BACKGROUND Endocannabinoids are showing great promise as effective mediators for controlling joint inflammation and pain. One strategy that could be harnessed to promote endogenous cannabinoid function is to inhibit the enzymatic break down of endocannabinoids locally in the joint. KML29 is an inhibitor of monoacylglycerol lipase (MAGL) activity which has been shown to promote increased 2-arachodonylglycerol (2-AG) levels in the circulation and in peripheral tissues. It is also known that 2-AG can be metabolised via the cyclo-oxygenase-2 (COX-2) pathway leading to the production of pro-inflammatory prostaglandins, which may counteract the effects of 2-AG. Therefore, this study examined the effect of KML29 alone as well as in combination with low-dose celecoxib (CXB) on joint pain and inflammation in the monoiodoacetate (MIA) model of osteoarthritis (OA) pain. METHODS Injection of MIA (3 mg) into the knee joints of male Wistar rats was used to model OA pain, inflammation, and nerve damage. Pain behaviour was assessed by von Frey hair algesiometry, and inflammation was evaluated using intravital microscopy to measure leukocyte trafficking in the synovial microvasculature. RESULTS Intra-articular injection of MIA produced mechanical hypersensitivity as measured by von Frey hair algesiometry. Local injection of KML29 (700 μg) reduced joint pain at day 14 post-MIA induction, and this analgesic effect was blocked by the cannabinoid receptor antagonists AM281 and AM630 (P < 0.0001; n = 6). During the acute inflammatory phase of the MIA model (day 1), a significant reduction in withdrawal threshold (P < 0.0001; n = 6-8) and leukocyte trafficking was seen after treatment with KML29 + CXB (P < 0.0001; n = 6-8). Early treatment of MIA-injected knees (days 1-3) with KML29 + CXB ameliorated the development of mechanical secondary allodynia (P < 0.0001; n = 8) in the later stages of the MIA model. CONCLUSIONS Combination therapy of KML29 plus CXB reduced joint pain and inflammation. Thus, dual inhibition of MAGL and cyclooxygenase-2 pathways could be a useful approach to alleviate joint inflammation and pain in OA joints.

中文翻译：

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在骨关节炎的大鼠模型中，通过单酰基甘油脂酶和环氧合酶-2的双重抑制来对抗关节疼痛和炎症。

背景技术内源性大麻素作为控制关节发炎和疼痛的有效介质显示出巨大的希望。可以用来促进内源性大麻素功能的一种策略是抑制关节中局部内源性大麻素的酶促分解。KML29是单酰基甘油脂肪酶（MAGL）活性的抑制剂，已显示可促进循环和周围组织中2-花生四烯酸甘油酯（2-AG）水平的升高。还已知2-AG可通过环加氧酶-2（COX-2）途径代谢，导致产生促炎性前列腺素，这可能抵消2-AG的作用。因此，这项研究检查了单独KML29以及与小剂量塞来昔布（CXB）联合使用对骨关节炎（OA）疼痛的单碘乙酸盐（MIA）模型的关节痛和炎症的影响。方法将3 mg MIA注射到雄性Wistar大鼠的膝关节中，以模拟OA疼痛，炎症和神经损伤。通过冯·弗雷（von Frey）毛发法进行疼痛行为评估，并使用活体显微镜术评估滑膜微脉管系统中的白细胞运输，评估炎症。结果关节腔内注射MIA产生了机械性超敏反应，通过von Frey头发法进行了测量。在MIA诱导后第14天，局部注射KML29（700μg）可以减轻关节疼痛，并且该镇痛作用被大麻素受体拮抗剂AM281和AM630阻断（P <0.0001； n = 6）。在MIA模型的急性发炎阶段（第1天），用KML29 + CXB治疗后观察到戒断阈值显着降低（P <0.0001； n = 6-8）和白细胞运输（P <0.0001; n = 6） -8）。用KML29 + CXB对MIA注射的膝盖进行早期治疗（第1-3天）可减轻MIA模型后期机械性继发性异常性疼痛的发生（P <0.0001； n = 8）。结论KML29加CXB联合治疗可减轻关节疼痛和炎症。因此，MAGL和环氧合酶2途径的双重抑制可能是减轻OA关节的炎症和疼痛的有用方法。用KML29 + CXB对MIA注射的膝盖进行早期治疗（第1-3天）可减轻MIA模型后期机械性继发性异常性疼痛的发生（P <0.0001； n = 8）。结论KML29加CXB联合治疗可减轻关节疼痛和炎症。因此，双重抑制MAGL和环氧合酶2途径可能是减轻OA关节的炎症和疼痛的有用方法。用KML29 + CXB对MIA注射的膝盖进行早期治疗（第1-3天）可减轻MIA模型后期机械性继发性异常性疼痛的发生（P <0.0001； n = 8）。结论KML29加CXB联合治疗可减轻关节疼痛和炎症。因此，双重抑制MAGL和环氧合酶2途径可能是减轻OA关节的炎症和疼痛的有用方法。