Plasticity of Na+ Channels in Afferent Neurones Innervating Rat Urinary Bladder Following Spinal Cord Injury (original) (raw)
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Neuroanatomical changes in the rat bladder after bladder outlet obstruction
BJU International, 1998
Objective To investigate the histological changes in blad-alterations in bladder capacity and voided pressures; obstructed animals had markedly increased bladder der innervation in response to partial bladder outlet obstruction in a rat model. capacities and higher voiding pressures (obstructed, 80-100 cmH 2 O; normal, 30-40 cmH 2 O). Neuronal Materials and methods Forty-eight adult female rats had their bladder outlet partially obstructed by ligating the changes in the obstructed bladder were most dramatic within the cholinergic and adrenergic neuro-proximal urethra over a 20 G angiocatheter; 18 shamoperated rats served as controls. Animals were transmitter systems within and surrounding the smooth muscle bundles, where there was less staining killed after 1, 2 and 4 weeks, and their bladders evaluated using computerized morphometry. than in control animals. PGP immunoreactivity increased slightly. The l-arginine-nitric oxide pathway Immunohistochemical staining for neuronal protein gene-product 9.5 (PGP, a general neuronal marker) appeared unperturbed after obstruction. Conclusions These histological findings suggest that and enzyme histochemical staining of acetylcholinesterase, adrenergic fibres and nitric oxide synthase were neuropathic changes in the bladder after outlet obstruction, including detrusor instability, are mainly performed. Results Bladder wall changes after obstruction consisted the result of anatomical perturbations in the cholinergic and adrenergic pathways. of a six-to sevenfold increase in bladder volume and weight. Smooth muscle hypertrophy was evident equ-Keywords Bladder, smooth muscle hypertrophy, neuronal changes ally at all sample times. Cystometry showed functional neurotransmitters within the bladder has generated
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
We investigated whether primary afferent neurons innervating different regions of the lower urinary tract have different histochemical and electrophysiological properties. Neurons in rat L6 -S1 DRG were identified by axonal transport of a fluorescent dye. Neurofilamentnegative C-fiber cells comprise ϳ70% of bladder and proximal urethral afferent neurons that send axons through the pelvic nerves, but comprise a smaller proportion (51%) of distal urethral neurons that send axons through the pudendal nerves. Isolectin-B4 (IB4) binding was detected in a higher percentage (49%) of C-fiber neurons innervating the distal urethra than in those innervating the bladder or proximal urethra (18 -22%). Neurofilament-positive A-fiber neurons innervating the distal urethra had a larger average somal size than neurons innervating the bladder or proximal urethra. In patch-clamp recordings, the majority (70%) of bladder and proximal urethral neurons were sensitive to capsaicin and exhibited TTX-resistant, high-threshold action potentials, whereas a smaller proportion (53%) of distal urethral neurons exhibited TTX-resistant spikes. T-type Ca 2ϩ currents were observed in 47% of distal urethral neurons with TTX-sensitive spikes, but not in TTX-sensitive bladder or proximal urethral neurons. In summary, afferent neurons innervating bladder or proximal urethra differ from those innervating distal urethra. The latter, which more closely resemble cutaneous afferent neurons, consist of a smaller number of C-fiber neurons containing a higher percentage of IB4-positive cells and a more diverse population of A-fiber neurons, some of which exhibit T-type Ca 2ϩ channels. These differences may be related to different functions of respective target organs in the lower urinary tract.
