- Email: [email protected]
Everyday Cold Exposure and Urgency in Translation
EUROPEAN UROLOGY 68 (2015) 662–663
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. 655–661 of this issue
Everyday Cold Exposure and Urgency in Translation Petter Hedlund [1_TD$IF]a,b,* [2_TD$IF]a
Division of Drug Research, Department of Medical and Health Sciences, Linko¨ping University, Linko¨ping, Sweden; [3_TD$IF]b Division of Oncology/Unit of Urology,
Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
In 2001, the gene for transient receptor potential (TRP)-p8 was identified from a prostate-specific complementary DNA library and found expressed in human prostate tissue [1]. The TRP-p8 that exhibited strong homology to other TRPs was considered to belong to the melastatin family and was denoted transient receptor potential cation channel, subfamily M, member 8 (TRPM8). It was shown to be activated by cold temperatures (8–28 8C) and cooling compounds such as menthol and icilin [2]. Among other TRPs expressed in the lower urinary tract, TRPM8 is under investigation as a target in lower urinary tract disorders. With possible variation between species, TRPM8 is reportedly located [4_TD$IF]in the urothelium and nerves of the lower urinary tract of rodents and humans, and altered TRPM8 expression in the bladder has been described as correlated with bladder dysfunction [3]. Together with transient receptor potential cation channel, subfamily A, member 1 (TRPA1), another putative coldsensing receptor in the lower urinary tract, TRPM8 has been implicated in bladder responses to cold [3]. Such responses include the controversial ice-water test that can elicit detrusor contractions (visceral reflex) and environmental cold-induced urgency that involves somatovisceral pathways [3,4]. Due to the limitations of pharmacologic tools and the unavailability of relevant models, the roles for TRPM8 or TRPA1 in bladder responses to environmental cold temperatures have not yet been fully elucidated [3,5]. Using mice that lack TRPM8 or TRPA1, the study by Uvin and coworkers in this month’s issue of European Urology presents convincing data that provocation of somatosensory functions by cold is linked to bladder responses via TRPM8 but not TRPA1 [5]. They further show that systemic pharmacologic blockade of TRPM8 inhibits the same
responses in rats, and the study corroborates previous data on the possible involvement of TRPM8 in a similar rat bladder reflex that was evaluated with less defined compounds [5,6]. The bladder contractions induced by cold provocation to the skin in anesthetized rodents of the current investigation correspond well with findings of bladder overactivity in response to skin cooling in awake rats [5,6]. Interestingly, the bladder responses described by Uvin and coworkers were not linked only to dermatomes, and they occurred regardless of whether the skin was from the hind paws or back or if the skin of the ears was exposed to cold [5]. Based on these findings, the authors challenged earlier work describing the convergence of skin and bladder afferents that was suggested to convey cold-induced TRPM8 activation in the skin to the bladder [4,5]. However, it may be speculated that the non–dermatome-dependent somatovisceral responses reported by Uvin and coworkers represent the discovery of additional yet undetermined connections between the central nervous system for processing of cutaneous TRPM8-mediated stimuli and central micturition pathways. The current study [5] does not address to what relative extent the two cold receptors may be involved in bladder responses to the ice-water test, and additional research seems required to characterize visceral bladder thermosensation. A previous report indicated differences in the transduction of temperature signals between somatic and visceral sensory neurons and suggested a role for TRPA1 in vagal visceral thermosensation [7]. Whether this is valid for pelvic visceral afferents is not established. The methodological approach by Uvin and coworkers [5] to elicit skin cooling–induced bladder responses may imply that these depend on a certain degree of bladder
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2015.03.037. * Division of Drug Research, Department of Medical and Health Sciences, Linko¨ping University, Krokgatan 3, 58731 Linko¨ping, Sweden. Tel. +46 768 871594. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2015.04.011 0302-2838/# 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
EUROPEAN UROLOGY 68 (2015) 662–663
mechanoafferent activation. During the test procedures, bladders were filled to 60% of their functional capacity, and at this volume, consistent bladder contractions were recorded in response to skin-cooling stimuli [5]. Information on the incidence of similar bladder contractions at lower volumes is not presented, but the suggested hypothesis agrees with previous reports that the activity of bladder and periurethral striated muscle arising from bladder afferents or perineal nociceptors depends on intravesical pressures [8]. Taken together, the interactions of visceral and somatic sensory functions seem to occur under certain conditions to cause a bladder reflex. Even so, the underlying neurophysiologic or pathophysiologic bases for the activation of this reflex in acute cold-induced urgency (ACIU) are not fully characterized. As discussed by the authors, urgency is difficult to assess in rodents and should rather be considered a human symptom [9]. Exploration of a direct measure for activity in sensory pathways in the currently described model would possibly further validate its relevance for ACIU, but a convenient experimental system for this purpose seems difficult to achieve. Although not presented as an end point in the investigation, it does appear from original figure tracings of the study that skin cooling–induced bladder contractions occur at lower intravesical pressures than those of normal bladder contractions, and pressure thresholds for detrusor contractions have previously been proposed to reflect indirectly on sensory bladder functions [10]. In conclusion, the authors add new relevant knowledge to the field from a series of well-designed experiments and with these nicely frame TRPM8 as a potential therapeutic target in ACIU [5]. Further investigations in this area will ideally provide additional information, for example, of the plasticity of bladder-sensing pathways and/or possible links to central nervous sensory processes that may explain why patients with functional lower urinary tract disorders can be predisposed to urgency by environmental cold stimuli.
