Neurourology and Urodynamics 26:439 (2007)

EDITORIAL COMMENT

Re: Liu L, Mansfield KJ, Kristiana I, et al. 2007. The Molecular Basis ofUrgency: Regional Difference of Vanilloid Receptor Expression in the

Human Urinary Bladder. Neurourol Urodynam 26:433–438

The origin of urinary urgency remains essentially amystery. According to the available evidence, three hypo-theses can be legitimately raised regarding the potentialmechanism involved in the generation of this abnormalbladder sensation. The observation that numerous bladderconditions cause urgency supports a peripheral hypothesis. Itis, however, unclear in this case if urgency results from theactivation of nerve fibers that also transmit normal bladderstimuli or is the consequence of the recruitment of usuallyinactive sensory fibers. Also unclear are the bladder stimulinecessary for sensory fiber activation. Another possiblemechanism for the generation of urgency involves the sacralspinal cord, the first relay station for bladder sensory input inthe central nervous system. Under pathological conditions,usually inactive sacral circuits may be called into themodulation of bladder sensory input, a circumstance thatmay generate urgency. Finally, urgency may be created at acortical level due to an incorrect interpretation of the sensoryinformation arriving at the cortex from the spinal cord. Thismight be the mechanism of urgency in patients withcerebral–vascular accidents or Parkinson’s disease. Theknowledge of the mechanism leading to urgency is not simplya matter of understanding the pathophysiology of the lowerurinary tract. Such information may be crucial to select theideal treatment for this bothersome symptom.

In this issue of Neurourology Urodynamics Liu and co-workers1 are to be congratulated by bringing the peripheralhypothesis of urinary urgency origin into a receptor level.They demonstrate, for the first time, an overexpression ofTRPV1 mRNA in the trigone of patients with urgency. Itis, therefore, highly probable that an excess of the receptorprotein also occurred in these patients, most likely placesbeing C-fibers and the urothelium. For the sake of accuracy theinvolvement of both structures in urgency had beensuggested by other groups, based on the clinical evidencethat the symptom was attenuated following TRPV1 inactiva-tion with resiniferatoxin, a neurotoxin that specifically bindsTRPV1.2,3 However, in those studies the receptors eventuallyinvolved were far from being completely elucidated.

TRPV1 was first described as responsive to heat above 43�C,pH below 5 and capsaicin.4 Humans do not endogenouslyproduce capsaicin. Although neither the temperature nor theurine pH of Liu’s patients was investigated, nothing suggeststhat they differ from controls. Thus, the identification of anexcess of TRPV1 in the bladder of patients with urinaryurgency does not explain how the excess of TRPV1 might beactivated to generate urgency. Future studies designed toidentify endogenous ligands of TRPV1 are necessary. At themoment only anandamide, a lipid with some structuralresemblance to capsaicin, was identified in experimentalmodels of chronic bladder inflammation as an endogenousagonist of TRPV1.5 However, it is unknown if anandamideplays a similar role in human bladder.

The study by Liu et al.1 may have profound consequenceson the strategy of urgency management. In fact, theparticipation of TRPV1 in urgency calls for the use ofcompounds able to desensitize or block the receptor. Resini-feratoxin is suitable for TRPV1 desensitization by intravesicalroute. Since the effect may last for several months theintravesical route does not seem to constitute an obstacle toits use. Unfortunately, stable resiniferatoxin preparations forclinical administration were never an object of active research.Although many other molecules are known to desensitizeTRPV1, the preference of the industry seems to be thedevelopment of receptor antagonists. Very recently, pain,another condition where TRPV1 is definitely implicated, wassuccessfully treated with the TRPV1 antagonist SB-705498, asreported to the American Pain Society this year.6 Liu’s study1

opens the opportunity for the application of the samecompound on urgency treatment. A clinical trial should, there-fore, be instituted as rapidly as possible.

Francisco Cruz*Department of Urology

Hospital S Joao and Faculty of MedicinePorto, Portugal

REFERENCES

1. Liu L, Mansfield KJ, Kristiana I, et al. The molecular basis of urgency: Regionaldifference of vanilloid receptor expression in the human urinary bladder.Neurourol Urodyn 2007;26:433–9.

2. Silva C, Ribeiro MJ, Cruz F. The effect of intravesical resiniferatoxin inpatients with idiopathic detrusor instability suggests that involuntarydetrusor contractions are triggered by C-fiber input. J Urol 2002;168:575–9.

3. Apostolidis A, Gonzales GE, Fowler CJ. Effect of intravesical resiniferatoxin(RTX) on lower urinary tract symptoms, urodynamic parameters, and qualityof life of patients with urodynamic increased bladder sensation. Eur Urol2006;50:1299–305.

4. Caterina MJ, Schumacher MA, Tominaga M, et al. The capsaicin receptor: Aheat-activated ion channel in the pain pathway. Nature 1997;389:816–24.

5. Dinis P, Charrua A, Avelino A, et al. Anandamide-evoked activation ofvanilloid receptor 1 contributes to the development of bladder hyperreflexiaand nociceptive transmission to spinal dorsal horn neurons in cystitis.J Neurosci 2004b;24:11253–63.

6. Chizh B, et al. The TRPV1 antagonist SB705498 attenuates TRPV1 receptor-mediated activity and inhibits inflammatory hyperalgesia in humans:Results from a phase 1 study. Am Pain Soc Meeting, San Antonio, TX, May 3–6, 2006.

No conflict of interest reported by the author(s).*Correspondence to: Francisco Cruz, Department of Urology, Hospital S Jo~ao andFaculty of Medicine, 4200-Porto, Portugal.E-mail: cruzfjmr@med.up.ptPublished online 28 March 2007 in Wiley InterScience(www.interscience.wiley.com)DOI 10.1002/nau.20419

� 2007 Wiley-Liss, Inc.