The endocannabinoid signaling pathway as an emerging target in pharmacotherapy, earmarking mitigation of destructive events in rheumatoid arthritis

Rheumatoid arthritis is an inflammatory autoimmune disease, characterized by synovial proliferation, destruction to articular cartilage and severe pain. The cannabinoids obtained from Cannabis sativa exhibited their actions via cannabinoid-1 and -2 receptors, which also provides a platform for endocannabinoids to act. The endocannabinoid system comprises endocannabinoid molecules involved in signaling processes, along with G-protein coupled receptors and enzymes associated with ligand biosynthesis, activation and degradation. The action of endocannabinoid system in immune system regulation, via primary CB2 activation, followed by inhibition of production of pro-inflammatory cytokines, auto-antibodies and MMPs, FLSs proliferation and T-cell mediated immune response, are elaborated as potential therapeutic regimes in rheumatoid arthritis. The involvement of endocannabinoid system in immune cells like, B cells, T cells and macrophages, as well as regulatory actions on sensory noniceptors to ameliorate pain is significantly highlighted in the review, elaborating the actions of endocannabinoid signaling in mitigating the disease events. The review also focuses on enhancement of endocannabinoid tone, either by inhibiting the degradation enzymes, like FAAH, MAGL, COX, CytP450, LOX, etc. or by retarding cellular uptake processes. Moreover, the review portrays the optimizing role of endocannabinoid system, in abbreviating the symptoms and complications of rheumatoid arthritis in patients and mitigating inflammation, pain and immune mediated effects significantly.