Identifying the mechanisms of action for CBD on chronic arthritis pain

项目总结 慢性疼痛是一个毁灭性的公共卫生问题，影响着美国20%的成年人和医疗费用 每年约6000亿美元，比其他任何疾病都要多。近2700万美国成年人患有骨性关节炎， 一种以疼痛为主要症状的慢性进行性疾病，使其成为一种常见的 慢性疼痛，在美国是导致残疾的主要原因。疼痛的治疗通常依赖于阿片类药物- 基于药物的干预，不仅缺乏长期疗效，而且存在不良反应的风险 阿片类药物滥用事件，并助长了阿片类药物滥用的全国流行。论小说的认定与发展 因此，治疗慢性疼痛的疼痛管理策略是一个高度优先的问题，也是一个尚未得到满足的需求。 尽管THC(大麻的主要成分)和CBD都显示出抗伤害作用--特别是 对于慢性炎症性疼痛、关节炎疼痛和神经病理性疼痛-CBD具有特殊的前景，因为它缺乏 具有精神活性和成瘾性。临床前研究表明，CBD有广泛的报道 抗惊厥、止痛、抗焦虑、抗fl、催眠等药理作用 抗精神病药物和神经保护作用；然而，这些作用的确切作用机制还没有 曾在慢性骨性关节炎疼痛中检查过。这项拟议的研究将是第一个确定 CBD的关键靶点与其治疗骨性关节炎疼痛的作用机制有关。这项研究的目的是 是加强证据基础，并通过确定 慢性疼痛引起的骨性关节炎的神经化学和行为改变及CBD对其的调节 与其他药物联合使用。在这项提案中，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，研究了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 神经成像研究和行为评估，具有广泛的药理学、机械性驱动 确定/确认CBD在OA中的作用机制的方法。通过这样做，CBD调制用于 神经化学变化(作用机制)可以与其止痛特性直接相关，如所反映的 在行为改变上。这一战略最终将提供强有力的证据基础来识别/确认 CBD作为治疗骨性关节炎慢性疼痛的潜在作用机制。这些 一套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治疗效果的标记物(或形成对 将指导我们微调进一步的机械性研究，以用于未来的OA患者的临床试验。

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.