5-HT3 receptor antagonists for neuropathic pain

项目总结/摘要 神经性疼痛（NeuP）影响超过1600万美国人，并导致治疗质量严重受损 生活现有药物无法充分缓解大多数NeuP患者的疼痛;此外， 诸如阿片类药物的药物具有主要的安全性问题。因此，迫切需要新的治疗方法。 needed. 5-羟色胺能5-HT 3受体（5-HT 3R）已被鉴定为治疗糖尿病的有前景的药理学靶点。 NeuP。周围神经损伤后，5-HT 3受体在脊髓神经元中的过度表达可改变周围神经损伤后脊髓神经元中5-HT 3受体的表达。 从抑制性到易化性的下行多巴胺能调节的特征，从而有助于持续的 痛苦鞘内注射5-HT 3R拮抗剂可减轻动物NeuP模型中诱发的超敏反应，但 镇痛效果与这些药物在神经性疼痛患者中的全身给药不一致。 我们的初步数据表明，外排转运蛋白，如P-糖蛋白（Pgp），限制中枢神经系统， 因此，在全身给药后，5-HT 3R拮抗剂的中枢神经系统（CNS）暴露可防止镇痛。 我们假设，如果5-HT 3R拮抗剂达到足够的CNS浓度，它们将是 有效缓解神经性疼痛。验证5-HT 3R作为神经病理性疾病的临床相关药物靶点 我们计划采取以下转化方法： 1)我们将描述模型5-HT 3R拮抗剂昂丹司琼和格拉司琼在大鼠中的CNS分布， 模型，并确定外排转运蛋白如Pgp对其CNS处置的影响。为此将 通过a）测定大鼠血浆和脑脊液（CSF）以及脑中的药物生物处置， 脊髓（全组织分析和微透析），和B）利用遗传和药理学敲除 的Pgp转运蛋白，以确定外排转运蛋白对药物处置的影响。 2)我们将确定Pgp外排对昂丹司琼在人中枢神经系统中分布的作用。会来做这项工作 测定健康受试者静脉注射昂丹司琼的血浆和CSF浓度的时程， 没有tariquidar-Pgp转运蛋白的选择性抑制剂。将在实验性疼痛中评估镇痛 模型，并将实施基于生理学的药代动力学模型来预测昂丹司琼 根据动物和人类研究的综合结果，确定了人类大脑和脊髓中的浓度。 3)我们将确定充分穿透CNS的昂丹司琼对神经性疼痛的影响。中 在NeuP患者中进行的实验性交叉研究中，将比较昂丹司琼给药时的镇痛作用 不管有没有塔里奎达在探索性的基于机制的分析中，我们将确定 个体下行疼痛易化程度与对5-HT 3R阻断的镇痛反应之间的关系。 我们希望这些结果能够成功地确定限制5-HT 3R暴露于CNS的机制 拮抗剂，并证明通过绕过这些机制，5-HT 3R拮抗剂可以减轻 神经性疼痛，特别是在感觉表型提示下行易化的患者中。

Project Summary / Abstract Neuropathic pain (NeuP) affects >16 million Americans and results in considerable impairment in quality of life. Available medications fail to adequately relief pain in the majority of NeuP patients; moreover, efficacious drugs such as opioids have major safety concerns. Therefore, new therapeutic approaches are urgently needed. Serotonergic 5-HT3 receptors (5-HT3R) have been identified as a promising pharmacological target in NeuP. After peripheral nerve damage, overexpression of 5-HT3 receptors in spinal cord neurons can shift the character of descending serotonergic modulation from inhibitory to facilitatory, thus contributing to ongoing pain. Intrathecal 5-HT3R antagonists alleviate evoked hypersensitivity in animal NeuP models, but the analgesic effects are inconsistent with systemic administration of these drugs in patients with neuropathic pain. Our preliminary data suggest that efflux transporters such as the P-glycoprotein (Pgp) limit the central nervous system (CNS) exposure of 5-HT3R antagonists, thus preventing analgesia following systemic administration. We hypothesize that if 5-HT3R antagonists were to reach adequate CNS concentrations, they would be efficacious in relieving neuropathic pain. To validate 5-HT3R as a clinically-relevant drug target in neuropathic pain, we plan to undertake the following translational approach: 1) We will characterize the CNS disposition of model 5-HT3R antagonsits ondansetron and granisteron in a rat model, and determine the effect of efflux transporters such as Pgp on their CNS disposition. This will be done by a) determining drug bio-disposition in rat plasma and cerebrospinal fluid (CSF), as well as in brain and spinal cord (whole tissue analysis and micro-dialysis), and b) utilizing genetic and pharmacological knockouts of Pgp transporters to determine the effects of efflux transporters on drug disposition. 2) We will determine the role of Pgp efflux on ondansetron disposition in human CNS. This will be done by detemining the time-course of plasma and CSF concentrations of IV ondansetron in healthy subjects, with and without tariquidar– a selective inhibitor of Pgp transporters. Analgesia will be assessed in an experimental pain model, and physiologically-based pharmacokinetic modeling will be implemented to predict ondansetron concentrations in human brain and spinal cord, based on combined results from animal and human studies. 3) We will determine the effect of adequately CNS-penetrating ondansetron on neuropathic pain. In an experimental cross-over study in NeuP patients, analgesia will be compared when ondansetron is administered with and without tariquidar. In an exploratory mechanism-based analysis, we will determine the association between the extent of individual descending pain facilitation and the analgesic response to 5-HT3R blockade. We expect the results to successfully determine the mechanisms limiting CNS exposure of 5-HT3R antagonists, and to demonstrate that by bypassing these mechanisms, 5-HT3R antagonists can alleviate neuropathic pain, particularly in patients with sensory phenotype suggesting descending facilitation.