Receptor Selective Spinal Analgesia

描述（由申请人提供）：本资助的长期目标是测试人类脊髓疼痛传递的机制，并测试动物和人类的实验性疼痛模型是否能预测脊髓镇痛药在临床疼痛状态下的疗效。我们关注脊髓，因为这是调节疼痛传递的重要部位，因为我们可以在术后和慢性疼痛患者中专门测试脊髓注射的镇痛机制。该基金在过去研究了疼痛和镇痛的脊髓a2-肾上腺素能、腺苷和胆碱能受体，并在最后一个周期开始研究脊髓前列腺素，使用环氧化酶（COX）抑制剂酮咯酸。实验室和临床研究表明，脊柱酮咯酸通过抑制术中和术后激活的脊髓小胶质细胞COX-1来实现术后镇痛。我们的头两个具体目标是：1。测定人鞘内酮罗拉酸对手术引起的机械过敏和疼痛以及急性全身性阿片类药物暴露的影响在动物实验中确定激活脊髓小胶质细胞COX-1并诱导手术和急性阿片类药物暴露引起的疼痛行为的关键因素相互作用，并探讨其机制。此外，该资助的最后一个周期资助了ST91的合成，ST91是一种a2肾上腺素能受体激动剂，在急性和慢性疼痛动物模型中比可乐定疗效更好，但没有可乐定的降血压和镇静副作用。我们认为ST91的这些优势反映了与可乐定相比，ST91对不同a2-肾上腺素受体亚型的作用。我们最后的具体目标是：完成临床前毒性筛选和化学文件，为探索性研究新药申请（IND）向FDA，并进行人体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、更安全的脊髓给药，而且这些转化研究也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。

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.