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.

项目概要/摘要 神经性疼痛 (NeuP) 影响超过 1600 万美国人，并导致患者的治疗质量严重受损 现有药物无法充分缓解大多数 NeuP 患者的疼痛； 阿片类药物等存在重大药物安全问题，因此迫切需要新的治疗方法。 血清素能 5-HT3 受体 (5-HT3R) 已被确定为有希望的药理学靶点。 NeuP。周围神经损伤后，脊髓神经元中 5-HT3 受体的过度表达可以改变 血清素能调节从抑制性到促进性的下降特征，从而有助于持续的 鞘内注射 5-HT3R 拮抗剂会在动物 NeuP 模型中引起超敏反应，但 这些药物对神经性疼痛患者的镇痛效果与全身给药不一致。 我们的初步数据表明，P-糖蛋白 (Pgp) 等外排转运蛋白限制中枢神经系统 5-HT3R拮抗剂的系统（CNS）暴露，从而防止全身给药后的镇痛。 我们追求的是，​​如果 5-HT3R 拮抗剂要达到足够的 CNS 浓度，它们将 有效缓解神经性疼痛，验证 5-HT3R 作为神经性疼痛的临床相关药物靶点。 痛苦，我们计划采取以下转化方法： 1) 我们将表征模型 5-HT3R 拮抗剂昂丹司琼和格拉司琼在大鼠中的中枢神经系统配置 模型，并确定外排转运蛋白（例如 Pgp）对其 CNS 处置的影响。 a) 确定药物在大鼠血浆和脑脊液 (CSF) 以及脑和组织中的生物处置 脊髓（全组织分析和微透析），b) 利用遗传和药理学敲除 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 外流对人类 CNS 中昂丹司琼处置的作用。 确定健康受试者静脉注射昂丹司琼的血浆和脑脊液浓度的时间过程，以及 没有塔里奎达——Pgp 转运蛋白的选择性抑制剂，将在实验性疼痛中评估镇痛作用。 模型和基于生理学的药代动力学模型将被用来预测昂丹司琼 根据动物和人类研究的综合结果，人脑和脊髓中的浓度。 3) 我们将确定充分中枢神经系统渗透的昂丹司琼对神经性疼痛的作用。 NeuP 患者的实验交叉研究，将比较恩丹司琼给药时的镇痛效果 在基于探索性机制的分析中，我们将确定有和没有塔里奎达的关联。 个体下行疼痛促进程度与对 5-HT3R 阻断的镇痛反应之间的关系。 我们期望结果能够成功确定限制 CNS 暴露 5-HT3R 的机制 拮抗剂，并证明通过绕过这些机制，5-HT3R 拮抗剂可以缓解 神经性疼痛，尤其是感觉表型提示下降易化的患者。

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