Identifying the mechanisms of action for CBD on chronic arthritis pain

确定 CBD 对慢性关节炎疼痛的作用机制

• 批准号: 10018639
• 负责人: YU-SHIN DING
• 金额: $ 21.19万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018639
• 关键词: Acute; Adult; Affect; Agonist; American; Analgesics; Animal Model; Animals; Anti-Anxiety Agents; Anticonvulsants; Antipsychotic Agents; Autoradiography; Behavior assessment; Behavioral; Buspirone; CNR1 gene; Cannabis; Capsaicin; Chronic; Chronic Disease; Chronic inflammatory pain; Clinical Research; Clinical Trials; Degenerative polyarthritis; Development; Dose; Dropout; Drug Targeting; Evaluation; Exhibits; FAAH inhibitor; Future; Goals; Inflammatory; Intervention; Intractable Pain; Link; Mechanics; Medical; Mission; Opioid; Opioid Analgesics; Pain; Pain Disorder; Pain Measurement; Pain management; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Positron-Emission Tomography; Progressive Disease; Property; Protocols documentation; Public Health; Reflex action; Reporting; Research; Research Design; Route; Site; Symptoms; TRPV1 gene; Testing; Tetrahydrocannabinol; Therapeutic; Therapeutic Effect; Time; United States; Up-Regulation; Weight-Bearing state; Withdrawal; adverse event risk; arthritic pain; base; behavioral study; capsazepine; chronic pain; cost; disability; evidence base; experience; hypnotic; imaging study; in vivo; marijuana use; mouse model; neurochemistry; neuroimaging; non-opioid analgesic; novel; opioid epidemic; opioid misuse; osteoarthritis pain; painful neuropathy; preclinical study; prevent; response; side effect; treatment strategy; uptake

PROJECT SUMMARY Chronic pain is a devastating public health issue that affects >20% of all adults in the United States and costs ~$600 billion annually, more than any other medical condition. Nearly 27 million US adults have osteoarthritis, a chronic and progressive disease for which pain is the primary symptom, making it a common cause of chronic pain, and a leading cause of disability in the US. The management of pain has often relied on opioid- based, pharmacologic interventions, which not only lack long-term efficacy but also carry risks for adverse events and contribute to the national epidemic of opioid misuse. The identification and development of novel pain management strategies for the treatment of chronic pain, therefore, is a high priority and an unmet need. Although both THC (the major constituent of cannabis) and CBD exhibit antinociceptive effects—particularly for chronic inflammatory pain, arthritic pain, and neuropathic pain—CBD holds particular promise as it lacks psychoactive and addictive properties. Preclinical studies showed that CBD has a wide range of reported pharmacological effects such as anticonvulsant, analgesic, anxiolytic, anti-inflammatory, hypnotic, antipsychotic and neuroprotective actions; however, the exact mechanisms of action for these effects have not been examined in chronic OA pain. The proposed study will be the first PET imaging study to determine the key targets of CBD that are related to its mechanisms of action on pain treatment in OA. The goal of this study is to bolster the evidence base and understand the underlying mechanisms of action of CBD by identifying the neurochemical and behavioral alterations induced by chronic pain in OA and their modulation by CBD, alone or in combination with other drugs. In this proposal, we will first identify the neurochemical alterations induced by chronic pain in an OA mouse model, as compared to controls, via state-of-the-art neuroimaging studies. We will then evaluate the CBD modulation on the neurochemical and behavioral alterations in OA animals, via neuroimaging studies and behavioral assessment, with an extensive pharmacological, mechanistic-driven approach to identify/confirm the mechanisms of action of CBD in OA. By doing so, CBD modulation for neurochemical changes (mechanisms of action) can be directly linked with its analgesic properties, as reflected in behavioral changes. This strategy will ultimately provide a strong evidence base to identify/confirm the underlying mechanisms of action of CBD as a potential therapeutic for chronic pain in OA. These comprehensive sets of neuroimaging and behavioral studies designed to identify the most valid mechanistic marker attributed to the therapeutic effects of CBD (or a set of mechanistic markers that form a “signature” for OA) will guide us to fine-tune further mechanistic studies for future clinical trials in patients with OA.

项目摘要 慢性疼痛是一个毁灭性的公共卫生问题，影响美国所有成年人的20％及其成本 每年约6000亿美元，比任何其他医学状况都要多。近2700万美国成年人患有骨关节炎， 疼痛是主要症状的慢性和进行性疾病，使其成为常见原因 慢性疼痛和美国残疾的主要原因。疼痛的管理通常一直依赖于Ooid- 基于药品干预措施，不仅缺乏长期有效性，而且还具有广告的风险 事件并有助于阿片类药物滥用的全国流行病。新颖的识别和发展 因此，治疗慢性疼痛的疼痛管理策略是高度优先且未满足的需求。 尽管THC（大麻的主要组成部分）和CBD都暴露了抗伤害感受效应 - 特别是 对于慢性炎症性疼痛，节肢动物疼痛和神经性疼痛 精神活性和加性特性。临床前研究表明，CBD报告了广泛的报道 药理学作用，例如抗惊厥药，镇痛，抗焦虑，抗炎性，催眠， 抗精神病药和神经保护作用；但是，这些影响的确切作用机制尚未 我们接受了慢性OA疼痛检查。拟议的研究将是第一项确定的宠物成像研究 CBD的主要靶标与其OA中疼痛治疗的作用机理有关。这项研究的目标 是通过识别来支持证据基础并了解CBD的基本作用机制 OA慢性疼痛引起的神经化学和行为改变，单独或单独通过CBD调节 与其他药物结合使用。在此提案中，我们将首先确定由 与对照组相比，OA小鼠模型中的慢性疼痛通过最新的神经影像学研究。我们 然后，将评估OA动物的神经化学和行为改变的CBD调制， 神经影像学研究和行为评估，具有广泛的药物，机械驱动的 识别/确认CBD在OA中的作用机理的方法。通过这样做，CBD调制 神经化学变化（作用机制）可以与其镇痛特性直接相关 在行为变化中。该策略最终将为识别/确认的强大证据基础提供 CBD的基本作用机理作为OA慢性疼痛的潜在治疗方法。这些 旨在识别最有效机械的全面神经影像学和行为研究集 标记归因于CBD的治疗作用（或一组形成“签名”的机械标记 OA）将指导我们对OA患者的未来临床试验进行进一步的机械研究。