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.