Polish Journal of Veterinary Sciences, 2000
TTX mode of action is based on a blocking of fast sodium channels in nerve cell membrane what, in turn, abolishes the propagation of the action potential along the nerve fibers. TTX is currently used in experimental therapies focused on neoplastic or neurogenic pain, however, as for now there is no data concerning the influence of TTX on DRG sensory neurons function. Thus, the present study was aimed at characterization of neurochemical coding of porcine sensory bladder-projecting cells after bladder instillation with TTX. Retrograde tracer Fast Blue (FB) was injected into the urinary bladder wall of six juvenile female pigs and three weeks later bladder instillation with TTX (12 μg per animal) was carried out in all animals. A week later, DRGs of interest were harvested from all animals and the neurochemical characterization of FB + neurons was performed using routine double-immunofluorescence labeling technique on 10-μm-thick cryostat sections. In TTX-treated animals the number of FB + cells containing galanin (GAL), nitric oxide synthase (NOS), somatostatin (SOM) and calbindin (CB) was 2.5%, 2%, 0.25% and 0.2%, respectively and that of pituitary adenylate cyclase-activating polypeptide (PACAP)-immunoreactive (IR) cells was 43%. These data when compared with previous reports, demonstrated that TTX profoundly changed the chemical coding of porcine bladder-projecting sensory neurons thus implicating that it may be used in case of hypoactivity of afferent part of reflex arc responsible for transmission of sensory information from the urinary bladder.
2016
The overactive bladder (OAB) is a syndrome based urinary dysfunction characterized by “urgency, with or without urge incontinence, usually with frequency and nocturia”. Earlier we developed a mathematical model of bladder nerve activity during voiding in anaesthetized rats and found that the nerve activity in the relaxation phase of voiding contractions was all afferent. In the present study, we applied this mathematical model to an acetic acid (AA) rat model of bladder overactivity to study the sensitivity of afferent fibers in intact nerves to bladder pressure and volume changes. The afferent activity in the filling phase and the slope i.e. the sensitivity of the afferent fibers to pressure changes in the post void relaxation phase, were found to be significantly higher in AA than in saline measurements, while the offset (nerve activity at pressure ~0) and maximum pressure were comparable. We have thus shown, for the first time, that the sensitivity of afferent fibers in the OAB c...
Nerve growth factor in the urinary bladder of the adult regulates neuronal form and function
Journal of Clinical Investigation, 1991
Urethral obstruction produces increased voiding frequency (0.7±0.06 to 1.1±0.08 h-') and hypertrophy of the urinary bladder (89±1.7 to 708±40 mg) with profound increments in the dimensions of afferent (4, 6) and efferent neurons (299±4.7 to 573±8.6 gm2) supplying this organ in the rat. We discovered that hypertrophied bladders of rat and human contain significantly more nerve growth factor (NGF) per milligram wet weight, protein, and DNA than normal bladders. The temporal correlation between NGF content, neuronal hypertrophy, and bladder weight was consistent with a role for this growth factor in the neurotrophic effects associated with obstruction. Autoimmunity to NGF abolished the hypertrophy of NGF-sensitive bladder neurons in the pelvic ganglion after obstruction. Relief of urethral obstruction reduced bladder size (349±78 mg), but neuronal hypertrophy (460.2±10.2 Mm2) and elevated NGF levels were only partially reversed. Bladder hypertrophy (133±43 mg) induced by osmotic diuresis slightly increased ganglion cell area (365.2±6.1 gm2) and only doubled NGF content of the bladder. These findings provide important new evidence that parenchymal cells in the hypertrophied bladder can synthesize NGF and possibly other molecular messengers that act to alter the size and function of neurons in adult animals and man. (J.
Journal of Neuroscience, 2006
Nerve growth factor (NGF) has been proposed as an important mediator inducing bladder overactivity under pathological conditions such as spinal cord injury, bladder outlet obstruction, or cystitis. We therefore examined the effects of chronic NGF treatment on bladder activity and the properties of bladder afferent neurons. In adult female rats, NGF (2.5 g/l) was infused continuously into the intrathecal space at the L6-S1 level of spinal cord for 1 or 2 weeks using osmotic pumps (0.5 l/h). Bladder afferent neurons were labeled with axonal transport of Fast Blue injected into the bladder wall. After intrathecal injection of NGF, cystometrograms under an awake condition showed bladder overactivity revealed by time-dependent reductions in intercontraction intervals and voided volume. ELISA analyses showed significant increases in NGF levels in L6-S1 dorsal root ganglia of NGF-treated rats. In patch-clamp recordings, dissociated bladder afferent neurons exhibiting tetrodotoxin (TTX)-resistant action potentials from NGF-treated animals were larger in diameter and had significantly lower thresholds for spike activation compared with sham rats. In addition, the number of TTX-resistant action potentials during 600 ms depolarizing pulses was significantly increased time dependently after 1 or 2 weeks of NGF application. The density of slowly inactivating A-type K ϩ currents was decreased by 52% in bladder afferent neurons with TTX-resistant spikes after 2 week NGF treatment. These results indicate that increased NGF levels in bladder afferent pathways and NGF-induced reduction in A-type K ϩ current density could contribute to the emergence of bladder overactivity as well as somal hypertrophy and hyperexcitability of bladder afferent neurons.
