Identifying the mechanisms of action for CBD on chronic arthritis pain

项目摘要 慢性疼痛是一个毁灭性的公共卫生问题，影响了美国20%以上的成年人， 每年约6000亿美元，超过任何其他医疗条件。近2700万美国成年人患有骨关节炎， 一种慢性和进行性疾病，疼痛是其主要症状，使其成为一种常见的原因， 慢性疼痛，在美国是导致残疾的主要原因。疼痛的管理通常依赖于阿片类药物- 基础的药物干预，不仅缺乏长期疗效，而且还存在不良反应的风险。 事件，并有助于阿片类药物滥用的全国流行病。小说的认定与发展 因此，用于治疗慢性疼痛的疼痛管理策略是高度优先的并且是未满足的需求。 尽管THC（大麻的主要成分）和CBD都表现出抗伤害作用， 对于慢性炎性疼痛，关节炎疼痛和神经性疼痛，CBD特别有希望，因为它缺乏 精神活性和成瘾性。临床前研究表明，CBD具有广泛的报道， 药理学作用如抗惊厥、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还没有 在慢性OA疼痛中进行了检查。这项拟议的研究将是第一个PET成像研究，以确定 CBD的关键目标，与其对OA疼痛治疗的作用机制有关。本研究的目的 是通过确定生物多样性公约的作用机制，加强证据基础和了解生物多样性公约的基本作用机制， OA慢性疼痛诱导的神经化学和行为改变及其由CBD单独或 与其他药物联合使用。在这个建议中，我们将首先确定由 通过最先进的神经成像研究，与对照组相比，OA小鼠模型中的慢性疼痛。我们 然后将评估CBD对OA动物神经化学和行为改变的调节，通过 神经影像学研究和行为评估，具有广泛的药理学，机械驱动 确定/确认CBD在OA中的作用机制的方法。通过这样做，CBD调节 神经化学变化（作用机制）可以直接与其镇痛性能，如反映 行为改变这一战略将最终提供一个强有力的证据基础，以确定/确认 CBD作为OA慢性疼痛潜在治疗剂的潜在作用机制。这些 全面的神经成像和行为研究，旨在确定最有效的机制， 归因于CBD的治疗效果的标记物（或形成CBD的“签名”的一组机械标记物）。 OA）将指导我们对未来OA患者的临床试验进行进一步的机制研究。

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.