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

Sai Yasukochi, Naoki Kusunose, Naoya Matsunaga, Satoru Koyanagi, Shigehiro Ohdo

研究成果: Contribution to journalArticle査読

1 被引用数 (Scopus)

抄録

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

本文言語英語
論文番号114411
ジャーナルBiochemical Pharmacology
185
DOI
出版ステータス出版済み - 3 2021

All Science Journal Classification (ASJC) codes

  • 生化学
  • 薬理学

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