Mechanisms of cannabinoid tolerance

大麻素耐受机制

基本信息

批准号：
10303717
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 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10303717
关键词：
Absence of pain sensation Address Adult Agonist Amygdaloid structure Analgesics Animals Anticonvulsants Binding Biological Assay CNR1 gene CNR2 gene Cancer Patient Cannabinoids Cannabis Chemicals Chemotherapy-Oncologic Procedure Cisplatin Clinical Clinical Research Coupling Data Dependence Development Disadvantaged Distal Dose Endocannabinoids Estradiol Estrogen Receptor alpha Estrogen Receptor beta Estrogens Female G protein coupled receptor kinase GPR55 receptor GTP-Binding Proteins Gene Expression Goals Gonadal Steroid Hormones Human Hyperalgesia Limb structure Literature MAPK8 gene Measures Mechanics Mediating Medicine Membrane Mifepristone Modeling Molecular Mechanisms of Action Mus Mutation N-terminal Nausea Numbness Operative Surgical Procedures Opioid Ovariectomy Pain Pain management Pharmacologic Substance Pharmacology Phenotype Phosphotransferases Play Prefrontal Cortex Progesterone Progesterone Receptors Property Proteins RNA Rattus Reporting Research Research Project Grants Role SP600125 Sampling Secondary to Sex Differences Signal Transduction Spinal Cord TRPV1 gene Tail Tamoxifen Temperature Testing Tetrahydrocannabinol Therapeutic Therapeutic Agents Thinking Time Tissues Western Blotting Woman Work addiction allodynia cancer pain cannabinoid drug chemical genetics chemotherapy chronic neuropathic pain chronic pain chronic pain management clinically relevant endogenous cannabinoid system estrogen disruption genetic approach genetic manipulation high risk hormonal signals human female improved in vivo inhibitor/antagonist innovation insight kinase inhibitor knowledge base male marijuana use midbrain central gray substance mutant nociceptive response novel osmotic minipump pain model pain relief pain sensitivity painful neuropathy protein expression protein protein interaction public health relevance radioligand receptor response sham surgery side effect

项目摘要

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我们的方法将检查化疗引起的神经性疼痛的耐受性。 Δ9-THC、CP55,940 和 WIN55,212-2（三种大麻素）的异常疼痛和镇痛作用具有独特信号传导和化学特征的激动剂，对尾部的 Δ9-THC 预期具有耐受性。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抗药性的耐受性本研究的第一个目标是全面、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。检验 JNK 介导的 Δ9-THC 耐受性需要 β−arrestin2 存在的假设。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第四个目标是检验 JNK 可以直接磷酸化 CB1 的假设。使用技术创新的化学遗传方法由 Δ9-THC 激活前三个。假设将在临床相关的化疗（顺铂）诱导模型中进行检验最后一个假设同样具有创新性，并将提供重要信息。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。