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5亿美元的社会，超过1亿美国人患有慢性疼痛。几个世纪以来，吗啡等阿片类药物一直是严重疼痛的一线治疗方法。但是，随着时间的流逝，对阿片类镇痛的耐受性会发展出来。当阿片类药物失去效力时，患者面临着增加的风险和痛苦。在该提案中，我描述了我们的开创性发现，即临床使用表皮生长因子受体（EGFR; ERBB1）拮抗剂Gefitinib（IRESSA）完全逆转了吗啡的耐受性。根据我们的发现，我们假设：1）ERBB信号传导是必要的，足以引起吗啡耐受； 2）慢性阿片类药物给药增加了ERBB信号传导，并可能是不完全交叉耐受的现象； 3）慢性阿片类药物给药差异调节背层神经节和明质质体的ERBB表达和共定位； 4）阿片类药物诱导的ERBB信号输出由严格调节的转录网络确定。 我们将通过以下特定目的进行研究来检验这些假设：1）定义ERBB受体信号介导阿片类药物耐受性的机制； 2）确定阿片类药物耐受性对ERBB信号传导的影响以及ERBB信号是否可以解释不完全的交叉耐受性； 3）定义特定的细胞亚型，在脊髓的背根神经节和背角中表达ERBB受体，并确定其解剖学关系是否因慢性阿片类药物的施用而改变； 4）确定阿片类药物诱导的ERBB信号反应的调节，并开始定义这些响应基础的网络结构。这些研究应大大提高我们对阿片类药物耐受性的分子机制的理解。它们还可能导致一种全新的方法来治疗慢性疼痛。我们的发现有可能大大减少人类的痛苦，并改善数百万患有疼痛的无数患者的生活质量。