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Mechanisms of cannabinoid tolerance

大麻素耐受机制

基本信息

批准号：
9765291
负责人：
Josee Guindon
金额：
$ 38.3万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9765291
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 clinically relevant desensitization expectation genetic approach improved in vivo inhibitor/antagonist 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.

本研究将探讨大麻素耐受的机制。这一目标将会实现