Mechanisms of cannabinoid tolerance

大麻素耐受机制

• 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
• 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

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.

这项研究将调查大麻素耐受的机制。这个目标将会实现 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 使用化疗引起的神经性疼痛模型。我们的方法将检查对 Δ9-THC、CP55,940 和 WIN55,212-2 的抗异常疼痛和抗伤害作用，三个 具有独特的信号传导和化学特征的大麻素激动剂。 Δ9-THC 耐受性 通过对 S426A/S430A 突变体进行预处理，消除了甩尾试验中的镇痛作用。 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 系统地检验大麻素耐受性是通过激动剂特异性介导的假设 机制。第二个目标是检验 JNK 介导的对 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 JNK 可以在体内形成蛋白质-蛋白质相互作用。第四个目标是检验以下假设： 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。前三个假设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。最后一个假设同样成立 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。

项目成果

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

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.

• DOI: 10.1016/j.pbb.2021.173107
• 发表时间: 2021-03
• 期刊: Pharmacology, biochemistry, and behavior
• 作者: Blanton HL;Barnes RC;McHann MC;Bilbrey JA;Wilkerson JL;Guindon J
• 通讯作者: Guindon J