CORM-2 and Ifenprodil improved joint oedema-associated mobility via the inhibition of thalamic P2X4 receptor-induced microglia activation in chronic polyarthritis rats

Abstract

Abstract Pain derived from rheumatoid arthritis (RA) is the most debilitating symptom suffered by patients although inflammation is successfully controlled. It is the main concern that is frequently overlooked due to unclear understandings of its occurrence. Medications to alleviate pain are limited and produce severe side effects. This study aimed to uncover possible involvement of nociceptive signalling N-methyl-D-aspartate-2B receptor (NMDAR-2B) or P2X4 receptor (P2X4R)-induced microglial activation at thalamus of chronic polyarthritis rat mimicking RA upon CORM-2 (selective P2X4R antagonist) and ifenprodil (non-competitive NMDAR-2B antagonist) administrations. Eighty Sprague-Dawley male rats were randomly assigned into five groups (n = 16): non-arthritic control(C), arthritic control(A), arthritic rats treated with either diclofenac (positive control) (A + Diclofenac), CORM-2 (A + CORM-2), or ifenprodil (A + Ifenprodil). The rat was induced with complete Freund’s adjuvant into chronic polyarthritis state for 15 days. Treatment of either sodium diclofenac, ifenprodil, CORM-2 or saline (as vehicle) was performed for seven days intrathecally. Bilateral ankle joint diameter and spontaneous behaviour activity (mobility) were evaluated to assess oedema-induced pain responses. Thalamus tissue was collected for qRT-PCR and immunohistochemistry analyses. Results revealed a significant reduction in ankle joint diameter and improved mobility in groups treated with CORM-2 and ifenprodil. The treatments significantly attenuated mRNA level and protein expression of thalamic P2X4R and activated microglia of arthritic rats. This study deduced possible contribution of thalamic NMDAR-2B-P2X4R-induced microglial activation in pathogenesis of RA pain. It also provides insights to understand the pathogenesis of RA pain and suggests CORM-2 and ifenprodil as possible new therapeutics in RA pain management.