Mechanisms of cannabinoid tolerance

大麻素耐受机制

• 批准号: 10457829
• 负责人: Josee Guindon
• 金额: $ 37.02万
• 依托单位: MARSHALL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457829
• 关键词: ADRBK2 gene; Acute Pain; Address; Agonist; Analgesics; Animal Model; Behavior assessment; Biochemical; Biochemistry; C-terminal; CNR1 gene; Cancer Patient; Cannabinoids; Cannabis; Cells; Chemicals; Chemotherapy-Oncologic Procedure; Cisplatin; Clinical; Clinical Management; Development; Disadvantaged; G protein coupled receptor kinase; Goals; Grant; Immunoprecipitation; Knockout Mice; Knowledge; Lead; MAPK8 gene; MAPK9 gene; Malignant Neoplasms; Mediating; Medical; Modeling; Molecular; Molecular Mechanisms of Action; Mus; Mutant Strains Mice; Mutate; Mutation; N-terminal; Nausea; Neurons; Pain; Pain management; Pathologic; Pharmacology; Phosphorylation; Phosphorylation Site; Phosphotransferases; Property; Protein Isoforms; Proteomics; Research Project Grants; Resistance; SP600125; Secondary to; Signal Pathway; Signal Transduction; Site; Tail; Testing; Tetrahydrocannabinol; Therapeutic; Thinking; Tissues; Work; alternative treatment; analog; base; cancer pain; chemical genetics; chemotherapy; chronic pain management; clinically relevant; desensitization; expectation; genetic approach; improved; in vivo; inhibitor; innovation; insight; kinase inhibitor; knowledge base; marijuana use; mouse model; mutant; novel; pain model; painful neuropathy; pre-clinical; protein protein interaction; response; sex; stable cell line

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.

本研究将探讨大麻素耐受的机制。这一目标将得以实现 通过确定大麻素耐受性是否通过激动剂特异性机制介导 使用化疗诱导的神经性疼痛模型。我们的方法将检查容忍度， 1999-THC，CP 55，940，和WIN 55，212-2，三种药物的抗异常性疼痛和抗伤害感受作用 具有不同信号传导和化学特征的大麻素激动剂。耐受1009-THC 甩尾试验中的抗伤害感受通过用以下物质预处理S426 A/S430 A突变体来消除： SP 600125，一种选择性c-Jun N-末端激酶（JNK）抑制剂，表明JNK（SP 600125） 抑制剂）和GRK/β arrestin 2（S426/S430 A突变）信号传导机制协调介导 对109-THC的抗伤害感受作用的耐受性。本研究的第一个目标是，充分和 系统地，测试大麻素耐受性是通过激动剂特异性介导的假设， 机制等第二个目的是检验JNK介导的对β 9-THC的耐受性是一个假设， 需要β-arrestin 2的存在。第三个目标是检验β-arrestin 2和β-arrestin 3的假设。 JNK可以在体内形成蛋白质-蛋白质相互作用。第四个目标是检验假设， JNK可以直接磷酸化CB 1时，激活的β 9-THC使用技术创新 化学遗传学方法前三个假设将在以下临床相关模型中进行检验： 化疗（顺铂）诱导的神经性疼痛模型。最后一个假设同样 创新，并将提供有关分子作用机制的重要信息， 负责JNK介导的THC耐受性。该项目的首要目标是获得 更好地了解负责大麻素耐受性的激动剂特异性机制， 将促进持久、高效和个性化疼痛治疗的发展。