Bladder Afferent Activity Research Articles

Impaired response to chemical irritation of the urinary tract in mice with disruption of the preprotachykinin gene

Previous studies demonstrated that acute irritation of the lower urinary tract (LUT) induces the expression of the immediate early gene, c-fos, in lumbo-sacral spinal cord neurons ‘J. Neurosci. 12 (1992) 4878’ ‘Am. J. Physiol. 265 (1993) 326’ ‘Somatosens. Mot. Res. 15 (1998) 5’. This effect was mediated in part by activation of capsaicin-sensitive bladder afferents ‘Am. J. Physiol. 265 (1993) 326’. Here we investigate the role of preprotachykinin gene products (neurokinin A and substance P) in the response to bladder irritation in urethane-anesthetized mice. Acute irritation of the LUT (intravesical acetic acid) induced smaller numbers of Fos-positive neurons in the spinal cord of mice with a mutated preprotachykinin gene than in wild type mice. Increased Fos expression following LUT irritation or a sham operation in wild type mice was also significantly reduced by pretreatment with the NK2 antagonist, MEN 11420, but Fos expression in mutant mice was not altered by the antagonist. During cystometrograms, a significantly higher percentage (83%) of mutant mice exhibited urinary retention and overflow incontinence as compared to wild type controls. These findings suggest an involvement of tachykinins and NK2 receptors in the response to chemical irritation of the LUT in mice and also suggest that tachykinins contribute to the regulation of normal reflex bladder activity.

Reduction in renal haemodynamics by exaggerated vesicovascular reflex in rats with acute urinary retention.

1. We examined the possibility that a vesicovascular reflex is exaggerated by acute urinary retention, and that the increase in renal vascular resistance caused by this reflex may lead to renal dysfunction. We evaluated the vesicovascular responses to normal micturition (NM, transcystometric condition) and acute urinary retention (isovolumetric condition mimicking complete bladder-outlet obstruction (CBOO) and partial urethral ligation mimicking partial bladder-outlet obstruction (PBOO)) in anaesthetized female Wistar rats. 2. Acute urinary retention due to CBOO or PBOO provoked a prolonged or increased intravesical pressure, an enhancement in both bladder pelvic afferent and bladder pelvic efferent nervous activity, and an elevation in mean arterial blood pressure. 3. Single-unit analysis showed that these vesicovascular reflexes were triggered by activation of low-threshold and high-threshold bladder mechanoreceptors, but not by renal uretropelvic mechanoreceptors. 4. Bladder contraction in CBOO and PBOO conditions and graded increases in bladder volume significantly reduced renal blood flow and cortical microvascular blood flow. The acute urinary retention-induced renal vasoconstriction was mediated by the renal nerve. Renal denervation, but not bilateral ureteral resection, abolished the renal vasoconstriction associated with the vesicovascular reflexes. 5. These findings indicate that exaggerated activation of bladder afferents exerts a positive feedback effect to increase sympathetic outflow to the kidney further, thereby contributing to significant renal vasoconstriction via a renal nerve-dependent mechanism.

Threshold for efferent bladder nerve firing in the rat

In this study, the mechanism involved in the initiation of voiding was investigated. Bladder pressure and bladder and urethral nerve activity were recorded in the anesthetized rat. Bladder nerve activity was resolved into afferent and efferent activity by means of a theoretical model. The beginning of an active bladder contraction was defined as the onset of bladder efferent firing at a certain time (t0). From t0 onward, bladder efferent activity increased linearly during deltat seconds (rise time) to a maximum. The pressure at t0 was 1.0 +/- 0.4 kPa, the afferent nerve activity at t0 was 2.0 +/- 0.6 microV (53 +/- 15% of maximum total nerve activity), and deltat was 11 +/- 13 s. Between contractions the afferent activity at t0 was never exceeded. Urethral afferent nerve activity started at bladder pressures of 2.1 +/- 1.1 kPa. Therefore, we concluded that urethral afferent nerve activity does not play a role in the initiation of bladder contractions; voiding contractions presumably are initiated by bladder afferent nerve activity exceeding a certain threshold.

Serotonergic modulation of spinal ascending activity and sacral reflex activity evoked by pelvic nerve stimulation in cats

Serotonin (5-HT) may be inhibitory to micturition at a spinal level. A potential mechanism of action for serotonergic inhibition of bladder function is a depression of the ascending limb of the supraspinal reflex mediating micturition. Ascending activity evoked by pelvic nerve stimulation was recorded in the thoracic spinal cord of anesthetized cats. For comparison, spinal reflex activity evoked by pelvic nerve stimulation was recorded on the pudendal nerve. The effects of intrathecal administration of serotonergic agents were examined to determine whether spinal and supraspinal responses to bladder afferent activation were modulated by 5-HT. Methysergide (60 nmol), a non-selective serotonergic antagonist, increased ascending activity by 61±7% and depressed spinal reflex activity by 38±6%. Zatosetron (10 nmol), a 5-HT 3 antagonist had a similar effect on both activities (increased by 93±24% and decreased by 77±7%, respectively). The effect on ascending activity of blocking 5-HT 3 receptors was also confirmed with ICS 205930 and MDL 72222. 2-Methyl-5-HT (800 nmol), a 5-HT 3 agonist, depressed ascending activity to 46±9% of control, but enhanced spinal reflex activity by 73±92%. These results demonstrate that stimulation of 5-HT 3 and methysergide-sensitive 5-HT receptors can inhibit ascending activity and facilitate spinal reflex activity elicited by activation of bladder afferents. It is suggested that descending serotonergic pathways may participate in the spinal coordination of urinary continence.

