Pieter Uvin1, Jan Franken1, Silvia Pinto2, Roma Rietjens1, Luc Grammet2, Yves Deruyver1, Yeranddy A Alpizar2, Karel Talavera2, Rudi Vennekens2, Wouter Everaerts1, Dirk De Ridder3, Thomas Voets4. 1. 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. 2. Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; TRP Research Platform Leuven (TRPLe), Leuven, Belgium. 3. Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; TRP Research Platform Leuven (TRPLe), Leuven, Belgium. 4. 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.
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.
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 humanpatients. 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.
Authors: Hiroki Ito; Anthony E Pickering; Yasuhiko Igawa; Anthony J Kanai; Christopher H Fry; Marcus J Drake Journal: Front Physiol Date: 2017-02-06 Impact factor: 4.566
Authors: Jan Franken; Helene De Bruyn; Roma Rietjens; Andrei Segal; Dirk De Ridder; Wouter Everaerts; Thomas Voets; Greetje Vande Velde Journal: Sci Adv Date: 2021-07-23 Impact factor: 14.136