Essential role of transient receptor potential M8 (TRPM8) in a model of acute cold-induced urinary urgency

Eur Urol. 2015 Oct;68(4):655-61. doi: 10.1016/j.eururo.2015.03.037. Epub 2015 Apr 3.

Abstract

Background: Acute exposure of part of the skin to cold stimuli can evoke urinary urgency, a phenomenon termed acute cold-induced urgency (ACIU). Despite its high prevalence, particularly in patients with overactive bladder, little is known about the mechanisms that induce ACIU.

Objective: To develop an animal model of ACIU and test the involvement of cold-activated ion channels transient receptor potential (TRP) M8 and TRPA1.

Design, setting, and participants: Intravesical pressure and micturition were monitored in female mice (wild-type C57BL/6J, Trpa1(-/-), Trpm8(+/+), and Trpm8(-/-)) and Sprague Dawley rats.

Interventions: An intravesical catheter was implanted. Localized cooling of the skin was achieved using a stream of air or topical acetone. The TRPM8 antagonist (N-(3-aminopropyl)-2-{[(3-methylphenyl) methyl]oxy}-N-(2-thienylmethyl)benzamide (AMTB) or vehicle was injected intraperitoneally.

Outcome measurements and statistical analysis: Frequencies of bladder contractions and voids in response to sensory stimuli were compared using the Mann-Whitney or Kruskal-Wallis test.

Results and limitations: Brief, innocuously cold stimuli applied to different parts of the skin evoked rapid bladder contractions and voids in anesthetized mice and rats. These responses were strongly attenuated in Trpm8(-/-) mice and in rats treated with AMTB. As rodent bladder physiology differs from that of humans, it is difficult to directly extrapolate our findings to human patients.

Conclusions: Our findings indicate that ACIU is an evolutionarily conserved reflex rather than subconscious conditioning, and provide a useful in vivo model for further investigation of the underlying mechanisms. Pharmacological inhibition of TRPM8 may be useful for treating ACIU symptoms in patients.

Patient summary: Brief cold stimuli applied to the skin can evoke a sudden desire to urinate, which can be highly bothersome in patients with overactive bladder. We developed an animal model to study this phenomenon, and found that it depends on a specific molecular cold sensor, transient receptor potential M8 (TRPM8). Pharmacological inhibition of TRPM8 may alleviate acute cold-induced urinary urgency in humans.

Keywords: Cold sensing; TRPM8; Urinary urgency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / administration & dosage
  • Cold Temperature*
  • Disease Models, Animal
  • Female
  • Hypothermia, Induced*
  • Injections, Intraperitoneal
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pressure
  • Rats, Sprague-Dawley
  • Reflex
  • Signal Transduction
  • Skin / drug effects
  • Skin / innervation
  • Skin / metabolism*
  • TRPM Cation Channels / antagonists & inhibitors
  • TRPM Cation Channels / deficiency
  • TRPM Cation Channels / genetics
  • TRPM Cation Channels / metabolism*
  • Thiophenes / administration & dosage
  • Time Factors
  • Urinary Bladder / innervation
  • Urinary Bladder / physiopathology*
  • Urinary Incontinence, Urge / etiology
  • Urinary Incontinence, Urge / metabolism*
  • Urinary Incontinence, Urge / physiopathology
  • Urinary Incontinence, Urge / prevention & control
  • Urination
  • Urodynamics

Substances

  • Benzamides
  • N-(3-aminopropyl)-2-(((3-methylphenyl) methyl)oxy)-N-(2-thienylmethyl)benzamide hydrochloride salt
  • TRPM Cation Channels
  • TRPM8 protein, mouse
  • Thiophenes
  • Trpm8 protein, rat