PHARMACOLOGY OF HUMAN EXPERIMENTAL AND NEUROPATHIC PAIN

人类实验性疼痛和神经病理性疼痛的药理学

• 批准号: 2891415
• 负责人: MARK S WALLACE
• 金额: $ 9.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2891415
• 关键词: NMDA receptors; afferent nerve; analgesics; anticonvulsants; capsaicin; clinical research; clonidine; dosage; drug screening /evaluation; electrostimulus; enzyme inhibitors; fentanyl; human subject; hyperalgesia; ion channel blocker; ketamine; lidocaine; nerve injury; nerve threshold; neuropharmacology; pain; pharmacokinetics; prostaglandin endoperoxide synthase; sensory thresholds; sodium channel

Animal models on pain emphasize that small afferent input leads to a facilitated state of hyperalgesia and allodynia. Parallel experimental models in humans have been developed using quantitative sensory testing (QST) and models using thermal pulses and subdermal capsaicin to evoke a state of hyperalgesia and allodynia. Preclinical studies have shown that these hyperpathic states in animals are mediated by a peripheral and spinal pharmacology distinct from that which mediates acute C fiber excitation. Several characteristics are noted: i) Acute high, but not low threshold afferent input is affected by mu, alpha 2 agonists, and NSAIDS; ii) A state is induced by small afferent input which is mediated in part by NMDA receptors; and iii) Injured nerves may induce a state mediated in part by spontaneous activity mediated by increased sodium channels. These observations suggest several hypotheses which reflect drug action in humans. 1) Mu, alpha 2 agonism, and NSAIDS will have little effect upon thermal and mechanical thresholds; will increase thermal and mechanical pain thresholds and, reduce secondary hyperalgesia induced by small afferent activation, whereas NMDA antagonism will have little effect upon acute thresholds, but will reduce the secondary hyperalgesia. 2) Sodium channel blockade will diminish the secondary hyperalgesia with minimum effect upon acute thresholds. Using QST for thermal and mechanical thresholds, the generation of a painful state with thermal pulses and intradermal capsaicin, and delivery of sodium channel blocker, mu opioid agonists, alpha-2-agonist, NSAIDS, NMDA antagonists, and some miscellaneous analgesic drugs by the oral and intravenous route, the hypotheses presented will be tested in humans. These experimental pain states are believed to reflect mechanisms underlying components of the post nerve injury pain state. Thus, based on hypotheses derived from our understanding of the pharmacology of afferent processing derived from preclinical work, this proposal seeks to define whether 1) certain receptor and channel mechanisms influence the experimental human pain models; and, 2) that certain clinical pain states are mediated by mechanisms which have a comparable pharmacology to experimental human pain models and the corresponding animal model. These studies will provide support for the premise that there is a correlation of mechanisms between experimental and clinical states and that the experimental models can predict clinical efficacy of agents in anomalous human pain states.

关于疼痛的动物模型强调，小的传入输入会导致疼痛 促进痛觉过敏和异常性疼痛的状态。 平行实验 人类模型是使用定量感官测试开发的 (QST) 和使用热脉冲和皮下辣椒素诱发的模型 痛觉过敏和异常性疼痛的状态。 临床前研究表明 动物中的这些过敏状态是由外周神经介导的 和脊髓药理学不同于介导急性 C 纤维的药理学 励磁。 注意到几个特征： i) 急性高，但不 低阈值传入输入受 mu、α2 激动剂和 非甾体抗炎药； ii）状态是由小的传入输入引起的，该输入是介导的 部分通过 NMDA 受体； iii) 受伤的神经可能会诱发一种状态 部分由钠增加介导的自发活动介导 渠道。这些观察结果提出了一些假设，反映了 药物对人体的作用。 1) Mu、α2 激动剂和 NSAIDS 会产生 对热阈值和机械阈值影响很小；将要 增加热和机械疼痛阈值，并减少继发性疼痛 由小传入激活引起的痛觉过敏，而 NMDA 拮抗作用对急性阈值影响不大，但会 减少继发性痛觉过敏。 2) 钠通道阻断 减少继发性痛觉过敏，对急性发作的影响最小 阈值。 使用 QST 作为热和机械阈值， 通过热脉冲和皮内注射产生疼痛状态 辣椒素，以及钠通道阻滞剂、μ阿片类激动剂的输送， α-2-激动剂、NSAIDS、NMDA 拮抗剂和一些杂项 镇痛药物通过口服和静脉途径给药，假设 所提出的将在人体中进行测试。 这些实验性疼痛状态是 据信反映了后神经成分的潜在机制 受伤疼痛状态。 因此，基于我们的假设 对传入加工药理学的理解源自 在临床前工作中，该提案旨在定义是否 1) 某些 受体和通道机制影响实验人类疼痛 模型； 2) 某些临床疼痛状态是由以下因素介导的 具有与实验人体相当的药理学机制 疼痛模型和相应的动物模型。 这些研究将 为存在相关性的前提提供支持 实验状态和临床状态之间的机制 实验模型可以预测异常药物的临床疗效 人类的痛苦状态。