Bladder afferents and their role in the overactive bladder* 1
Urology, 2002
The role of afferent innervation of the bladder in the pathophysiology of urinary incontinence has become the focus of intense interest. In normal health, the afferent pathway is mediated largely by A␦-fibers, which ultimately send information about the state of bladder fullness to the pontine micturition center via the periaqueductal gray matter. However, after spinal disruption, a different type of afferent pathway emerges, mediated by capsaicin-sensitive C-fibers that drive a spinal segmental reflex pathway, causing neurogenic detrusor overactivity. The common sources of afferent information for either pathway are likely to be afferents from the urothelium, lamina propria, and afferents that originate in the bladder wall. Ultrastructural investigations of the constituent neural elements of these structures contribute to our knowledge of their role in both health and disease and help provide a rational approach to treatment strategies. Evidence of the involvement of capsaicin-sensitive C-fibers in the spinal reflex pathway has been supported by the successful treatment of patients with neurogenic incontinence with intravesical capsaicin or its ultrapotent nonpungent analog, resiniferatoxin. On the other hand, capsaicin has not been shown to be clearly effective in treatment of overactive bladder caused by detrusor overactivity or suprapontine pathology without the emergent C-fiber-mediated reflex. It is hoped that continued investigation of neurotoxins that have the potential to act on afferent innervation will lead to other treatment strategies for bladder disorders and other disorders involving afferent dysfunction. UROLOGY 59 (Suppl 5A): 37-42, 2002. © 2002,
Brain Research, 2006
Afferent pathways innervating the urinary bladder consist of myelinated Aδ-fibers and unmyelinated C-fibers. Normal voiding is dependent on mechanoceptive Aδ-fiber bladder afferents that respond to bladder distention. However, the mechanisms for controlling the excitability of Aδ-fiber bladder afferents are not fully understood. We therefore used whole cell patch-clamp techniques to investigate the properties of hyperpolarization-activated, cyclic nucleotide-gated (HCN) currents (I h ) in dorsal root ganglion (DRG) neurons innervating the urinary bladder of rats. The neurons were identified by axonal tracing with a fluorescent dye, Fast Blue, injected into the bladder wall. Hyperpolarizing voltage step pulses from −40 to −130 mV produced voltage-and time-dependent inward I h currents in bladder afferent neurons. The amplitude and current density of I h at a holding potential of − 130 mV was significantly larger in medium-sized bladder afferent neurons (diameter: 37.8 ± 0.3 μm), a small portion (19%) of which were sensitive to capsaicin (1 μM), than in uniformly capsaicinsensitive small-sized (27.6 ± 0.5 μm) bladder neurons. In medium-sized bladder neurons, a selective HCN channel inhibitor, ZD7288, dose-dependently inhibited I h currents. ZD7288 (10 μM) also increased the time constant of the slow depolarization phase of spike afterhyperpolarization from 91.8 to 233.0 ms. These results indicate that I h currents are predominantly expressed in medium-sized bladder afferent neurons innervating the bladder and that inhibition of I h currents delayed recovery from the spike afterhyperpolarization. Thus, it is assumed that I h currents could control excitability of mechanoceptive Aδ-fiber bladder afferent neurons, which are usually capsaicininsensitive and larger in size than capsaicin-sensitive C-fiber bladder afferent neurons. Dorsal root ganglion Urinary bladder I h HCN channel ZD7288 Hyperpolarization B R A I N R E S E A R C H 1 0 9 6 ( 2 0 0 6 ) 4 0 -5 2 ava i l a b l e a t w w w. s c i e n c e d i r e c t . c o m w w w. e l s ev i e r. c o m / l o c a t e / b r a i n r e s