Abstract
Chronic inflammation in rheumatoid arthritis (RA) is accompanied by activation of the sympathetic nervous system, which can support the immune system to perpetuate inflammation. Several animal models of arthritis already demonstrated a profound influence of adrenergic signaling on the course of RA. Peripheral norepinephrine release from sympathetic terminals is controlled by cannabinoid receptor type 1 (CB1), which is activated by two major endocannabinoids (ECs), arachidonylethanolamine (anandamide) and 2-arachidonylglycerol. These ECs also modulate function of transient receptor potential channels (TRPs) located on sensory nerve fibers, which are abundant in arthritic synovial tissue. TRPs not only induce the sensation of pain but also support inflammation via secretion of pro-inflammatory neuropeptides. In addition, many cell types in synovial tissue express CB1 and TRPs. In this review, we focus on CB1 and transient receptor potential vanilloid 1 (TRPV1)-mediated effects on RA since most anti-inflammatory mechanisms induced by cannabinoids are attributed to cannabinoid receptor type 2 (CB2) activation. We demonstrate how CB1 agonism or antagonism can modulate arthritic disease. The concept of functional antagonism with continuous CB1 activation is discussed. Since fatty acid amide hydrolase (FAAH) is a major EC-degrading enzyme, the therapeutic possibility of FAAH inhibition is studied. Finally, the therapeutic potential of ECs is examined since they interact with cannabinoid receptors and TRPs but do not produce central side effects.
Highlights
Rheumatoid arthritis (RA) is a debilitating disease that affects around 1.3 million people in the US alone [1]
While the impact of cannabinoid receptor type 2 (CB2) on immune function has already been investigated and reviewed elsewhere [33, 36], this review focuses on cannabinoid receptor type 1 (CB1)
Besides CB1 and CB2, ECs as well as synthetic and phytocannabinoids bind to members of the Transient receptor potential channel (TRP) family [54, 61, 72,73,74]
Summary
Rheumatoid arthritis (RA) is a debilitating disease that affects around 1.3 million people in the US alone [1]. CB2 regulates immune cell function directly While CB1 functions mainly through modulation of central and peripheral neurotransmitter release, activation of CB2 elicits direct anti-inflammatory effects in target cells [33]. The conundrum of functional antagonism at CB1 and TRPV1 Throughout this review, similar effects of CB1 agonists and CB1 antagonists on features of arthritic inflammation are described This conundrum can be explained by rapid desensitization and downregulation/internalization of CB1 upon agonist exposure [45,46,47]. This phenomenon was described with MAGL inhibitors, which increase levels of 2-AG [42] Another possibility to achieve antagonistic effects with agonists is the use of CB1 partial agonists like AEA, which lack full activation of CB1 signaling pathways. Reduction of tolerance to CB1 agonists with FAAH inhibitors can be important since this process leads to a loss of efficacy when repeatedly
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