Abstract
IntroductionDuring the progression of rheumatoid arthritis (RA), there are frequent but intermittent flares in which the joint becomes acutely inflamed and painful. Although a number of drug therapies are currently used to treat RA, their effectiveness is variable and side effects are common. Endocannabinoids have the potential to ameliorate joint pain and inflammation, but these beneficial effects are limited by their rapid degradation. One enzyme responsible for endocannabinoid breakdown is fatty acid amide hydrolase (FAAH). The present study examined whether URB597, a potent and selective FAAH inhibitor, could alter inflammation and pain in a mouse model of acute synovitis.MethodsAcute joint inflammation was induced in male C57BL/6 mice by intra-articular injection of 2% kaolin/2% carrageenan. After 24 hr, articular leukocyte kinetics and blood flow were used as measures of inflammation, while hindlimb weight bearing and von Frey hair algesiometry were used as measures of joint pain. The effects of local URB597 administration were then determined in the presence or absence of either the cannabinoid (CB)1 receptor antagonist AM251, or the CB2 receptor antagonist AM630.ResultsURB597 decreased leukocyte rolling and adhesion, as well as inflammation-induced hyperaemia. However, these effects were only apparent at low doses and the effects of URB597 were absent at higher doses. In addition to the anti-inflammatory effects of URB597, fatty acid amide hydrolase (FAAH) inhibition improved both hindlimb weight bearing and von Frey hair withdrawal thresholds. The anti-inflammatory effects of URB597 on leukocyte rolling and vascular perfusion were blocked by both CB1 and CB2 antagonism, while the effect on leukocyte adherence was independent of cannabinoid receptor activation. The analgesic effects of URB597 were CB1 mediated.ConclusionsThese results suggest that the endocannabinoid system of the joint can be harnessed to decrease acute inflammatory reactions and the concomitant pain associated with these episodes.
Highlights
During the progression of rheumatoid arthritis (RA), there are frequent but intermittent flares in which the joint becomes acutely inflamed and painful
The anti-inflammatory effects of URB597 on leukocyte rolling and vascular perfusion were blocked by both cannabinoid type 1 (CB1) and CB2 antagonism, while the effect on leukocyte adherence was independent of cannabinoid receptor activation
The analgesic effects of URB597 were CB1 mediated. These results suggest that the endocannabinoid system of the joint can be harnessed to decrease acute inflammatory reactions and the concomitant pain associated with these episodes
Summary
During the progression of rheumatoid arthritis (RA), there are frequent but intermittent flares in which the joint becomes acutely inflamed and painful. Blood flow is increased to the inflamed area and leukocytes are recruited to the affected joint. These events can lead to a potentiation of the inflammatory response; During synovitis, pro-inflammatory molecules released into the joint initiate local inflammatory vasodilatation and increased vascular permeability [2]. Vascular endothelial cells begin to express cell adhesion molecules (CAMs) that bind other CAMs expressed on the surface of passing leukocytes. These interactions initiate the capture of activated leukocytes, which commence a rolling behaviour where the cells move slower than the surrounding circulation. Adherent leukocytes are able to exit the blood vessels and enter the surrounding tissue, where they can release various mediators that influence local inflammation [3]
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