Cannabinoid-based drugs targeting CB1 and TRPV1, the sympathetic nervous system, and arthritis.
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.
Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, University Hospital of Regensburg, D-93053, Regensburg, Germany. torsten.lowin@ukr.de.
Torsten
T
Lowin
Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, University Hospital of Regensburg, D-93053, Regensburg, Germany.
Rainer H
RH
Straub
D000818:Animals; D001168:Arthritis / Q000188:drug therapy* / Q000503:physiopathology; D002186:Cannabinoids / Q000627:therapeutic use*; D006801:Humans; D008954:Models, Biological; D058990:Molecular Targeted Therapy / Q000379:methods; D010146:Pain / Q000503:physiopathology / Q000517:prevention & control; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000503:physiopathology*; D050916:TRPV Cation Channels / Q000502:physiology*
D002186:Cannabinoids; D043884:Receptor, Cannabinoid, CB1; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human