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

摘要 膝关节骨关节炎(OA)引起的慢性疼痛是导致残疾的一大因素，影响了1400多万美国人。然而，治疗很困难，结果也很差。这是因为疼痛不是一成不变的，潜在疼痛机制的不同会影响治疗反应。虽然膝骨性关节炎疼痛可能是由于组织和关节损伤(伤害性疼痛)，但它也可以通过中枢神经系统(CNS)功能障碍--即中枢性或肿瘤性疼痛--来扩大和维持。不同的中枢神经系统贡献解释了为什么有些人有严重的膝部放射损伤但报告没有疼痛，而另一些人有“正常”的X光照片但报告严重疼痛。我们的团队和其他人已经表明，这种集中的表型几乎在所有的慢性疼痛条件下都会发生。此外，我们已经证明了匹配疼痛机制与治疗的临床相关性，表明疼痛集中度越高，对旨在减少膝骨性关节炎患者伤害性疼痛的干预措施(如阿片类药物和手术)的反应性就会降低。潜在机制的差异可能解释了大麻素类药物临床试验结果不一致的原因。大麻素类化合物是大麻中的活性化合物。临床试验表明，大麻素可以是有效的止痛剂，但这主要表现在以Δ[9]-四氢大麻酚(THC)为主的制剂中，这些制剂具有滥用潜力。然而，最近的一项研究表明，大麻二醇(CBD)可以减轻膝盖骨关节炎患者的疼痛并提高其功能。CBD无毒，具有止痛和抗炎作用。这项拟议的研究首次试图通过检测CBD和THC对疼痛集中程度不同的人膝关节骨关节炎的影响，来了解CBD和THC如何影响不同的慢性疼痛机制。我们的主要假设是，CBD将减轻外周炎症，THC将改变中枢神经系统的疼痛处理，联合CBD THC将两者兼而有之。为了检验这一假设，我们提出了三个具体目标。目的1：在一项随机、双盲、2x2析因设计研究中，使用一组患者报告的结果表型、实验敏感性测试和神经成像，纵向评估CBD和THC对炎症(白介素6)和集中性疼痛的神经生物学相关性(即默认模式网络到岛的连接)的外周和中枢神经系统的影响。目的2：检测THC和CBD及其代谢产物对脑连通性、神经化学和炎症标志物的影响。目的3(探索性)：评估疼痛集中是否预示对CBD和THC的不同止痛反应。鉴于疼痛集中在许多慢性疼痛情况下都会发生，我们在膝盖骨关节炎中的方法将作为一个转换模型，几乎可以应用于所有其他疼痛情况，并将对开发用于疼痛管理的非阿片类止痛药具有广泛的影响。

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.