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: 9895227
• 负责人: YU-SHIN DING
• 金额: $ 25.43万
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895227
• 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.

项目概要 慢性疼痛是一个毁灭性的公共卫生问题，影响着美国超过 20% 的成年人，并造成高昂的费用 每年约 6000 亿美元，比任何其他疾病都多，近 2700 万美国成年人患有骨关节炎， 一种以疼痛为主要症状的慢性进行性疾病，使其成为以下疾病的常见原因 慢性疼痛是美国残疾的主要原因，疼痛的治疗通常用阿片类药物替代。 基于药物的干预措施不仅缺乏长期疗效，而且还存在不良反应的风险 事件并有助于全国阿片类药物滥用流行病的识别和开发。 因此，治疗慢性疼痛的疼痛管理策略是当务之急，也是一个未满足的需求。 尽管 THC（大麻的主要成分）和 CBD 都表现出镇痛作用，尤其是 对于慢性炎症疼痛、关节炎疼痛和神经性疼痛——CBD 具有特殊的前景，因为它缺乏 临床前研究表明 CBD 具有广泛的精神活性和成瘾特性。 药理作用如抗惊厥、镇痛、抗焦虑、抗炎、催眠、 抗精神病和神经保护作用；然而，这些作用的确切作用机制尚未确定。 这项研究将是第一个确定慢性 OA 疼痛的 PET 成像研究。 CBD 的关键目标与其治疗 OA 疼痛的作用机制有关。 是通过确定 CBD 的证据基础并了解 CBD 的潜在作用机制 OA 慢性疼痛引起的神经化学和行为改变及其通过 CBD 的调节，单独或 在本提案中，我们将首先确定与其他药物联合使用所引起的神经化学变化。 通过最先进的神经影像学研究，我们对 OA 小鼠模型的慢性疼痛进行了比较。 然后将评估 CBD 对 OA 动物神经化学和行为改变的调节作用，通过 神经影像学研究和行为评估，具有广泛的药理学、机制驱动 方法来确定/确认 CBD 在 OA 中的作用机制。 神经化学变化（作用机制）可以与其镇痛特性直接相关，如所反映的 该策略最终将为识别/确认行为变化提供强有力的证据基础。 CBD 作为 OA 慢性疼痛潜在治疗方法的潜在作用机制。 旨在确定最有效机制的综合性神经影像学和行为研究 归因于 CBD 治疗效果的标记（或一组形成“签名”的机械标记） OA）将指导我们对未来针对 OA 患者的临床试验进行进一步的机制研究。