663
Conflicts of interest: The author has nothing to disclose.
References [1] Tsavaler L, Shapero MH, Morkowski S, Laus R. Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins. Cancer Res 2001;61: 3760–9. [2] McKemy DD, Neuhausser WM, Julius D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 2002;416:52–8. [3] Franken J, Uvin P, De Ridder D, Voets T. TRP channels in lower urinary tract dysfunction. Br J Pharmacol 2014;171: 2537–51. [4] Shibata Y, Ugawa S, Imura M, et al. TRPM8-expressing dorsal root ganglion neurons project dichotomizing axons to both skin and bladder in rats. Neuroreport 2011;22:61–7. [5] Uvin P, Franken J, Pinto S, et al. Essential role of transient receptor potential M8 (TRPM8) in a model of acute cold-induced urinary urgency. Eur Urol 2015;68:655–61. [6] Lei Z, Ishizuka O, Imamura T, et al. Functional roles of transient receptor potential melastatin 8 (TRPM8) channels in the cold stress-induced detrusor overactivity pathways in conscious rats. Neurourol Urodyn 2013;32:500–4. [7] Fajardo O, Meseguer V, Belmonte C, Viana F. TRPA1 channels mediate cold temperature sensing in mammalian vagal sensory neurons: pharmacological and genetic evidence. J Neurosci 2008;28:7863–75. [8] Morrison JF, Sato A, Sato Y, Yamanishi T. The influence of afferent inputs from skin and viscera on the activity of the bladder and the skeletal muscle surrounding the urethra in the rat. Neurosci Res 1995;23:195–205. [9] Andersson KE, Soler R, Fu¨llhase C. Rodent models for urodynamic investigation. Neurourol Urodyn 2011;30:636–46. [10] Gratzke C, Streng T, Stief CG, et al. Effects of cannabinor, a novel selective cannabinoid 2 receptor agonist, on bladder function in normal rats. Eur Urol 2010;57:1093–100.
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. 655–661 of this issue
Everyday Cold Exposure and Urgency in Translation Petter Hedlund [1_TD$IF]a,b,* [2_TD$IF]a
Division of Drug Research, Department of Medical and Health Sciences, Linko¨ping University, Linko¨ping, Sweden; [3_TD$IF]b Division of Oncology/Unit of Urology,
Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
In 2001, the gene for transient receptor potential (TRP)-p8 was identified from a prostate-specific complementary DNA library and found expressed in human prostate tissue [1]. The TRP-p8 that exhibited strong homology to other TRPs was considered to belong to the melastatin family and was denoted transient receptor potential cation channel, subfamily M, member 8 (TRPM8). It was shown to be activated by cold temperatures (8–28 8C) and cooling compounds such as menthol and icilin [2]. Among other TRPs expressed in the lower urinary tract, TRPM8 is under investigation as a target in lower urinary tract disorders. With possible variation between species, TRPM8 is reportedly located [4_TD$IF]in the urothelium and nerves of the lower urinary tract of rodents and humans, and altered TRPM8 expression in the bladder has been described as correlated with bladder dysfunction [3]. Together with transient receptor potential cation channel, subfamily A, member 1 (TRPA1), another putative coldsensing receptor in the lower urinary tract, TRPM8 has been implicated in bladder responses to cold [3]. Such responses include the controversial ice-water test that can elicit detrusor contractions (visceral reflex) and environmental cold-induced urgency that involves somatovisceral pathways [3,4]. Due to the limitations of pharmacologic tools and the unavailability of relevant models, the roles for TRPM8 or TRPA1 in bladder responses to environmental cold temperatures have not yet been fully elucidated [3,5]. Using mice that lack TRPM8 or TRPA1, the study by Uvin and coworkers in this month’s issue of European Urology presents convincing data that provocation of somatosensory functions by cold is linked to bladder responses via TRPM8 but not TRPA1 [5]. They further show that systemic pharmacologic blockade of TRPM8 inhibits the same
responses in rats, and the study corroborates previous data on the possible involvement of TRPM8 in a similar rat bladder reflex that was evaluated with less defined compounds [5,6]. The bladder contractions induced by cold provocation to the skin in anesthetized rodents of the current investigation correspond well with findings of bladder overactivity in response to skin cooling in awake rats [5,6]. Interestingly, the bladder responses described by Uvin and coworkers were not linked only to dermatomes, and they occurred regardless of whether the skin was from the hind paws or back or if the skin of the ears was exposed to cold [5]. Based on these findings, the authors challenged earlier work describing the convergence of skin and bladder afferents that was suggested to convey cold-induced TRPM8 activation in the skin to the bladder [4,5]. However, it may be speculated that the non–dermatome-dependent somatovisceral responses reported by Uvin and coworkers represent the discovery of additional yet undetermined connections between