Bexarotent Attenuated Chronic Constriction Injury-Induced Spinal Neuroinflammation and Neuropathic Pain by Targeting Mitogen-Activated Protein Kinase Phosphatase-1

Abstract

It is widely accepted that neuroinflammation in the spinal cord contributes to the development of central sensitization in neuropathic pain. Mitogen-activated protein kinase (MAPK) activation plays a vital role in the development of neuroinflammation in the spinal cord. In this study, we investigated the effect of bexarotene (bex), a retinoid X receptor agonist, on MAPKs activation in chronic constriction injury (CCI)-induced neuropathic pain. The data showed that daily treatment with bex 50 mg/kg significantly alleviated CCI-induced nociceptive hypersensitivity in rats. Bex 50 mg/kg/day inhibited CCI-induced MAPKs (p38MAPK, ERK1/2, and JNK) activation and upregulation of proinflammatory factors (IL-1β, tumor necrosis factor-α and IL-6). Bex also reversed CCI-induced microglia activation in the ipsilateral spinal cord. Furthermore, bex treatment significantly upregulated MKP-1 in the spinal cord. These effects were completely abrogated by MKP-1 inhibitor BCI. These results indicated that bex relieved CCI-induced neuroinflammation and neuropathic pain by targeting MKP-1. Therefore, bex might be a potential agent for the treatment of neuropathic pain. PerspectiveBex could relieve neuropathic pain behaviors in animals by reversing MKP-1 downregulation and MAPKs activation in the spinal cord. Therapeutic applications of bex may be extended beyond cutaneous T-cell lymphoma.