Regional differences in sensory innervation and suburothelial interstitial cells in the bladder neck and urethra.
ABSTRACT To identify and characterize possible structural specialisations in the wall of the lower urinary tract (LUT) in the region of the bladder urethral junction (BUJ), with the specific objective of identifying regional variations in sensory nerve fibres and interstitial cells (ICs).
The bladder base and urethra was removed from five male guinea pigs killed by cervical dislocation. Tissue pieces were incubated in Krebs' solution at 36 degrees C, gassed with 95% O(2) and 5% CO(2), fixed in 4% paraformaldehyde and processed for immunohistochemistry. The nonspecific marker vimentin and the general neuronal marker protein gene product (PGP) 9.5 were used to identify ICs and nerve fibres, respectively. Specific antibody binding was visualized using the appropriate secondary antibodies.
The wall of the LUT in the region immediately between the bladder base and the urethra, the BUJ, differed in its cellular composition relative to the adjacent areas. PGP-positive (PGP(+)) nerve fibres, presumptive afferent fibres, lay within the urothelium running between the epithelial cells. There were two general nerve patterns: branching fibres with no varicosities, and complex fibres with varicosities. Fibre collaterals with varicosities exited the urothelium and occupied the space under the urothelium adjacent to the layer of suburothelial ICs. The latter, lamina propria and around the muscle bundles were identified using vimentin (vim(+)). In the base a few vim(+) cells were also PGP(+). In the region of the BUJ there was a decrease in the amount of smooth muscle. In this region, below the lamina propria, there was an area densely populated with vim(+)/PGP(+) ICs. Nerve fibres ran between the cells in this region.
These structural specialisations within the urothelium and deeper layers of the BUJ suggest that they might be associated with specific functions. The localized highly branched network of the putative afferent nerves suggests the presence of a local axonal reflexes involving possible cross-talk between the urothelium and suburothelial layer. The function of the specialized region of ICs is not known and must await further information on the functional properties of this novel cell type. These observations show further the cellular heterogeneity of the cells in the LUT and the complexity of the structures. One of the major current challenges in functional urology is to understand the relationships between these novel structures and overall bladder and urethral function.
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ABSTRACT: Artemin is a member of the glial cell line-derived neurotrophic factor (GDNF) family that has been strongly implicated in development and regeneration of autonomic nerves, and modulation of nociception. Whereas other members of this family (GDNF and neurturin) primarily target parasympathetic and non-peptidergic sensory neurons, the artemin receptor (GFRα3) is expressed by sympathetic and peptidergic sensory neurons that are also the primary sites of action of nerve growth factor, a powerful modulator of bladder nerves. Many bladder sensory neurons express GFRα3 but it is not known if they represent a specific functional subclass. Therefore, our initial aim was to map the distribution of GFRα3-immunoreactive (-IR) axons in the female rat bladder, using cryostat sections and whole wall thickness preparations. We found that GFRα3-IR axons innervated the detrusor, vasculature and urothelium, but only part of this innervation was sensory. Many noradrenergic sympathetic axons innervating the vasculature were GFRα3-IR, but the noradrenergic innervation of the detrusor was GFRα3-negative. We also identified a prominent source of non-neuronal GFRα3-IR that is likely to be glial. Further characterisation of bladder nerves revealed specific structural features of chemically distinct classes of axon terminals, and a major autonomic source of axons labelled with neurofilament-200, which is commonly used to identify myelinated sensory axons within organs. Intramural neurons were also characterised and quantified. Together, these studies reveal a diverse range of potential targets by which artemin could influence bladder function, nerve regeneration and pain, and provide a strong micro-anatomical framework for understanding bladder physiology and pathophysiology. J. Comp. Neurol., 2014. © 2014 Wiley Periodicals, Inc.The Journal of Comparative Neurology 12/2014; 522(17). DOI:10.1002/cne.23648 · 3.51 Impact Factor
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ABSTRACT: To present a brief review on discussions from "Do we understand any more about lower urinary tract interstitial cells?" session at the 2013 International Consultation on Incontinence-Research Society (ICI-RS) meeting in Bristol, UK.Neurourology and Urodynamics 06/2014; 33(5). DOI:10.1002/nau.22591 · 2.46 Impact Factor
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ABSTRACT: The pain response to urinary tract infection is largely uncharacterized, but the symptomatic response to urinary tract infection contrasts with the lack of pain response among individuals with asymptomatic bacteriuria. Quantifying pelvic pain in a murine urinary tract infection model, uropathogenic Escerichia coli induces transient pelvic pain, whereas an asymptomatic bacteriuria E. coli isolate causes no pain, thus recapitulating the spectrum of clinical responses to intravesical E. coli. These differential pain responses are not correlated with bladder colonization or inflammation, but instead are intrinsic to E. coli lipopolysaccharide and dependent on the lipopolysaccharide receptor, TLR4. Epidemiological data suggest a link between interstitial cystitis and a history of urinary tract infection, so it was evaluated whether repetitive uropathogenic E. coli instillation would result in chronic pain through central sensitization. Although repeated infection with wild type uropathogenic E. coli results in only transient episodes of acute pain, a uropathogenic E. coli mutant lacking O-antigen causes chronic, post-urinary tract infection pelvic pain. Similarly, a K-12 E. coli strain lacking O-antigen induces chronic pain that persisted long after bacterial clearance, and expressing O-antigen nullified the pain phenotype. Spinal cords isolated from mice with post-urinary tract infection chronic pain showed deficits in short-term depression consistent with central sensitization. Deleting O-antigen gene complex from a uropathogenic E. coli strain and subsequent heterologous expression of O-antigen gene clusters shows that a single bacterial isolate can exhibit pain phenotypes ranging from a null phenotype, an acute pain phenotype, to a chronic pain phenotype. Post-urinary tract infection chronic pain is also associated with voiding dysfunction and anxious/depressive behavior. These effects are also mediated by TRPV1 at the level of pain establishment and CCR2 at the level of pain maintenance. Together, these findings show that transient infection with E. coli might result in chronic visceral pain with the hallmarks of neuropathic pain. This pattern of behaviors mimics the spectrum of interstitial cystitis symptoms, thus supporting the possibility of an infectious etiology of interstitial cystitis.International Journal of Urology 04/2014; 21 Suppl S1:26-32. DOI:10.1111/iju.12309 · 1.80 Impact Factor