5-HT3 receptor antagonists for neuropathic pain

5-HT3受体拮抗剂治疗神经性疼痛

• 批准号: 10339438
• 负责人: Simon Haroutounian
• 金额: $ 42.31万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10339438
• 关键词: ABCB1 gene; Absence of pain sensation; Affect; American; Analgesics; Animal Model; Animals; Biodistribution; Blood; Blood - brain barrier anatomy; Blood capillaries; Brain; Brain Stem; Bypass; Cerebrospinal Fluid; Clinical; Clinical Trials; Cross-Over Studies; Data; Dependence; Development; Drug Modelings; Drug Targeting; Exposure to; Future; Genetic; Granisetron; HTR3A gene; Human; Hypersensitivity; Impairment; Individual; Intravenous; Ion Channel; Knock-out; Ligands; Mechanics; Mediating; Microdialysis; Modeling; Neuraxis; Neurons; Ondansetron; Opioid; Pain; Patients; Penetration; Persistent pain; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phenotype; Physiological; Plasma; Posterior Horn Cells; Pre-Clinical Model; Psychophysics; Quality of life; Rattus; Research; Research Methodology; Role; Safety; Sensory; Serotonin; Serotonin Receptors 5-HT-3; Site; Spinal Cord; Spinal cord posterior horn; Tariquidar; Testing; Time; Tissues; Toxic effect; Translational Research; Tricyclic Antidepressive Agents; Validation; antagonist; base; clinically relevant; dorsal horn; drug disposition; improved outcome; inhibitor; nerve injury; non-opioid analgesic; novel therapeutic intervention; overexpression; pain model; pain patient; pain relief; painful neuropathy; peripheral nerve damage; pharmacokinetic model; pre-clinical; prevent; receptor; response; serotonin receptor; translational approach

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.

项目摘要 /摘要 神经性疼痛（NEUP）影响> 1600万美国人，并导致质量巨大损害 生活。可用的药物无法充分缓解大多数NEUP患者的疼痛；而且，高效 阿片类药物等药物有主要的安全问题。因此，新的治疗方法是迫切的 需要。血清素能5-HT3受体（5-HT3R）已被确定为有前途的药物靶标 Neup。周围神经损伤后，脊髓神经元中5-HT3受体的过表达可以移动 从抑制性到促进性的血清能调节降序的特征，从而有助于持续 疼痛。鞘内5-HT3R拮抗剂减轻了动物NEUP模型中的超敏反应，但是 镇痛作用与神经性疼痛患者的这些药物的全身给药不一致。 我们的初步数据表明，诸如P-糖蛋白（PGP）等外排转运蛋白限制了中枢神经 5-HT3R拮抗剂的系统（CNS）暴露，从而阻止全身给药后镇痛。 我们假设5-HT3R拮抗剂要达到足够的CNS浓度，它们将是 有效缓解神经性疼痛。验证5-HT3R作为神经性临床上的药物靶标 痛苦，我们计划采用以下翻译方法： 1）我们将表征5-HT3R Antagons onDansetron和Granisteron的CNS处置 模型，并确定外排转运蛋白（例如PGP）对其中枢神经系统处置的影响。这将完成 通过a）确定大鼠血浆和脑脊液（CSF）的药物生物脱位，以及大脑和大脑和 脊髓（全组织分析和微透析），b）使用遗传和药物敲除 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外排在人CNS中ondansetron处置的作用。这将由 在健康受试者，与和 没有塔基动物 - PGP转运蛋白的选择性抑制剂。镇痛将在实验性疼痛中评估 将实施模型和基于物理的药代动力学建模以预测Ondansetron 基于动物和人类研究的综合结果，人脑和脊髓的浓度。 3）我们将确定充分的中枢神经系统穿透ondansetron对神经性疼痛的影响。在 在NEUP患者中，实验性跨界研究将在ondansetron进行时进行比较 有和没有塔基动物。在基于探索机制的分析中，我们将确定关联 在个体下降疼痛设施的程度与对5-HT3R阻滞的镇痛反应之间。 我们期望结果成功确定限制5-HT3R中枢神经系统暴露的机制 拮抗剂，并证明，通过绕过这些机制，5-HT3R拮抗剂可以减轻 神经性疼痛，特别是在有感觉表型的患者中表明降级设施。

项目成果

Pharmacokinetic Modeling of the Impact of P-glycoprotein on Ondansetron Disposition in the Central Nervous System.

• DOI: 10.1007/s11095-020-02929-2
• 发表时间: 2020-09-28
• 期刊: Pharmaceutical research
• 影响因子: 3.7
• 作者: Chiang M;Back HM;Lee JB;Oh S;Guo T;Girgis S;Park C;Haroutounian S;Kagan L
• 通讯作者: Kagan L

Plasma and cerebrospinal fluid pharmacokinetics of ondansetron in humans.

• DOI: 10.1111/bcp.14412
• 发表时间: 2021-03
• 期刊: British journal of clinical pharmacology
• 影响因子: 3.4
• 作者: Chiang MD;Frey K;Lee C;Kharasch ED;Tallchief D;Sawyer C;Blood J;Back H;Kagan L;Haroutounian S
• 通讯作者: Haroutounian S