Long-term folic acid treatment relieves chronic inflammatory pain and pain-induced anxiety by reducing MMP2 expression in rats

Abstract

Chronic inflammatory pain is a top priority for arthritis patients seeking medical care. Despite the availability of NSAIDs and glucocorticoids, pain management becomes increasingly challenging due to central and peripheral sensitization. Previous studies have shown that Matrix metalloproteinase 2 (MMP2) promotes neuroinflammation by cleaving extracellular matrix proteins and activating pro-inflammatory cytokines. Folic acid acts as a promising candidate for the treatment of neuroinflammatory diseases due to its neuroprotective effects. However, the role of folic acid in inflammatory pain remains unclear. This study investigated the analgesic mechanisms of folic acid in inflammatory pain. Adult rats underwent inflammatory pain by injecting complete freund's adjuvant (CFA) into the right hindpaw. Behavioral tests were used to assess the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). The results demonstrated that CFA injection induced abnormal mechanical and thermal pain and increased MMP2 expression in L3-L5 DRG and SDH of CFA rats. MMP2 was mainly expressed in neurons rather than glial cells in L3-L5 DRG of CFA rats. We further discovered that MMP2 inhibitor auraptene or knockdown alleviated inflammatory pain in CFA rats. Interestingly, we observed that long-term folic acid treatment reversed MMP2 overexpression, resulting in sustained relief of chronic inflammatory pain. Consistently, long-term folic acid treatment also relieved pain-induced anxiety. These results indicated that folic acid had a protective role in chronic inflammatory pain and pain-induced anxiety by repressing MMP2 expression. Folic acid or auraptene might be promising therapeutic options for the treatment of chronic inflammatory pain.