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Mechanisms of cannabinoid tolerance

大麻素耐受机制

基本信息

批准号：
10673220
负责人：
Josee Guindon
金额：
$ 5.9万
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/10673220
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.

本研究将探讨大麻素耐受的机制。这一目标将会实现

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Decursinol-mediated antinociception and anti-allodynia in acute and neuropathic pain models in male mice: Tolerance and receptor profiling.

雄性小鼠的急性和神经性疼痛模型中的十字酚介导的抗伤害感受和抗差异：耐受性和受体分析。

DOI：
10.3389/fphar.2022.968976
发表时间：
2022
期刊：
FRONTIERS IN PHARMACOLOGY
影响因子：
5.6
作者：
Crawford, LaTaijah C.;Kim, Sangyub;Karelia, Deepkamal;Sepulveda, Diana E.;Morgan, Daniel J.;Lu, Junxuan;Henderson-Redmond, Angela N.
通讯作者：
Henderson-Redmond, Angela N.

Role of sex hormones in modulating breast and ovarian cancer associated pain.

DOI：
10.1016/j.mce.2021.111320
发表时间：
2021-08-01
期刊：
Molecular and cellular endocrinology
影响因子：
4.1
作者：
McHann MC;Blanton HL;Guindon J
通讯作者：
Guindon J

Assessing Dose- and Sex-Dependent Antinociceptive Effects of Cannabidiol and Amitriptyline, Alone and in Combination, and Exploring Mechanism of Action Involving Serotonin 1A Receptors.

DOI：
10.1124/jpet.123.001855
发表时间：
2024-01-17
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
0
作者：
通讯作者：

Front and hind paw differential analgesic effects of amitriptyline, gabapentin, ibuprofen, and URB937 on mechanical and cold sensitivity in cisplatin-induced neuropathy.

阿米替林、加巴喷丁、布洛芬和 URB937 对顺铂引起的神经病变的机械和冷敏感性的前爪和后爪差异镇痛作用。

DOI：
10.1177/1744806919874192
发表时间：
2019
期刊：
Molecular pain
影响因子：
3.3
作者：
Thompson,JeremyM;Blanton,HenryL;Pietrzak,Agata;Little,William;Sherfey,Caitlyn;Guindon,Josée
通讯作者：
Guindon,Josée

Sex differences and the endocannabinoid system in pain.