title: Essential role of transient receptor potential M8 (TRPM8) in a model of acute cold-induced urinary urgency.
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.
  
  
  METHODS
  Intravesical pressure and micturition were monitored in female mice (wild-type C57BL/6J, Trpa1(-/-), Trpm8(+/+), and Trpm8(-/-)) and Sprague Dawley rats.
  
  
  METHODS
  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.
  
  
  METHODS
  Frequencies of bladder contractions and voids in response to sensory stimuli were compared using the Mann-Whitney or Kruskal-Wallis test.
  
  
  CONCLUSIONS
  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.
  
  
  RESULTS
  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.
authors.affiliation: Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; TRP Research Platform Leuven (TRPLe), Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Uvin
authors.affiliation: Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; TRP Research Platform Leuven (TRPLe), Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Franken
authors.affiliation: Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; TRP Research Platform Leuven (TRPLe), Leuven, Belgium.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pinto
authors.affiliation: Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; TRP Research Platform Leuven (TRPLe), Leuven, Belgium.
authors.forename: Roma
authors.initials: R
authors.lastname: Rietjens
authors.affiliation: Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; TRP Research Platform Leuven (TRPLe), Leuven, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Grammet
authors.affiliation: Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; TRP Research Platform Leuven (TRPLe), Leuven, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Deruyver
authors.affiliation: Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; TRP Research Platform Leuven (TRPLe), Leuven, Belgium.
authors.forename: Yeranddy A
authors.initials: YA
authors.lastname: Alpizar
authors.affiliation: Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; TRP Research Platform Leuven (TRPLe), Leuven, Belgium.
authors.forename: Karel
authors.initials: K
authors.lastname: Talavera
authors.affiliation: Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; TRP Research Platform Leuven (TRPLe), Leuven, Belgium.
authors.forename: Rudi
authors.initials: R
authors.lastname: Vennekens
authors.affiliation: Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; TRP Research Platform Leuven (TRPLe), Leuven, Belgium.
authors.forename: Wouter
authors.initials: W
authors.lastname: Everaerts
authors.affiliation: Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; TRP Research Platform Leuven (TRPLe), Leuven, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: De Ridder
authors.affiliation: Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; TRP Research Platform Leuven (TRPLe), Leuven, Belgium. Electronic address: thomas.voets@med.kuleuven.be.
authors.forename: Thomas
authors.initials: T
authors.lastname: Voets
mesh_terms: D000818:Animals; D001549:Benzamides / Q000008:administration & dosage; D003080:Cold Temperature; D004195:Disease Models, Animal; D005260:Female; D007036:Hypothermia, Induced; D007274:Injections, Intraperitoneal; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011312:Pressure; D017207:Rats, Sprague-Dawley; D012018:Reflex; D015398:Signal Transduction; D012867:Skin / Q000187:drug effects / Q000294:innervation / Q000378:metabolism*; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013876:Thiophenes / Q000008:administration & dosage; D013997:Time Factors; D001743:Urinary Bladder / Q000294:innervation / Q000503:physiopathology*; D053202:Urinary Incontinence, Urge / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D014554:Urination; D014563:Urodynamics
chemical_list: D001549:Benzamides; C532415:N-(3-aminopropyl)-2-(((3-methylphenyl) methyl)oxy)-N-(2-thienylmethyl)benzamide hydrochloride salt; D050053:TRPM Cation Channels; C492297:TRPM8 protein, mouse; D013876:Thiophenes; C498947:Trpm8 protein, rat
keywords: Cold sensing; TRPM8; Urinary urgency