Department of Neural Sciences, Center for Substance Abuse Research, Temple University, Philadelphia, Pennsylvania (M.I., S.A.H., S.J.W.) and Pennsylvania Biotechnology Center, Kannalife Sciences Inc, Doylestown Pennsylvania (W.K., D.E.B.)
Department of Neural Sciences, Center for Substance Abuse Research, Temple University, Philadelphia, Pennsylvania (M.I., S.A.H., S.J.W.) and Pennsylvania Biotechnology Center, Kannalife Sciences Inc, Doylestown Pennsylvania (W.K., D.E.B.).
J Pharmacol Exp Ther. 2024 Oct 18;391(2):231-240. doi: 10.1124/jpet.124.002190.
Neuropathic pain is a form of chronic pain that develops because of damage to the nervous system. Treatment of neuropathic pain is often incompletely effective, and most available therapeutics have only moderate efficacy and present side effects that limit their use. Opioids are commonly prescribed for the management of neuropathic pain despite equivocal results in clinical studies and significant abuse potential. Thus, neuropathic pain represents an area of critical unmet medical need, and novel classes of therapeutics with improved efficacy and safety profiles are urgently needed. The cannabidiol structural analog and novel antagonist of GPR55, KLS-13019, was screened in rat models of neuropathic pain. Tactile sensitivity associated with chemotherapy exposure was induced in rats with once-daily 1-mg/kg paclitaxel injections for 4 days or 5 mg/kg oxaliplatin every third day for 1 week. Rats were then administered KLS-13019 or comparator drugs on day 7 in an acute dosing paradigm or days 7-10 in a chronic dosing paradigm, and mechanical or cold allodynia was assessed. Allodynia was reversed in a dose-dependent manner in the rats treated with KLS-13019, with the highest dose reverting the response to prepaclitaxel injection baseline levels with both intraperitoneal and oral administration after acute dosing. In the chronic dosing paradigm, four consecutive doses of KLS-13019 completely reversed allodynia for the duration of the phenotype in control animals. Additionally, coadministration of KLS-13019 with paclitaxel prevented the allodynic phenotype from developing. Together, these data suggest that KLS-13019 represents a potential new drug for the treatment of neuropathic pain. SIGNIFICANCE STATEMENT: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating side effect of cancer treatment with no known cure. The GPR55 antagonist KLS-13019 represents a novel class of drug for this condition that is a potent, durable inhibitor of allodynia associated with CIPN in rats in both prevention and reversal-dosing paradigms. This novel therapeutic approach addresses a critical area of unmet medical need.
神经病理性疼痛是一种慢性疼痛，由于神经系统损伤而发展。神经病理性疼痛的治疗通常效果不完全，大多数可用的治疗方法只有中等疗效，并且存在副作用，限制了它们的使用。尽管临床研究结果存在争议，且具有明显的滥用潜力，但阿片类药物仍常被用于治疗神经病理性疼痛。因此，神经病理性疼痛代表了一个急需解决的医学需求领域，迫切需要具有更好疗效和安全性的新型治疗药物。大麻素受体 5 (GPR55) 的新型拮抗剂 KLS-13019 的类似物，在神经病理性疼痛的大鼠模型中进行了筛选。通过每天一次给予 1 毫克/千克紫杉醇注射 4 天或每 3 天给予 5 毫克/千克奥沙利铂 1 周，诱导大鼠产生与化疗暴露相关的触觉敏感性。然后在急性给药方案中，在第 7 天或慢性给药方案中在第 7-10 天给予 KLS-13019 或比较药物，并评估机械性或冷性痛觉过敏。在 KLS-13019 治疗的大鼠中，痛觉过敏呈剂量依赖性逆转，最高剂量可使紫杉醇预处理后注射的反应在急性给药后通过腹腔内和口服途径恢复到基线水平。在慢性给药方案中，KLS-13019 的连续 4 个剂量完全逆转了对照动物的痛觉过敏表型的持续时间。此外，KLS-13019 与紫杉醇共同给药可防止痛觉过敏表型的发展。综上所述，这些数据表明 KLS-13019 代表了一种治疗神经病理性疼痛的潜在新药。
意义陈述：化疗引起的周围神经病（CIPN）是癌症治疗的一种常见且使人虚弱的副作用，目前尚无已知的治愈方法。GPR55 拮抗剂 KLS-13019 代表了一种用于这种疾病的新型药物类别，它是一种有效的、持久的 CIPN 相关痛觉过敏抑制剂，在预防和逆转剂量方案中在大鼠中均有效。这种新的治疗方法解决了一个急需解决的医学需求领域。
