PHARMACOLOGY OF HUMAN EXPERIMENTAL AND NEUROPATHIC PAIN

关于疼痛的动物模型强调，少量的传入输入会导致 易患痛觉过敏和痛觉异常的状态。平行实验 利用定量感官测试开发了人体模型 (QST)和使用热脉冲和皮下辣椒素的模型 一种痛觉过敏和超常疼痛的状态。临床前研究表明 动物的这些过激状态是由外周神经调节的 和脊椎药理学不同于介导急性C纤维的 激动人心。注意到几个特征：i)急性兴奋，但不是 低阈值传入输入受MU、α2激动剂和 非甾体抗炎药；II)一种状态是由少量的传入输入引起的，这种输入是由 部分通过NMDA受体；以及iii)受损的神经可能导致一种状态 部分由钠升高引起的自发活动调节 频道。这些观察结果提出了几个假设，它们反映了 人体内的药物作用。1)Mu、α2激动症和非甾体抗炎药 对热阈值和机械阈值影响很小；将 提高热痛和机械痛阈值，减少继发性疼痛 小传入兴奋引起的痛觉过敏，而NMDA 对抗不会对急性阈值产生什么影响，但会 减少继发性痛觉过敏。2)钠离子通道阻断将 减少继发性痛敏，对急性疼痛影响最小 阈值。使用QST作为热阈值和机械阈值， 用热脉冲和皮内刺激产生疼痛状态 辣椒素，钠通道阻滞剂，Mu阿片类激动剂， α-2-激动剂、非甾体抗炎药、NMDA拮抗剂和一些其他药物 口服和静脉途径的止痛药，假说 将在人体上进行测试。这些实验性的疼痛状态是 据信反映了后神经成分的潜在机制 伤痛状态。因此，根据我们的假设， 神经递质来源的传入加工药理学研究进展 临床前工作，这项提案试图定义1)是否 受体和通道机制对实验性人类疼痛的影响 模型；以及，2)某些临床疼痛状态是由 具有与实验人类相似的药理学的机制 疼痛模型及相应的动物模型。这些研究将 支持存在以下关联的前提： 实验状态和临床状态之间的机制以及 实验模型可以预测药物在异常情况下的临床疗效 人类的疼痛状态。

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.