Receptor Selective Spinal Analgesia

描述(申请人提供)：这笔赠款的长期目标是测试疼痛在人类脊髓中的传递机制，并测试动物和人类的实验性疼痛模型是否可以预测脊椎止痛剂在临床疼痛状态下的疗效。我们将重点放在脊髓上，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止痛机制。这项资助在过去研究了脊髓中的a2-肾上腺素能、腺苷和胆碱能受体在疼痛和止痛中的作用，并在最后一个周期中开始了对脊髓前列腺素的研究，使用了环氧合酶(COX)抑制剂酮咯酸。实验室和临床研究表明，脊髓酮咯酸通过抑制术中和术后激活的脊髓小胶质细胞中的COX-1而达到术后镇痛的效果。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所致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COX-1并在手术和急性阿片类药物暴露中诱导疼痛行为的关键因素相互作用，并探讨其机制。此外，这笔赠款的最后一个周期资助了ST91的合成，这是一种在急性和慢性疼痛动物模型中比可乐定更有效但没有可乐定降压和镇静副作用的a2-肾上腺素能受体激动剂ST91。我们认为，ST91的这些优势反映了与可乐定不同的a2肾上腺素受体亚型的作用。我们的最后一个具体目标是：3.为FDA的探索性研究新药应用(IND)完成临床前毒性筛选和化学文件，并在人体上进行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。这不仅可能导致更好和更安全的脊椎给药，而且这些翻译研究也为开发针对特定受体的口服药物提供了概念证据，以更好和更安全地缓解疼痛。

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.