Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan; Department of Glocal Healthcare Science, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Biochem Pharmacol. 2021 Mar;185:114411. doi: 10.1016/j.bcp.2021.114411. Epub 2021 Jan 8.
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 NN bond, which is therapeutically effective for inflammatory bowel diseases. However, the NN 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.
痛觉过敏的昼夜变化在慢性疼痛障碍中很常见。神经病理性疼痛过敏的时间恶化取决于肾上腺糖皮质激素分泌的昼夜变化。我们之前的研究表明，血清和糖皮质激素诱导的激酶-1（SGK-1）在脊髓中的表达与糖皮质激素诱导的痛觉过敏恶化有关，但目前还没有抑制脊髓中 SGK-1 的可用策略。通过筛选临床批准的药物库（超过 1200 种药物），我们发现柳氮磺胺吡啶（SSZ）对 SGK-1 具有抑制作用。SSZ 是由 5-氨基水杨酸和磺胺吡啶通过 NN 键连接而成的前体药物，对炎症性肠病具有治疗作用。然而，SSZ 中 NN 键对其抑制 SGK-1 的作用是必要的。尽管鞘内注射 SSZ 到神经损伤的小鼠显著减轻机械性痛觉过敏，但由于其生物利用度低和有限的脊髓分布，口服 SSZ 后没有检测到明显的抗神经病理性疼痛作用，这与外排转运蛋白乳腺癌耐药蛋白（BCRP）有关。同时口服 SSZ 与非布司他（FBX），一种抑制 BCRP 的批准药物，改善了 SSZ 向脊髓的分布。同时口服 FBX 也增加了 SSZ 的抗神经病理性疼痛作用。我们的研究揭示了 SSZ 缓解 SGK-1 诱导的痛觉外周神经病变的先前未被认识的药理学作用，同时口服 SSZ 与 FBX 也可能是预防神经病理性疼痛过敏昼夜恶化的选择。
