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 神经病理性疼痛(NeuP)影响着1600万美国人，并导致严重的疼痛质量下降 生活。现有的药物不能充分缓解大多数NeuP患者的疼痛；此外， 阿片类药物等药物有重大的安全问题。因此，迫切需要新的治疗方法。 需要的。5-羟色胺能5-羟色胺受体(5-HT3R)已被认为是一种有前途的药理靶点。 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 5-羟色胺能下行调节从抑制性到易化性，从而有助于进行中 疼痛。鞘内注射5-HT3R拮抗剂可减轻NeuP动物模型的诱发超敏反应，但 在神经病理性疼痛患者中，止痛效果与这些药物的全身给药不一致。 我们的初步数据表明，外流转运体，如P-糖蛋白(PGP)，限制了中枢神经 中枢神经系统暴露5-HT3R拮抗剂，从而阻止全身给药后的镇痛。 我们推测，如果5-HT3R拮抗剂达到足够的中枢神经系统浓度，它们将是 能有效缓解神经病理性疼痛。5-HT3R作为神经病临床相关药物靶点的验证 Pain，我们计划采取以下翻译方法： 1)我们将研究模型5-HT3R拮抗剂丹西酮和格拉司琼对大鼠中枢神经系统的作用 模型，并确定Pgp等外流转运体对其中枢神经系统处置的影响。这件事会做到的 通过a)测定药物在大鼠血浆和脑脊液中的生物处置，以及在脑和 脊髓(全组织分析和微透析)，以及b)利用遗传和药物敲除 以确定外排转运体对药物处置的影响。 2)我们将确定Pgp外流在人中枢神经系统恩丹西酮处置中的作用。这将通过以下方式完成 测定健康受试者静脉注射恩丹西酮后血浆和脑脊液浓度的时程变化 没有使用Pgp转运蛋白的选择性抑制剂--达奎达。止痛性将在实验性疼痛中进行评估 模型和基于生理的药代动力学模型将用于预测恩丹西酮 根据动物和人体研究的综合结果，在人脑和脊髓中的浓度。 3)确定中枢神经系统充分穿透恩丹西酮对神经病理性疼痛的影响。在一个 NeuP患者的实验性交叉研究，恩丹西酮的止痛效果将进行比较 无论有没有TARQUIDAR。在基于探索性机制的分析中，我们将确定关联 个体下行疼痛易化程度与5-HT3R阻滞剂的镇痛反应之间的关系。 我们期望结果能够成功地确定限制5-HT3R中枢暴露的机制 并证明通过绕过这些机制，5-HT3R拮抗剂可以缓解 神经病理性疼痛，尤其是感觉表型提示下行促进的患者。

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