6.0 Cannabinoids and joint inflammation
Inflammatory mediators such as neuropeptides, including substance P (SP), calcitonin gene-related peptide (CGRP) and neurokinin A, released during neurogenic inflammation by local afferent neurons act on adjacent mast cells with subsequent release of histamine (Barrie and Manolios, 2017). The histamine released then induces the release of additional SP from terminal varicosities of branches of neurons in the dorsal horn, and CGRP, thus creating a positive feedback loop which amplifies the inflammatory response (Rosa and Fantozzi, 2013). In the arthritic joint, subsequent release of these neuropeptides from peripheral terminals of Aδ and C-fibers result in the development of local neurogenic inflammation, and also neuropathic pain via increased TRPV1 expression (Bánvölgyi et al., 2004; Heppelmann and Pawlwak, 1997). The release of other mediators of inflammation such as prostaglandins, nerve growth factor and bradykinins, within the synovium also contributes to the development and sustenance of joint inflammation in rheumatoid arthritis (RA) by sensitizing TRPV1 (Raychaudhuri et al., 2011).
It has been shown that CB1 and CB2co-localize with TRPV1, and that an interplay between the endocannabinoid and endovanilloid systems may play a potential role in the modulation of inflammatory responses (Mlost et al., 2018). For instance, anandamide and some of its lipoxygenation products, also function as potent ligands on TRPV1 (Ahluwalia et al., 2003; Starowicz et al., 2013). Depending on whether or not cyclic adenosine monophosphate (cAMP) signaling pathway is activated, stimulation of CB1 receptors may either inhibit or potentiate stimulation of TRPV1 by its ligands (Hermann et al., 2003). Because cAMP-dependent protein kinase A can phosphorylate TRPV1 and enhance its sensitivity, it is possible that increased phosphorylation of TRPV1 during inflammation by protein kinase A can be inhibited by CB1-mediated inhibition of adenylate cyclase (Maione et al., 2006).
In a rat monoiodoacetic acid model of osteoarthritis, the FAAH inhibitor and TRPV1 antagonist, OMDM198, inhibitor reversed some of the monoiodoacetic acid effects on the spinal cord. In that study, OMDM198 exclusively upregulated the expression of CB1 on the ipsilateral side of the spinal cord, but did not affect CB2 expression. Moreover, OMDM198 significantly inhibited the expression of Mapk14 and Prkcg mRNA compared to non-diseased controls, in the ipsilateral side of the spinal cord (Mlost et al., 2018). Thus, dual regulation of endocannabinoid system and endovanilloid receptors may provide a very useful alternative in multi-drug therapy for osteoarthritis. Fig. 3 summarizes the hypothetical mechanisms of action underpinning the potential therapeutic relevance of OMDM198 in osteoarthritis.