Modeling Kappa Opioid Analgesic Mechanisms in Chronic Orofacial Pain Disorders

模拟卡帕阿片类药物治疗慢性口面部疼痛的镇痛机制

基本信息

批准号：
7644492
负责人：
JON DAVID LEVINE
金额：
$ 54.84万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7644492
关键词：
Absence of pain sensation Acute Adverse effects Affinity Agonist Analgesics Animal Model Behavior Binding Biochemistry Biological Butorphanol Chronic Clinical Clinical Research Clinical Trials Constipation Development Disease Dose Drug Kinetics Female Future Goals Human Interdisciplinary Study Laboratories Measures Modeling Morphine Nalbuphine Naloxone Narcotic Analgesics Narcotics Nociceptive Reflex Opioid Opioid Analgesics Opioid Receptor Orofacial Pain Pain Pain Disorder Patient Self-Report Patients Pentazocine Pharmaceutical Preparations Pharmacology Pharmacotherapy Research Personnel Sedation procedure Series Sex Characteristics Stimulus Syndrome Testing Therapeutic Treatment Efficacy Ventilatory Depression Woman Work addiction base clinically relevant design drug candidate experience improved insight male men neurophysiology orofacial pharmacodynamic model pre-clinical prevent programs receptor receptor binding sex sexual dimorphism

项目摘要

DESCRIPTION (provided by applicant): The use of narcotic analgesics to treat severe chronic orofacial pain conditions is limited by potentially serious side-effects. Kappa (kappa opioid drugs have fewer clinically limiting adverse effects than other narcotics (notably including much lower abuse potential), but candidate drugs have proved disappointing in clinical trials, due largely to their poor analgesic efficacy. Preliminary work in our laboratory has revealed that one of the most important limits on analgesic efficacy of kappa opioid drugs in clinical orofacial pain is their activation of a distinct anti-analgesic mechanism that opposes their analgesic effect. This anti-analgesic effect is strongly sex-dependent, causing males to experience a net increase in pain when administered kappa opioids, while females experience potent dose-dependent analgesia similar in magnitude to that induced by high-dose morphine. We propose a series of studies to assess the impact of the anti-analgesia mechanism on kappa opioid analgesic efficacy in chronic orofacial pain syndromes. Successful future use of kappa opioid analgesic drugs in orofacial pain syndromes will likely depend on therapeutic strategies designed to minimize their antianalgesic effect. Achieving this goal will require a deeper understanding of the mechanisms of kappa opioid anti-analgesia, and therefore, we will also investigate receptor pharmacology of the anti-analgesia circuitry in a clinical model of orofacial pain. Consistent with the stated goals of RFA-DE-07-006, our proposal will employ clinical studies of patients with chronic and acute painful orofacial disorders to provide important insights into the biological mechanisms underlying analgesic treatment of chronic orofacial pain. These studies will involve the efforts of a multidisciplinary research team that will include expertise in clinical orofacial pain practice, human drug studies in orofacial pain, computational pharmacology, and receptor binding biochemistry. Our observations are likely to directly impact clinical strategies to improve the efficacy of analgesic therapy in chronic orofacial pain conditions, and eliminate gender differences in therapeutic efficacy.

描述（由申请人提供）：使用麻醉镇痛药治疗严重的慢性口面疼痛条件受到潜在严重的副作用的限制。 Kappa (kappa opioid drugs have fewer clinically limiting adverse effects than other narcotics (notably including much lower abuse potential), but candidate drugs have proved disappointing in clinical trials, due largely to their poor analgesic efficacy. Preliminary work in our laboratory has revealed that one of the most important limits on analgesic efficacy of kappa opioid drugs in clinical orofacial pain is their activation of一种反对其镇痛作用的独特的抗动物机制。我们提出了一系列研究，以评估抗扰动机制对慢性口面部疼痛综合征中Kappa阿片类镇痛功效的影响。未来在口腔疼痛综合征中成功使用Kappa阿片类镇痛药可能会取决于旨在最大程度地减少其抗凝乳作用的治疗策略。实现这一目标将需要更深入地了解Kappa阿片类抗Antaalgesia的机制，因此，我们还将在口面疼痛的临床模型中研究抗扰流电路的受体药理学。与RFA-DE-07-006的既定目标一致，我们的提案将采用慢性和急性疼痛的口面疾病患者的临床研究，以对慢性口粮疼痛的镇痛治疗的生物学机制提供重要见解。这些研究将涉及多学科研究团队的努力，该研究团队将包括临床口面疼痛实践，人类药物研究，口面疼痛，计算药理学和受体结合生物化学方面的专业知识。我们的观察结果可能会直接影响临床策略，以提高镇痛治疗在慢性口面疼痛状况中的功效，并消除治疗功效的性别差异。