Fig. 2

Possible effects of CB₁ antagonism and fatty acid amid hydrolase (FAAH) inhibition on inflammation in the joint. During the course of arthritis, sympathetic nerve fibers are repelled from synovial tissue (1). Released norepinephrine (NE) (2) stimulates lipolysis, since concentrations are high enough to activate β-adrenergic receptors on adipocytes. Synovial tissue NE concentrations, however, are below the threshold for β-activation. Beyond the 'α/β demarcation line' (3), only pro-inflammatory α-adrenergic signaling is expected. Hypothetically, inflammation can be blocked in the following way. Firstly, CB₁ antagonism shifts the α/β demarcation line (indicated by dotted arrow) due to enhanced release of NE and its co-transmitters. Secondly, concomitant FAAH inhibition increases local endocannabinoid/N-acylethanolamine concentrations, which enhance sprouting of sympathetic fibers back into synovial tissue. This is followed by a sequence of events: an increase in NE decreases the production of pro-inflammatory cytokines (4) and increases the production of anti-inflammatory cytokines (5). This would reduce cartilage and bone destruction (6). Lipolysis is increased under these conditions since CB₁ antagonism leads to direct lipolytic effects on adipocytes (7), which are enhanced by β-adrenergic activation. In addition, TRPV1 activated by FAAH inhibition can also contribute to lipolysis (7). Although blockade of CB₁ enhances TRPV1 sensitization on sensory nerves, this can be counteracted by TRPV1 desensitization through FAAH inhibition but also by reduction of pro-inflammatory cytokines that sensitize TRPV1 (8). Eventually, this can also lead to a reduction of afferent sensory nerve fiber signaling to the central nervous system (9). Direct anti-inflammatory effects of FAAH substrates and CB₁ antagonists reduce cytokine levels in the joint (10). The STOP symbol indicates inhibition, the PRIORITY ROAD symbol indicates an enhancement of a given effect. CGRP, calcitonin gene-related peptide; IFN, interferon