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

摘要 膝骨关节炎 (OA) 引起的慢性疼痛是造成残疾的一个重要原因，影响超过 1400 万美国人。但治疗困难且疗效不佳。这是因为疼痛并不是单一的，潜在疼痛机制的差异会影响治疗反应。虽然膝骨关节炎疼痛可能是由于组织和关节损伤（伤害性疼痛）引起的，但中枢神经系统 (CNS) 功能障碍（即集中性疼痛或伤害性疼痛）也会加剧和维持这种疼痛。不同的中枢神经系统贡献解释了为什么有些人有严重的X光膝关节损伤但报告没有疼痛，而另一些人的X光片“正常”却报告严重疼痛。我们的小组和其他人已经表明，这种集中表型发生在几乎所有慢性疼痛病症中。此外，我们还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化会降低对旨在减少膝关节骨关节炎伤害性疼痛的干预措施（例如阿片类药物和手术）的反应性。潜在机制的差异可能解释了大麻素（大麻中的活性化合物）临床试验结果不一致的原因。临床试验表明大麻素可以是有效的镇痛药，但这主要是通过 Δ[9]-四氢大麻酚 (THC) 占主导地位的制剂来证明的，这些制剂具有滥用的可能性。然而，最近的一项研究表明，大麻二酚 (CBD) 可减轻膝关节骨关节炎男性的疼痛并增强其功能。 CBD无毒，具有镇痛和抗炎作用。拟议的研究是首次尝试通过检查这些化合物对不同程度疼痛集中的个体的膝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。我们的总体假设是 CBD 会减少外周炎症，THC 会改变中枢神经系统疼痛处理，而组合 CBD THC 会两者兼而有之。为了检验这一假设，我们提出了三个具体目标。目标 1：在一项随机、双盲、2x2 析因设计研究中，使用我们已成功应用于其他药物和疼痛状况的一系列患者报告结果的表型分析、实验敏感性测试和神经影像学，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（即默认模式网络到岛叶连接）的外周和 CNS 影响。目标 2：检查 THC 和 CBD 及其代谢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。 目标 3（探索性）：评估疼痛集中化是否可以预测对 CBD 和 THC 的镇痛反应差异。鉴于许多慢性疼痛状况中疼痛集中发生，我们在膝关节 OA 方面的方法将作为一种转化模型，可应用于几乎所有其他疼痛状况，并将对开发用于疼痛管理的非阿片类镇痛药产生广泛影响。

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.