Activation of MSK-1 exacerbates neuropathic pain through histone H3 phosphorylation in the rats’ dorsal root ganglia and spinal dorsal horn

• Published in: Brain research bulletin 2024-12, Vol.219, p.111135, Article 111135
• Main Authors: Wang, Li, Gao, Yan, Qiao, Yiming, Wang, Xueli, Liang, Zongyi, Xu, Ji-Tian, Li, Liren
• Format: Article
• Language: English
• Subjects: Animals; Disease Models, Animal; DRG; Ganglia, Spinal - metabolism; Histones - metabolism; Male; MSK-1; Neuralgia - metabolism; Neuropathic pain; P-H3S10; Phosphorylation - drug effects; Rats; Rats, Sprague-Dawley; Ribosomal Protein S6 Kinases, 90-kDa - metabolism; RNA, Small Interfering - pharmacology; Spinal cord; Spinal Cord Dorsal Horn - drug effects; Spinal Cord Dorsal Horn - metabolism; Spinal Nerves - injuries; Spinal Nerves - metabolism
• ISSN: 0361-9230; 1873-2747; 1873-2747
• DOI: 10.1016/j.brainresbull.2024.111135

The exact mechanism underlies the development of neuropathic pain is not yet completely understood. Mitogen and stress-activated kinase 1 (MSK-1) is an important downstream kinase of the mitogen-activated protein kinase (MAPK). It has been extensively studied in the central nervous system, but whether MSK-1 is associated with the neuropathic pain remains elusive. In this experiment, Lumbar 5 spinal nerve ligation (SNL) was used to establish a neuropathic pain condition in the rats. Western blotting, qRT-PCR, immunohistochemistry, intrathecal catheterization and drugs delivery were evaluated to study the physiological responses of the animals. The results showed that SNL resulted in elevated phosphorylated MSK-1 (p-MSK-1) expression in the ipsilateral dorsal root ganglion (DRG) and the spinal dorsal horn in rats, while total MSK-1 (t-MSK-1) did not change significantly. Intrathecal injection of the MSK-1 inhibitor SB747651A partially reversed established neuropathic pain. Additionally, intrathecal administration of MSK-1 siRNA either preoperatively or 7 days postoperatively relieves the development and maintenance of pain, respectively. Meanwhile, the expression levels of p-H3S10, a downstream target of MSK-1, also displayed a significant increase after SNL. And these changes could be reversed by using MSK-1 siRNA. Collectively, the increase of MSK-1 induced by SNL participates in the development and maintenance of neuropathic pain by regulating the expression of p-H3S10 in DRG and spinal dorsal horn. Concentrating on MSK-1 may result in a novel approach to the treatment of neuropathic pain. [Display omitted] •SNL caused an increase of p-MSK-1 in the DRG and spinal dorsal horn.•MSK-1 inhibition reduced SNL-induced neuropathic pain.•MSK-1 inhibition reduced the phosphorylation of p-H3S10 induced by SNL.