Combatting joint pain and inflammation by dual inhibition of monoacylglycerol lipase and cyclooxygenase-2 in a rat model of osteoarthritis

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.