2. Academic Validation
  3. Morphine Tolerance Gated through EZH2-Mediated Suppression of Trpc5 in Spinal GABAergic Interneurons in Male Mice

Morphine Tolerance Gated through EZH2-Mediated Suppression of Trpc5 in Spinal GABAergic Interneurons in Male Mice

  • Adv Sci (Weinh). 2025 Oct 20:e07908. doi: 10.1002/advs.202507908.
Li Wan 1 2,  Mengyao Zhang 1,  Haiyue Guo 1,  Yan Xu 3,  Chenjie Xu 4,  Fan Hu 1,  Yinbing Pan 5,  Xian Wang 6,  Wentao Liu 1,  Chun-Yi Jiang 1
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
  • 2 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, 210023, China.
  • 3 Department of Pain, the first people 's hospital of Changzhou, Soochow University, Changzhou, Jiangsu, 213000, China.
  • 4 Department of Anesthesiology and Pain, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, 210006, China.
  • 5 Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China.
  • 6 Department of Anesthesiology, Women's Hospital of Nanjing Medical University, Nanjing Women and Children's Healthcare Hospital, Nanjing, Jiangsu, 210004, China.
PMID: 41111460 DOI: 10.1002/advs.202507908
Abstract

A major unresolved issue in managing severe pain is tolerance caused by repeated treatment of opioid analgesics. Here, it is demonstrated that tolerance-inducing treatment with morphine results in the persistent downregulation of transient receptor potential canonical 5 (TRPC5), impairing the CA2+ homeostasis in GABAergic interneurons of the spinal dorsal horn (SDH) and consequently reducing GABA release. Spinal activation of TRPC5 by riluzole (RLZ) or lentiviral-mediated TRPC5 overexpression in GABAergic interneurons produces a long-lasting enhancement of morphine's analgesic effect. In contrast, pharmacological inhibition of TRPC5 and mice lacking TRPC5 accelerates the development of morphine tolerance. Mechanistically, it is found that transcriptional suppression of Trpc5 results from enhancer of zeste homolog 2 (EZH2)-mediated epigenetic modifications at the Trpc5 gene promoter. Morphine decreases the enrichment of RNA polymerase II at the Trpc5 promoter. Moreover, exposure to morphine increases EZH2 binding to the Trpc5 promoter, leading to the enrichment of histone H3 lysine-27 trimethylation (H3K27me3). Pharmacological blockade of EZH2 by EPZ6438 or genetic silencing in GABAergic interneurons reverses morphine tolerance. Thus, it is proposed that the clinical translation of these findings may help reduce the suffering of individuals with intractable pain.

Keywords

EZH2; GABAergic interneurons; Morphine tolerance; TRPC5.

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