Mechanisms of cannabinoid tolerance

大麻素耐受机制

• 批准号: 10399779
• 负责人: Josee Guindon
• 金额: $ 1.42万
• 依托单位: MARSHALL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399779
• 关键词: Address; Agonist; Analgesics; CNR1 gene; Cancer Patient; Cannabinoids; Cannabis; Chemicals; Chemotherapy-Oncologic Procedure; Cisplatin; Clinical; Development; Disadvantaged; G protein coupled receptor kinase; Goals; MAPK8 gene; Mediating; Modeling; Molecular Mechanisms of Action; Mutation; N-terminal; Nausea; Pain management; Phosphotransferases; Property; Research Project Grants; SP600125; Secondary to; Signal Transduction; Tail; Testing; Tetrahydrocannabinol; Therapeutic; cancer pain; chemical genetics; chemotherapy; clinically relevant; genetic approach; improved; in vivo; inhibitor/antagonist; innovation; insight; kinase inhibitor; knowledge base; marijuana use; mutant; novel; painful neuropathy; protein protein interaction; public health relevance

Project Summary/Abstract This study will investigate the mechanisms of cannabinoid tolerance. This objective will be achieved by determining whether cannabinoid tolerance is mediated through agonist-specific mechanisms using a model of chemotherapy-induced neuropathic pain. Our approach will examine tolerance to the anti- allodynic and antinociceptive effects of ∆9-THC, CP55,940, and WIN55,212-2, three cannabinoid agonists with distinct signaling and chemical features. Tolerance to ∆9-THC antinociception in the tail- flick test was eliminated by pre-treatment of S426A/S430A mutants with SP600125, a selective c-Jun N-terminal kinase (JNK) inhibitor suggesting that JNK (SP600125 inhibitor) and GRK/βarrestin2 (S426/S430A mutation) signaling mechanisms coordinate to mediate tolerance to the antinociceptive effect of ∆9-THC. The first objective of this study is to, fully and systematically, test the hypothesis that cannabinoid tolerance is mediated through agonist-specific mechanisms. The second objective is to test the hypothesis that JNK-mediated tolerance for ∆9-THC requires the presence of β−arrestin2. The third objective is to test the hypothesis that β−arrestin2 and JNKs can form protein-protein interactions in vivo. The fourth objective is to test the hypothesis that JNKs can directly phosphorylate CB1 when activated by ∆9-THC using a technologically innovative chemical-genetic approach. The first three hypotheses will be tested in a clinically relevant model of chemotherapy (cisplatin)-induced model of neuropathic pain. The last hypothesis is equally innovative and will provide important information regarding the molecular mechanism of action that is responsible for JNK-mediated ∆9-THC tolerance. The overarching goal of this project is to gain a better understanding of the agonist-specific mechanisms responsible for cannabinoid tolerance that will facilitate the development of long lasting, highly efficacious, and personalized pain therapies.

项目概要/摘要 这项研究将调查大麻素耐受的机制。这一目标将通过以下方式实现 确定大麻素耐受性是否是通过激动剂特异性机制介导的 化疗引起的神经性疼痛模型。我们的方法将检查对抗病毒药物的耐受性 Δ9-THC、CP55,940 和 WIN55,212-2（三种大麻素）的异常疼痛和抗伤害作用 具有独特的信号传导和化学特征的激动剂。尾部对 Δ9-THC 抗伤害作用的耐受性 通过用选择性 c-Jun SP600125 对 S426A/S430A 突变体进行预处理，消除了轻弹测试 N 末端激酶 (JNK) 抑制剂表明 JNK（SP600125 抑制剂）和 GRK/βarrestin2 （S426/S430A 突变）信号传导机制协调介导对镇痛药的耐受性 Δ9-THC 的影响。本研究的首要目标是全面、系统地检验以下假设： 大麻素耐受性是通过激动剂特异性机制介导的。第二个目标是 检验 JNK 介导的 Δ9-THC 耐受性需要 β−arrestin2 存在的假设。这 第三个目标是检验 β−arrestin2 和 JNK 可以形成蛋白质-蛋白质相互作用的假设 体内。第四个目标是检验以下假设：JNK 在以下情况下可以直接磷酸化 CB1： 使用技术创新的化学遗传方法由 Δ9-THC 激活。前三名 假设将在临床相关的化疗（顺铂）诱导模型中进行检验 神经性疼痛。最后一个假设同样具有创新性，将提供重要信息 关于 JNK 介导的 Δ9-THC 耐受性的分子作用机制。 该项目的总体目标是更好地了解激动剂特异性机制 负责大麻素耐受性，这将促进持久、高度 有效且个性化的疼痛治疗。