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Updated: Jan 14, 2026

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
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Morphine Tolerance Gated through EZH2-Mediated Suppression of Trpc5 in Spinal GABAergic Interneurons in Male Mice

Li Wan1,2, Mengyao Zhang1, Haiyue Guo1

  • 1Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|October 20, 2025
PubMed

Insights

Repeated morphine use reduces TRPC5 channels, impairing pain relief. Activating TRPC5 channels with riluzole or gene therapy can restore morphine

Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • Opioid analgesics are crucial for severe pain management.
  • Tolerance to opioids, like morphine, limits their long-term effectiveness.
  • The underlying mechanisms of opioid tolerance are not fully understood.

Purpose of the Study:

  • To investigate the role of transient receptor potential canonical 5 (TRPC5) in morphine tolerance.
  • To explore the potential of TRPC5 modulation for enhancing opioid analgesia.
  • To elucidate the epigenetic mechanisms regulating TRPC5 expression during morphine treatment.

Main Methods:

  • Investigated TRPC5 expression and function in spinal dorsal horn (SDH) GABAergic interneurons following morphine treatment.
  • Utilized pharmacological activators (riluzole) and inhibitors of TRPC5.
  • Employed lentiviral vectors for TRPC5 overexpression and genetic silencing.
  • Analyzed epigenetic modifications at the Trpc5 gene promoter using techniques like ChIP-seq.
  • Assessed the impact of TRPC5 and EZH2 modulation on morphine analgesia and tolerance in vivo.

Main Results:

  • Morphine treatment persistently downregulates TRPC5 in SDH GABAergic interneurons, impairing calcium homeostasis and GABA release.
  • Spinal TRPC5 activation (riluzole, overexpression) enhances and prolongs morphine's analgesic effects.
  • TRPC5 inhibition or deficiency accelerates morphine tolerance.
  • EZH2-mediated epigenetic silencing (H3K27me3 enrichment) at the Trpc5 promoter suppresses Trpc5 transcription.
  • Pharmacological or genetic blockade of EZH2 reverses morphine tolerance.

Conclusions:

  • TRPC5 downregulation in spinal GABAergic interneurons is a key mechanism driving morphine tolerance.
  • Targeting TRPC5 offers a novel strategy to enhance opioid efficacy and combat tolerance.
  • EZH2-mediated epigenetic regulation of TRPC5 is critical in the development of opioid tolerance.
  • These findings suggest potential clinical applications for treating intractable pain and reducing opioid reliance.
Keywords:
EZH2GABAergic interneuronsMorphine toleranceTRPC5

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