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Urogenital
Laboratory

innervation, bladder, syndromes...

Suburothelial nociceptive capsaicin-sensitive
afferent fibres immunoreactive for a marker of
peptidergic sensory nerves (CGRP)

 

Research Summary

Lower urogenital organs receive complex extrinsic efferent (motor) and afferent (sensory) innervation. There are significant changes in the neural control of these organs (bladder, urethra, prostate, uterus, etc) in disease states such as overactive bladder, painful bladder syndromes (interstitial cystitis) and chronic pelvic pain syndrome. In many cases, sensitization (i.e. increased excitability) of sensory neurons is responsible for the generation of pain, as well as other lower urinary tract symptoms, like urgency and frequency. Our main research interest is to determine the anatomical and functional properties of major classes of sensory neurons that innervate lower urogenital organs in normal condition and to identify the mechanisms of their changes in various disease states. For this, we use a variety of in vitro and in vivo techniques and approaches, allowing detailed characterization of sensory and motor innervation of the lower urogenital organs in animal models of human diseases such as experimentally-induced cystitis and bladder outlet obstruction. These include electrophysiological techniques (single unit extracellular recordings in vitro and electromyographic recordings in vivo), antero- and retrograde tracing techniques combined with immunohistochemistry, and in vivo and in vitro cystometric techniques combined with pharmacological tools. The significance of our research is that it will provide a strong rationale for the development of novel targeted therapies and diagnostic tools for common disorders of the lower urogenital organs.

Research Projects

More than a half of males above the age of 50 start to develop bladder outlet obstruction due to prostate enlargement, which partially occludes the urethra. For reasons that are still unclear, partial obstruction often leads to bladder overactivity with characteristic symptoms such as urgency, frequency, nocturia and in many cases, urge incontinence. In this project we unravel which mechanisms, myogenic (due to changes in bladder muscle function) and/or neural (due to changes in motor and/or sensory nerve function), account for bladder overactivity in obstruction, using animal models of gradual partial bladder outflow obstruction.

Cystitis is one of the common bladder disorders characterized by lower abdominal or pelvic pain, frequency, nocturia and urgency. It is likely that changes in spinal sensory nerve function are responsible for the generation of these symptoms but exact underlying mechanisms are still unclear. The main aim of this project is to determine which pro-inflammatory mediator(s) underlie functional and anatomical changes of sensory neurons, in experimental animal model of cystitis induced by instillation of zymosan (a derivative of yeast cell walls) in the guinea pig bladder. We use a combination of functional, electrophysiological and anatomical techniques both in vitro and in vivo to achieve this aim.

Selected Publications

Nicholas S, Yuan SY, Brookes SJ, Spencer NJ, Zagorodnyuk VP (2017) Hydrogen peroxide preferentially activates capsaicin-sensitive high threshold afferents via TRPA1 channels in the guinea pig bladder. Br J Pharmacol, 174(2):126-138

 

Spencer NJ, Zagorodnyuk V, Brookes SJ, Hibberd T (2016) Spinal afferent nerve endings in visceral organs: recent advances. Am J Physiol Gastrointest Liver Physiol, 311:G1056-G1063

 

Humenick A, Chen BN, Wiklendt L, Spencer NJ, Zagorodnyuk VP, Dinning PG, Costa M, Brookes S (2015) Activation of intestinal spinal afferent endings by changes in intra-mesenteric arterial pressure. Journal of Physiology, 593(16):3693-709

 

Nicholas S, Keightley L, Brookes S, Costa M, Gibbins I and Zagorodnyuk V (2015) Conscious voiding during bladder obstruction in guinea pigs correlates with contractile activity of isolated bladders. Autonomic Neuroscience, 193:74-83

 

Yuan SY, Vilimas P, Zagorodnyuk V and Gibbins I (2015) Novel spinal pathways identified by neuronal c-Fos expression after urethrogenital reflex activation in female guinea pigs. Neuroscience, 288:37-50

 

Chen B, Sharrad DF, Hibberd T, Zagorodnyuk V, Costa M and Brookes S (2015) Neurochemical characterization of extrinsic nerves in myenteric ganglia of the guinea pig distal colon. Journal of Comparative Neurology, 523(3):742-756

 

Hibberd T, Spencer N, Zagorodnyuk V, Chen B and Brookes S (2014) Targeted electrophysiological analysis of viscerofugal neurons in the myenteric plexus of guinea-pig colon. Neuroscience, 275:272-284

 

Brookes S, Spencer N, Costa M, Zagorodnyuk V (2013) Extrinsic primary afferent signalling in the gut. Nature Reviews Gastroenterology & Hepatology, 10(5): 286-296

 

Zagorodnyuk VP, Kyloh M, Brookes SJ, Nicholas SJ, Spencer NJ (2012) Firing patterns and functional roles of different classes of spinal afferents in rectal nerves during colonic migrating motor complexes in mouse colon. American Journal of Physiology - Gastrointestinal and Liver Physiology, 303(3):G404-11

 

Hibberd TJ, Zagorodnyuk VP, Spencer NJ, Brookes SJ (2012) Identification and mechanosensitivity of viscerofugal neurons. Neuroscience, 225:118-29

 

Hibberd TJ, Zagorodnyuk VP, Spencer NJ, Brookes SJ (2012) Viscerofugal neurons recorded from guinea-pig colonic nerves after organ culture. Neurogastroenterology and Motility, 24(11):1041-e548

 

Kyloh M, Nicholas S, Zagorodnyuk VP, Brookes SJH & Spencer NJ (2011) Identification of the visceral pain pathway activated by noxious colorectal distension in mice. Frontiers in Neuroscience, 5(16):1-7

 

Zagorodnyuk VP & Spencer NJ (2011) Localization of the sensory neurons and mechanoreceptors required for stretch-evoked colonic migrating motor complexes in mouse colon. Frontiers in Physiology, 2(98):1-8

 

Zagorodnyuk VP, Kyloh M, Nicholas S, Peiris H, Brookes SJH, Chen BN & Spencer NJ (2011) Loss of visceral pain following colorectal distension in an endothelin-3 deficient mouse model of Hirschsprung’s disease. Journal of Physiology, 589(7):1691-1706

 

Spencer N, Nicholas S, Robinson L, Kyloh M, Flack N, Brookes SJH, Zagorodnyuk VP & Keating D (2011) Mechanisms underlying distension-evoked peristalsis in guinea-pig distal colon: is there a role for enterochromaffin (EC) cells? American Journal of Physiology - Gastrointestinal and Liver Physiology, 301:G519-527

 

Yuan SY, Gibbins IL, Zagorodnyuk VP & Morris JL (2011) Sacro-lumbar intersegmental spinal reflex in autonomic pathways mediating female sexual function. Journal of Sexual Medicine, 8:1931-1942

 


Investigator

  • Vladimir P Zagorodnyuk, PhD

Support Staff

  • Lauren Keightley, Technical Assistant

    Harman Sharma, Research Assistant


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