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Transient Receptor Potential Melastatin 8 Contributes to Cystitis-Induced Neuronal Sprouting and Pain

Liyang Wu1, Ran Chang2, Peng Zhang1

  • 1Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.

Lower Urinary Tract Symptoms
|November 11, 2024
PubMed
Abstract

Insights

Transient Receptor Potential Melastatin 8 (TRPM8) induces pain and nerve growth in bladder pain models by activating the Akt/mTOR pathway. Blocking TRPM8 may offer new treatments for interstitial cystitis/bladder pain syndrome (IC/BPS).

Area of Science:

  • Urology
  • Neuroscience
  • Pain Research

Background:

  • Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic condition characterized by pelvic pain and urinary urgency.
  • The role of Transient Receptor Potential Melastatin 8 (TRPM8) in IC/BPS pathophysiology, particularly in neuroproliferation and pain signaling, remains incompletely understood.
  • The Akt/mammalian target of rapamycin (mTOR) signaling pathway is implicated in cell growth and survival, but its specific involvement in IC/BPS is under investigation.

Purpose of the Study:

  • To elucidate the mechanism by which TRPM8 contributes to neuroproliferation and pain in a mouse model of IC/BPS.
  • To investigate the role of the Akt/mTOR signaling pathway in TRPM8-mediated effects within the context of IC/BPS.
  • To assess the therapeutic potential of targeting TRPM8 for IC/BPS.

Main Methods:

  • Establishment of an IC/BPS mouse model using wild-type and TRPM8 knockout mice.
  • Assessment of mechanical sensitivity, and quantification of neurite growth parameters (number, length, density).
  • Detection of Interleukin-6 (IL-6) and norepinephrine levels via ELISA, and Western blot analysis for TRPM8, Akt, p-Akt, mTOR, and p-mTOR expression.

Main Results:

  • IC/BPS mice exhibited decreased pain threshold and enhanced neurite growth compared to controls.
  • TRPM8 knockout mice showed reduced neurite proliferation and lower IL-6 and norepinephrine levels compared to IC/BPS mice.
  • TRPM8 expression, along with elevated p-Akt/Akt and p-mTOR/mTOR ratios, was observed in IC/BPS model mice, indicating Akt/mTOR pathway activation.

Conclusions:

  • TRPM8 activation drives pain hypersensitivity and sensory nerve proliferation in IC/BPS models, partly through the Akt/mTOR pathway.
  • Elevated IL-6 and norepinephrine levels are associated with TRPM8-induced pathology in IC/BPS.
  • Targeting TRPM8 presents a promising therapeutic strategy for managing IC/BPS.
Keywords:
Akt/mTOR signaling pathwayinterstitial cystitis (IC)/bladder pain syndrome (BPS)neuronal sproutingpain hypersensitivitytransient receptor potential melastatin 8 (TRPM8)

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