Evaluation of peripheral cannabinoid receptors as a target for pain management

外周大麻素受体作为疼痛管理靶点的评估

• 批准号: 10374943
• 负责人: Richard Slivicki
• 金额: $ 5.53万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374943
• 关键词: Ablation; Affective; Agonist; Analgesics; Animals; Behavior; CB1 knockout; CNR1 gene; CNR2 gene; Cannabinoids; Cell Culture Techniques; Cells; Clinical; Clinical Trials; Comparative Study; Conflict (Psychology); Data; Dinoprostone; Electrophysiology (science); Epidemic; Evaluation; Exhibits; Female; Future; Genetic; Genetic Models; Goals; Hippocampus (Brain); Human; Hypersensitivity; Image; Investigation; Knockout Mice; Ligands; Measures; Mechanics; Mentors; Mus; Neurons; Nociception; Nociceptors; Opioid; Outcome; Pain; Pain Disorder; Pain Measurement; Pain management; Peripheral; Pharmacology; Pharmacotherapy; Population; Property; Receptor Signaling; Reflex action; Reporting; Research Personnel; Rodent; Sensory; Sex Differences; Signal Transduction; Site; Spinal Cord; Spinal Ganglia; TRPV1 gene; Testing; Therapeutic; Tissues; Training; Translating; Validation; base; behavior measurement; cannabinoid receptor; chronic pain; chronic pain management; chronic painful condition; clinically relevant; conditional knockout; disability; efficacy evaluation; endogenous cannabinoid system; experimental study; genetic approach; human tissue; inflammatory pain; mRNA Differential Displays; male; metabotropic glutamate receptor 2; mouse genetics; novel; opioid overdose; pain model; painful neuropathy; pre-clinical; prescription opioid; promoter; receptor; receptor function; side effect; therapeutic target; therapeutically effective

ABSTRACT Chronic pain impacts 11.2% of the U.S. population, and leads to considerable disability. Current pharmacotherapies for chronic pain are largely ineffective and rely heavily on opioids. Over-prescription of opioid-based compounds for pain disorders has contributed to an opioid overdose epidemic in the U.S., highlighting the urgent need to develop safer and more effective therapeutics for pain. The endocannabinoid system, which consists of cannabinoid receptors (CB1 and CB2) and their endogenous ligands, has emerged as an alternative therapeutic target to currently available pain medications. Exogenously administered cannabinoids (CBs) display mixed outcomes in clinical trials for chronic pain suggesting the therapeutic potential of CB-based therapies in pain disorders is largely unknown. CB agonists also exhibit unwanted side- effects (e.g. tolerance and psychoactivity) largely due to central CB1R activation. Dorsal root ganglion (DRG) contain the cell bodies of primary afferents responsible transmitting peripheral nociceptive signaling to the spinal cord. Activation of peripheral CB1R receptors in DRG has been viewed as a potential means to harness the therapeutic actions of CB1Rs while circumventing unwanted CNS-related side-effects. Yet, there have been few investigations regarding antinociceptive effects of peripheral CB ligands. In the present proposal I plan to incorporate pharmacological and novel genetic-based approaches to elucidate the contributions of peripheral CB1R receptors in reducing sensory and non-reflexive components of pain in both male and female mice. The mentor's lab previously demonstrated functional differences of metabotropic glutamate receptor 2/3 receptors activity in cultured neurons derived from mouse and human dorsal root ganglion. This suggests the mechanistic basis of other pharmacological targets, such as CBs, may differ between species. Human and mouse CB1 exhibit differential signaling in hippocampal autaptic cultures. Only one report to-date investigated CB signaling in human-derived DRG and no comparative studies regarding CB receptor signaling have ever been conducted between rodent and human in this tissue. To better understand the clinical validity of targeting peripheral CB1Rs I will take advantage of an extremely unique opportunity to conduct comparative studies of CB receptor function in mouse and human DRG. These studies have potential to generate transformative data in understanding transability of preclinical findings regarding peripheral antinociceptive effects of CBs. The central hypothesis that CB1R present on nociceptors in DRG are responsible for the antinociceptive effects of peripheral CB administration observed in mice and that this mechanism will translate to humans will be evaluated in the present proposal. The data generated from the proposed experiments will greatly aid in our understanding of the underlying mechanisms in which peripheral CB1R activation promotes antinociceptive like effects in mouse and whether or not similar approaches will translate into humans; potentially leading to better approaches of utilizing CB1R signaling for the treatment of chronic pain disorders.

摘要 慢性疼痛影响了11.2%的美国人口，并导致相当大的残疾。电流 用于慢性疼痛的药物疗法在很大程度上是无效的，并且严重依赖阿片类药物。处方过量 用于疼痛障碍的阿片类化合物导致了美国的阿片类药物过量流行， 突出了开发更安全和更有效的疼痛治疗方法的迫切需要。内源性大麻素 由大麻素受体（CB 1和CB 2）及其内源性配体组成的系统已经出现 作为目前可用的止痛药的替代治疗靶点。外源施用的 大麻素（CB）在慢性疼痛的临床试验中显示出混合的结果，这表明治疗 基于CB的疗法在疼痛疾病中的潜力在很大程度上尚不清楚。CB激动剂也表现出不需要的副作用， 影响（如耐受性和精神活性），主要是由于中央CB1R激活。背根神经节 包含负责将外周伤害性信号传递到 脊髓背根神经节中外周CB1R受体的激活已被视为一种潜在的手段， CB 1 Rs的治疗作用，同时避免不必要的中枢神经系统相关副作用。然而， 关于外周CB配体的抗伤害感受作用的研究很少。在目前的建议中，我计划 结合药理学和新的基于遗传学的方法来阐明外周血淋巴细胞的贡献， CB1R受体在减少雄性和雌性小鼠疼痛的感觉和非反射成分中的作用的 Mentor的实验室先前证明了代谢型谷氨酸受体2/3受体的功能差异 活性的培养神经元来源于小鼠和人类背根神经节。这表明 其他药理学靶点（如CB）的机制基础可能因物种而异。人力和 小鼠CB 1在海马autaptic培养中表现出差异信号传导。迄今只调查了一份报告 CB信号转导在人源性DRG中的研究和关于CB受体信号转导的比较研究还没有 在啮齿类动物和人类之间进行的实验为了更好地了解靶向治疗的临床有效性， 我将利用一个极其独特的机会，对外周CB1Rs进行比较研究， 小鼠和人DRG中CB受体功能。这些研究有可能产生变革性的数据 在理解关于CB的外周抗伤害感受作用的临床前发现的可传递性方面。的 中心假说认为，存在于DRG中的伤害感受器上的CB1R负责 在小鼠中观察到的外周CB给药，并且该机制将转化为人类， 在本提案中进行了评估。从拟议的实验中产生的数据将大大有助于我们 了解外周CB1R激活促进抗伤害感受性的潜在机制， 在小鼠中的效果以及类似的方法是否会转化为人类;可能会导致更好的 利用CB1R信号传导治疗慢性疼痛疾病的方法。