Sulfasalazine alleviates neuropathic pain hypersensitivity in mice through inhibition of SGK-1 in the spinal cord

Diurnal variations in pain hypersensitivity are common chronic disorders. Temporal exacerbation of neuropathic is dependent on diurnal glucocorticoid secretion from the adrenal glands. We previously demonstrated that spinal expression serum- and glucocorticoid-inducible kinase-1 (SGK-1) associated with glucocorticoid- induced hypersensitivity, but there no available strategies to inhibit SGK-1 cord. By screening a clinically approved drug library (more than 1,200 drugs), we found sulfasalazine (SSZ) has inhibitory effects SGK-1. SSZ prodrug composed 5-aminosalicylic acid sulfapyridine linked by NN bond, which therapeutically effective for inflammatory bowel diseases. However, bond was necessary its action against Although intrathecal injection nerve-injured mice significantly alleviated mechanical significant anti- were detected after oral administration due low bioavailability limited distribution, efflux xenobiotic transporter breast cancer resistance protein (BCRP). Concomitant febuxostat (FBX), an BCRP, improved distribution The concomitant FBX also increased anti-neuropathic SSZ. Our study revealed unrecognized pharmacological effect alleviate SGK-1-induced painful peripheral neuropathy, may be preventative option hypersensitivity.