Receptor Selective Spinal Analgesia

受体选择性脊髓镇痛

• 批准号: 7922878
• 负责人: James Eisenach
• 金额: $ 20.75万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-29 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7922878
• 关键词: Absence of pain sensation; Acute; Adenosine; Adrenergic Agents; Adrenergic Receptor; Adverse effects; Agonist; Analgesics; Animal Model; Animals; Antihypertensive Agents; Chemistry; Cholinergic Receptors; Clinical; Clinical Research; Clonidine; Complex; Cyclooxygenase Inhibitors; Development; Documentation; Dose; Evaluation; Funding; Goals; Grant; Human; Hypersensitivity; In Vitro; Investigational Drugs; Investigational New Drug Application; Ketorolac; Knowledge; Laboratories; Laboratory Study; Laparotomy; Lead; Mechanics; Microglia; Modeling; Neuronal Plasticity; Nociception; Operative Surgical Procedures; Opioid; Oral; Pain; Patients; Pharmaceutical Preparations; Phase; Postoperative Pain; Postoperative Period; Process; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Public Health; Rattus; Regulation; Risk; Role; Safety; Screening procedure; Sensory; Signal Transduction; Site; Spinal; Spinal Cord; Spinal Injections; Surgical incisions; Testing; Withdrawal; adrenergic; chronic pain; cyclooxygenase 1; efficacy trial; human study; in vivo; motivated behavior; neuronal excitability; neurotoxicity; pain behavior; preclinical toxicity; receptor; research study; response; sedative; surgical pain; tissue/cell culture; translational study; transmission process; volunteer

DESCRIPTION (provided by applicant): The long term goals of this grant are to test mechanisms of pain transmission in the spinal cord of humans and to test whether experimental pain models in animals and humans predict efficacy of spinal analgesics in clinical pain states. We focus on the spinal cord, since this is an important site of regulation of pain transmission and since we can specifically test analgesic mechanisms with spinal injection in the postoperative period and in patients with chronic pain. This grant has in the past examined spinal a2- adrenergic, adenosine, and cholinergic receptors in pain and analgesia, and in the last cycle began the study of spinal prostaglandins, using the cyclooxygenase (COX) inhibitor, ketorolac. Laboratory and clinical studies indicate efficacy of spinal ketorolac for postoperative analgesia by inhibiting COX-1 in spinal microglia which are activated during and after surgery. Our first two specific aims are to: 1. determine in humans the effect of intrathecal ketorolac on mechanical hypersensitivity and pain from surgery and acute systemic opioid exposure 2. determine in animals the key factors interactions which activate COX-1 in spinal microglia and induce pain behaviors from surgery and acute opioid exposure and probe their mechanisms In addition, the last cycle of this grant funded the synthesis of ST91, an a2-adrenoceptor agonist with better efficacy in animal models of acute and chronic pain than clonidine, but without clonidine's hypotensive and sedative side effects. We believe these advantages of ST91 reflect actions on different a2-adrenoceptor subtypes than clonidine. Our last specific aim is to: 3. complete preclinical toxicity screening and chemistry documentation for exploratory investigational new drug application (IND) to the FDA, and perform Phase I safety and efficacy trials in humans The relevance of these studies to public health is to better understand the processes in the human spinal cord which contribute to acute and chronic pain. Not only might this lead to better and safer spinally administered drugs, but these translational studies also provide proof of concept for development of oral drugs to target specific receptors for better and safer pain relief.

描述（由申请人提供）：这项资助的长期目标是测试人类脊髓中的疼痛传递机制，并测试动物和人类的实验性疼痛模型是否可以预测脊髓镇痛药在临床疼痛状态下的功效。我们关注脊髓，因为这是调节疼痛传递的重要部位，而且我们可以在术后期间和慢性疼痛患者中专门测试脊髓注射的镇痛机制。这笔资助过去曾检查脊髓a2-肾上腺素能、腺苷和胆碱能受体在疼痛和镇痛方面的作用，并在上一个周期开始使用环氧合酶（COX）抑制剂酮咯酸研究脊髓前列腺素。实验室和临床研究表明，脊髓酮咯酸通过抑制手术期间和术后激活的脊髓小胶质细胞中的 COX-1 来实现术后镇痛。我们的前两个具体目标是： 1. 在人类中确定鞘内酮咯酸对手术和急性全身阿片类药物暴露引起的机械过敏和疼痛的影响 2. 在动物中确定激活脊髓小胶质细胞中的 COX-1 并诱发疼痛的关键因素相互作用此外，本次资助的最后一个周期资助了 ST91 的合成，ST91 是一种 α2 肾上腺素受体激动剂，在动物模型中具有更好的疗效。急、慢性疼痛优于可乐定，但无可乐定的低血压和镇静副作用。我们相信 ST91 的这些优势反映了与可乐定相比对不同 α2-肾上腺素受体亚型的作用。我们的最后一个具体目标是： 3. 完成向 FDA 提交的探索性研究新药申请 (IND) 的临床前毒性筛选和化学文件，并在人体中进行 I 期安全性和有效性试验。这些研究与公共卫生的相关性是为了更好地了解人类脊髓中导致急性和慢性疼痛的过程。这不仅可能带来更好、更安全的脊髓给药药物，而且这些转化研究还为开发针对特定受体的口服药物提供了概念证明，以更好、更安全地缓解疼痛。