the central nervous system for processing of cutaneous TRPM8-mediated stimuli and central micturition pathways. The current study [5] does not address to what relative extent the two cold receptors may be involved in bladder responses to the ice-water test, and additional research seems required to characterize visceral bladder thermosensation. A previous report indicated differences in the transduction of temperature signals between somatic and visceral sensory neurons and suggested a role for TRPA1 in vagal visceral thermosensation [7]. Whether this is valid for pelvic visceral afferents is not established. The methodological approach by Uvin and coworkers [5] to elicit skin cooling–induced bladder responses may imply that these depend on a certain degree of bladder
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2015.03.037. * Division of Drug Research, Department of Medical and Health Sciences, Linko¨ping University, Krokgatan 3, 58731 Linko¨ping, Sweden. Tel. +46 768 871594. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2015.04.011 0302-2838/# 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
EUROPEAN UROLOGY 68 (2015) 662–663
mechanoafferent activation. During the test procedures, bladders were filled to 60% of their functional capacity, and at this volume, consistent bladder contractions were recorded in response to skin-cooling stimuli [5]. Information on the incidence of similar bladder contractions at lower volumes is not presented, but the suggested hypothesis agrees with previous reports that the activity of bladder and periurethral striated muscle arising from bladder afferents or perineal nociceptors depends on intravesical pressures [8]. Taken together, the interactions of visceral and somatic sensory functions seem to occur under certain conditions to cause a bladder reflex. Even so, the underlying neurophysiologic or pathophysiologic bases for the activation of this reflex in acute cold-induced urgency (ACIU) are not fully characterized. As discussed by the authors, urgency is difficult to assess in rodents and should rather be considered a human symptom [9]. Exploration of a direct measure for activity in sensory pathways in the currently described model would possibly further validate its relevance for ACIU, but a convenient experimental system for this purpose seems difficult to achieve. Although not presented as an end point in the investigation, it does appear from original figure tracings of the study that skin cooling–induced bladder contractions occur at lower intravesical pressures than those of normal bladder contractions, and pressure thresholds for detrusor contractions have previously been proposed to reflect indirectly on sensory bladder functions [10]. In conclusion, the authors add new relevant knowledge to the field from a series of well-designed experiments and with these nicely frame TRPM8 as a potential therapeutic target in ACIU [5]. Further investigations in this area will ideally provide additional information, for example, of the plasticity of bladder-sensing pathways and/or possible links to central nervous sensory processes that may explain why patients with functional lower urinary tract disorders can be predisposed to urgency by environmental cold stimuli.
663
Conflicts of interest: The author has nothing to disclose.
References [1] Tsavaler L, Shapero MH, Morkowski S, Laus R. Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins. Cancer Res 2001;61: 3760–9. [2] McKemy DD, Neuhausser WM, Julius D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 2002;416:52–8. [3] Franken J, Uvin P, De Ridder D, Voets T. TRP channels in lower urinary tract dysfunction. Br J Pharmacol 2014;171: 2537–51. [4] Shibata Y, Ugawa S, Imura M, et al. TRPM8-expressing dorsal root ganglion neurons project dichotomizing axons to both skin and bladder in rats. Neuroreport 2011;22:61–7. [5] Uvin P, Franken J, Pinto S, et al. Essential role of transient receptor potential M8 (TRPM8) in a model of acute cold-induced urinary urgency. Eur Urol 2015;68:655–61. [6] Lei Z, Ishizuka O, Imamura T, et al. Functional roles of transient receptor potential melastatin 8 (TRPM8) channels in the cold stress-induced detrusor overactivity pathways in conscious rats. Neurourol Urodyn 2013;32:500–4. [7] Fajardo O, Meseguer V, Belmonte C, Viana F. TRPA1 channels mediate cold temperature sensing in mammalian vagal sensory neurons: pharmacological and genetic evidence. J Neurosci 2008;28:7863–75. [8] Morrison JF, Sato A, Sato Y, Yamanishi T. The influence of afferent inputs from skin and viscera on the activity of the bladder and the skeletal muscle surrounding the urethra in the rat. Neurosci Res 1995;23:195–205. [9] Andersson KE, Soler R, Fu¨llhase C. Rodent models for urodynamic investigation. Neurourol Urodyn 2011;30:636–46. [10] Gratzke C, Streng T, Stief CG, et al. Effects of cannabinor, a novel selective cannabinoid 2 receptor agonist, on bladder function in normal rats. Eur Urol 2010;57:1093–100.