Spinal Ganglia; Spinal cord posterior horn; Structure; Substantia Gelatinosa; Testing; Time; Urinary Retention; Ventilatory Depression; aqueous; base; chronic pain; cost; improved; inhibitor/antagonist; novel; novel strategies; receptor; receptor-mediated signaling; research study; response

DESCRIPTION (provided by applicant): It is estimated that over 100 million Americans suffer from chronic pain at an annual cost to our society of over 500 billion dollars. For centuries, opioid drugs such as morphine have been the first-line treatment for severe pain. However, over time tolerance to opioid analgesia develops. Patients face increased risk as well as suffering when opioids lose effectiveness. In this proposal I describe our groundbreaking discovery that the clinically used epidermal growth factor receptor (EGFR; ErbB1) antagonist gefitinib (Iressa) completely reverses morphine tolerance. Based on our findings, we hypothesize that: 1) ErbB signaling is necessary and sufficient to cause morphine tolerance; 2) Chronic opioid administration increases ErbB signaling and may underlie the phenomenon of incomplete cross tolerance; 3) Chronic opioid administration differentially regulates ErbB expression and co-localization in the dorsal root ganglion and substantia gelatinosa; and 4) Opioid-induced ErbB signaling outputs are determined by a tightly regulated transcriptional network. We will test these hypotheses by performing studies with the following Specific Aims: 1) Define the mechanisms by which ErbB receptor signaling mediates opioid tolerance; 2) Determine the effects of opioid tolerance on ErbB signaling and whether ErbB signaling can explain incomplete cross tolerance; 3) Define the specific cellular subtypes expressing ErbB receptors in the dorsal root ganglion and dorsal horn of the spinal cord, and determine if their anatomic relationships are altered by chronic opioid administration; and 4) Determine the regulation of ErbB signaling responses induced by opioids, and begin to define the network structure that underlies these responses. These studies should dramatically improve our understanding of the molecular mechanisms underlying opioid tolerance. They also may lead to a completely new approach for the treatment of chronic pain. Our findings have the potential to dramatically reduce human suffering and improve the quality of life for untold millions of patients suffering from intractabl pain.

描述（由申请人提供）：据估计，超过 1 亿美国人患有慢性疼痛，每年给我们的社会造成的损失超过 5000 亿美元。几个世纪以来，吗啡等阿片类药物一直是治疗剧烈疼痛的一线药物。然而，随着时间的推移，人们会对阿片类镇痛产生耐受性。当阿片类药物失效时，患者面临更大的风险和痛苦。在本提案中，我描述了我们的突破性发现，即临床使用的表皮生长因子受体（EGFR；ErbB1）拮抗剂吉非替尼（易瑞沙）完全逆转吗啡耐受。根据我们的研究结果，我们假设：1）ErbB 信号传导对于引起吗啡耐受是必要且充分的； 2) 长期使用阿片类药物会增加 ErbB 信号传导，并可能导致不完全交叉耐受现象； 3) 慢性阿片类药物给药差异调节背根神经节和胶质质中 ErbB 的表达和共定位； 4) 阿片类药物诱导的 ErbB 信号输出由严格调控的转录网络决定。 我们将通过进行以下具体目标的研究来检验这些假设： 1) 定义 ErbB 受体信号传导介导阿片类药物耐受的机制； 2）确定阿片类药物耐受对ErbB信号传导的影响以及ErbB信号传导是否可以解释不完全交叉耐受； 3）定义脊髓背根神经节和背角表达ErbB受体的特定细胞亚型，并确定它们的解剖关系是否因长期阿片类药物给药而改变； 4) 确定阿片类药物诱导的 ErbB 信号反应的调节，并开始定义这些反应背后的网络结构。这些研究应该极大地提高我们对阿片类药物耐受性分子机制的理解。它们还可能带来一种治疗慢性疼痛的全新方法。我们的研究结果有可能显着减少人类痛苦，并改善数百万患有顽固性疼痛的患者的生活质量。