Cannabinoid interactions with central and peripheral pain mechanisms in osteoarthritis of the knee

摘要 由于膝关节骨关节炎（OA）引起的慢性疼痛是残疾的主要原因，影响超过1400万美国人。然而，治疗困难，结果很差。这是因为疼痛不是单一的，潜在疼痛机制的差异会影响治疗反应。虽然膝关节OA疼痛可能是由于组织和关节损伤（伤害性疼痛），但它也可能因中枢神经系统（CNS）功能障碍而增强和维持-即，集中性或伤害性疼痛。不同的中枢神经系统的贡献解释了为什么有些人有严重的放射学膝关节损伤，但报告没有疼痛，而其他人有“正常”的放射学照片，但报告严重的疼痛。我们的研究小组和其他人已经表明，这种集中表型发生在几乎所有的慢性疼痛条件。此外，我们已经证明了疼痛机制与治疗相匹配的临床相关性，表明更大程度的疼痛集中会降低对干预的反应性（例如，阿片类药物和手术），旨在减少膝关节OA的伤害性疼痛。潜在机制的差异可以解释大麻素-大麻中的活性化合物-的不一致临床试验结果。临床试验表明，大麻素可以是有效的镇痛剂，但这主要是在Δ[9]-四氢大麻酚（THC）占主导地位的制剂中显示的，这些制剂具有滥用潜力。然而，最近的一项研究表明，大麻二酚（CBD）可减轻膝关节OA患者的疼痛并增加其功能。CBD是无毒的，并发挥镇痛和抗炎作用。拟议的研究是第一次尝试了解CBD和THC如何影响不同的慢性疼痛机制，通过检查这些化合物对具有不同程度疼痛集中的个体的膝关节OA的影响。我们的总体假设是，CBD将减少外周炎症，THC将改变CNS疼痛处理，CBD+THC组合将两者兼而有之。为了验证这一假设，我们提出了三个具体目标。目标1：在一项随机、双盲、2x2析因设计研究中，纵向评估CBD和THC对炎症（白细胞介素6）和中枢性疼痛的神经生物学相关性（即，默认模式的网络连接）使用患者报告的结果的表型电池、实验敏感性测试和我们已成功应用于其他药物和疼痛状况的神经成像。目标二：检查THC和CBD及其代谢产物对大脑连接和神经化学以及炎症标志物的其他指标的影响。 目的3（探索性）：评估疼痛集中是否预示着对CBD和THC的不同镇痛反应。鉴于疼痛集中发生在许多慢性疼痛疾病的一个频谱上，我们在膝关节OA中的方法将作为一个转化模型，可以应用于几乎所有其他疼痛疾病，并将对开发非阿片类镇痛药进行疼痛管理产生广泛的影响。

Abstract Chronic pain due to knee osteoarthritis (OA) is a large contributor to disability, affecting over >14 million Americans. However, treatment is difficult and outcomes are poor. This is because pain is not monolithic, and differences in underlying pain mechanisms affect treatment response. While knee OA pain can be due to tissue and joint damage (nociceptive pain), it can also be augmented and maintained by central nervous system (CNS) dysfunction – i.e., centralized or nociplastic pain. Variable CNS contributions explain why some people have severe radiographic knee damage yet report no pain, while others have “normal” radiographs yet report severe pain. Our group and others have shown that this centralized phenotype occurs in nearly all chronic pain conditions. Further, we have demonstrated the clinical relevance of matching pain mechanisms with therapies, showing that a greater degree of pain centralization lowers responsiveness to interventions (e.g., opioids and surgeries) directed toward reducing nociceptive pain in knee OA. Differences in underlying mechanisms may explain inconsistent clinical trial results with cannabinoids - the active compounds in Cannabis sativa. Clinical trials suggest that cannabinoids can be effective analgesics, but this has been shown primarily with Δ[9]-tetrahydrocannabinol (THC) dominant preparations, which have abuse potential. However, a recent study showed that cannabidiol (CBD) reduced pain and increased function in men with knee OA. CBD is non-intoxicating, and exerts analgesic and anti-inflammatory effects. The proposed studies are the first attempt to understand how CBD and THC affect different chronic pain mechanisms by examining the effects of these compounds on knee OA in individuals with varying degrees of pain centralization. Our overarching hypothesis is that CBD will decrease peripheral inflammation, THC will modify CNS pain processing, and combined CBD+THC will do both. To test this hypothesis, we propose three specific aims. Aim 1: In a randomized, double-blinded, 2x2 factorial design study, longitudinally assess peripheral and CNS effects of CBD and THC on inflammation (interleukin 6) and neurobiological correlates of centralized pain (i.e., default mode network to insula connectivity) using a phenotyping battery of patient reported outcomes, experimental sensitivity testing, and neuroimaging that we have successfully applied to other drugs and pain conditions. Aim 2: Examine effects of THC and CBD and their metabolites on additional indices of brain connectivity and neurochemistry as well as inflammatory markers. Aim 3 (exploratory): Assess whether pain centralization predicts differential analgesic responsiveness to CBD and THC. Given that pain centralization occurs on a spectrum in many chronic pain conditions, our approach in knee OA will act as a translational model that can be applied to nearly all other pain conditions and will have broad implications for developing non-opioid analgesics for pain management.