Mechanisms of cannabinoid tolerance

大麻素耐受机制

基本信息

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
项目类别：
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

项目摘要

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.

这项研究将研究大麻素耐受的机制，这一目标将会实现。通过确定大麻素耐受性是否是通过激动剂特异性机制介导的我们的方法将使用化疗引起的神经性疼痛模型来检查对化疗的耐受性。 Δ9-THC、CP55,940 和 WIN55,212-2 的抗痛觉和镇痛作用，三个具有独特信号传导和化学特征的大麻素激动剂。对 Δ9-THC 具有耐受性。通过对 S426A/S430A 突变体进行预处理，消除了甩尾测试中的预感。 SP600125，一种选择性 c-Jun N 末端激酶 (JNK) 抑制剂，表明 JNK (SP600125 抑制剂）和 GRK/βarrestin2（S426/S430A 突变）信号机制协调介导对 Δ9-THC 的抗伤害作用的耐受性本研究的首要目标是充分且有效地耐受。广泛地检验大麻素耐受性是通过激动剂特异性介导的假设第二个目标是检验 JNK 介导的 Δ9-THC 耐受性的假设。需要 β−arrestin2 的存在第三个目标是检验 β−arrestin2 和的假设。 JNK 可以在体内形成蛋白质-蛋白质相互作用。当使用创新技术被 Δ9-THC 激活时，JNK 可以直接磷酸化 CB1 化学遗传学方法将在临床相关模型中进行测试。化疗（顺铂）诱导的神经性疼痛模型同样如此。具有创新性，将提供有关分子作用机制的重要信息负责 JNK 介导的 Δ9-THC 耐受性。该项目的总体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、高效和个性化疼痛疗法的开发。