SIRT1-mediated deacetylation and activation of MEK/ERK pathway decreased IL-6 in spinal dorsal horn to promote oxycodone tolerance

Shenghui Hu; Fengjia Zhou; Baoguang Lin; Tong Jiang; Xin-Yu Fan; Shuohan Xu

doi:10.1016/j.neuropharm.2025.110585

SIRT1-mediated deacetylation and activation of MEK/ERK pathway decreased IL-6 in spinal dorsal horn to promote oxycodone tolerance

Neuropharmacology. 2025 Jul 3:110585. doi: 10.1016/j.neuropharm.2025.110585. Online ahead of print.

Authors

Shenghui Hu¹, Fengjia Zhou¹, Baoguang Lin¹, Tong Jiang¹, Xin-Yu Fan², Shuohan Xu³

Affiliations

¹ Department of Radiotherapy, General Hospital of Northern Theater Command, Shenyang, China.
² Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, China. Electronic address: fanxy@sj-hospital.org.
³ Department of Radiotherapy, General Hospital of Northern Theater Command, Shenyang, China. Electronic address: xushuohan@hotmail.com.

PMID: 40617466
DOI: 10.1016/j.neuropharm.2025.110585

Abstract

Oxycodone, an opioid analgesic, exhibits limited clinical utility due to the development of tolerance. This study aims to investigate the role of Sirtuin 1 (SIRT1), a histone deacetylase, in oxycodone-induced analgesic tolerance. Adult ICR mice were administered oxycodone subcutaneously once a day for seven consecutive days. The tail-flick test was used to establish a mouse model of oxycodone tolerance. RT-qPCR was employed to assess the mRNA levels of SIRT1-SIRT7. Western blotting was performed to measure the expression levels of SIRT1, interleukin (IL)-6, H3K9ac, H3K14ac, H3K18ac, total/phosphorylated extracellular signal-regulated kinase (ERK) (1/2), and mitogen-activated protein kinase/ERK kinase (MEK) (1/2). ChIP-qPCR were used to localize SIRT1/IL-6 expression, and to quantify histone acetylation at the IL-6 promoter. Mice developed analgesic tolerance by Day 7 of oxycodone administration. Oxycodone significantly reduced SIRT1 mRNA and protein levels in the lumbar spinal cord. Bioinformatics analysis identified IL-6 as the most prominently upregulated gene in the spinal cord. Correspondingly, IL-6 protein levels were elevated, along with increased levels of total H3K9ac (but not H3K14ac or H3K18ac) and enriched H3K9ac at the IL-6 promoter. While total ERK(1/2) and MEK(1/2) levels remained unchanged, their phosphorylated forms were significantly upregulated in tolerant mice. An SIRT1 agonist (SRT1720) inhibited the development of oxycodone tolerance, suppressed IL-6 overexpression, normalized H3K9ac and phospho-ERK/MEK levels, and reduced H3K9ac expression at the IL-6 promoter. Thus, SIRT1 promotes oxycodone tolerance by deacetylating histone H3K9 at the IL-6 promoter and activating the MEK/ERK pathway to upregulate IL-6 expression.

Keywords: Deacetylation; IL-6; MEK/ERK; Oxycodone Tolerance; SIRT1.