DMSO: EFFECT ON BLADDER AFFERENT NEURONS AND NITRIC OXIDE RELEASE

Purpose Interstitial cystitis (IC), a chronic disorder of the urinary bladder, is characterized by increased voiding frequency, urgency and pain. Patients with IC also exhibit reduced urinary nitric oxide synthase activity. Intravesical administration of dimethyl sulfoxide (DMSO) has been used to provide symptomatic relief in patients with IC. The present experiments were undertaken to determine if intravesical DMSO affects neural pathways involved in bladder function in the rat and if DMSO can influence the release of nitric oxide in the bladder or from afferent neurons. Materials and Methods The effects of intravesical DMSO (10% solution in saline) on reflex bladder activity, firing on bladder nerves and c-fos gene expression in spinal neurons was examined in urethane anesthetized female Wistar rats. The effect of DMSO (1-10%) on nitric oxide release from urinary bladder strips or acutely dissociated dorsal root ganglion cells was monitored in vitro with a porphyrinic microsensor. Results DMSO acutely increased reflex firing of pelvic nerve efferent axons, decreased bladder capacity and also increased neuronal c-fos expression in spinal cord regions that exhibit c-fos expression after chemical activation of capsaicin-sensitive bladder afferents. DMSO, like capsaicin, also directly released nitric oxide (NO) from both dissociated dorsal root ganglion neurons and from isolated strips of urinary bladder. Conclusions These results suggest that DMSO induced stimulation of bladder afferent pathways and NO release from afferent neurons may be a reflection of the initial event in the desensitization of nociceptive pathways in the lower urinary tract (LUT).

Pressure, volume, and chemosensitivity in afferent innervation of urinary bladder in rats.

Bladder afferent nerve activity was recorded from the pelvic and hypogastric nerves of rats anesthetized with pentobarbital sodium. Bladder filling with isotonic NaCl at a rate of 250 microl/min excited multiunit afferent activity in the hypogastric nerve by 190 +/- 38% over background at a pressure of 30 mmHg, whereas 150 meq/l KCl at the same filling rate excited hypogastric nerve activity by 498 +/- 103% (P < 0.0001). This difference was localized to a group of chemosensitive fibers that are excited by bladder filling with KCl in a concentration-dependent fashion but are insensitive to bladder filling with NaCl. Bladder filling with 200 meq/l KCl at different filling rates caused a bursting pattern of discharge in these fibers at consistent bladder volumes but with a pressure threshold that increased proportionately with filling rate. Other hypogastric bladder afferent fibers were activated to a similar extent by NaCl and KCl solutions. Chemoreceptive bladder afferent fibers were rare in the pelvic nerve (1 of 15 units), and multiunit preparations showed comparable excitations during bladder filling with NaCl and KCl solutions. The bursting activation of bladder chemoreceptive afferent nerves in hypogastric nerves could signal noxious overdistension and/or inflammation of the bladder.

Neurophysiological modeling of voiding in rats: bladder pressure and postganglionic bladder nerve activity.

A model was developed that describes the relations between bladder pressure and both efferent and afferent nerve activity in postganglionic bladder nerves in urethan-anesthetized rats. Nerve activity was calculated as the 100-ms time integral of the rectified nerve signal. Afferent and efferent nerve signals were measured separately by crushing the nerve proximally or distally. A linear relation was found between bladder pressure and afferent nerve activity (fit error < 7%), and the relation between bladder pressure and efferent nerve activity was described by a low-pass filter (fit error < 90%). In most experiments, combined (efferent and afferent) nerve activity was measured. Absence of efferent nerve activity was assumed during the pressure decrease immediately after voiding. From this episode, the afferent nerve activity was estimated for the entire measurement. Efferent nerve activity was then estimated assuming linear addition in the bidirectionally conducting nerves. The model described the measured data very well (fit error < 7%), and the model parameters showed a good reproducibility in each rat (SD was approximately 30% of the mean).

Vesico-sympathetic reflexes in cat vasoconstrictor neurones supplying skin and skeletal muscle depend on the integrity of the sacral bladder afferents

In anesthetized cats, distension of the urinary bladder induces powerful reflexes in postganglionic sympathetic neurones projecting to the hindlimb: muscle vasoconstrictor neurones (MVC) are excited and cutaneous vasoconstrictor neurones (CVC) are inhibited. We investigated these reflexes quantitatively before and after sacral rhizotomy. The reflex responses in MVC and CVC neurones were completely abolished after elimination of the pelvic afferent input demonstrating that these reflexes are generated exclusively by excitation of sacral bladder afferents. The activation of lumbar bladder afferents which are supposed to be able to elicit painful sensations did not contribute to vesico-sympathetic reflexes in MVC and CVC neurones.

Detrusor-sphincteric dyssynergia in humans with spinal cord lesions may be caused by a loss of stable phase relations between and within oscillatory firing neuronal networks of the sacral micturition center

(1) Single-fibre action potentials (APs) were recorded with 2 pairs of wire electrodes from lower sacral nerve roots during surgery in patients with spinal cord lesions and in a brain-dead human. Conduction velocity distribution histograms were constructed for afferent and efferent fibres, nerve fibre groups were identified and simultaneous impulse patterns of α and γ-motoneurons and secondary muscle spindle afferents (SP2) were constructed. Temporal relations between afferent and efferent APs were analysed by interspike interval (II) and phase relation changes. (2) In a paraplegic with hyperreflexia of the bladder, urinary bladder stretch (S1) and tension receptor afferents (ST) fired already when the bladder was empty, and showed a several times higher bladder afferent activity increase upon retrograde bladder filling than observed in the brain-dead individual. Two α 2-motoneurons (FR) innervating the external bladder sphincter were already oscillatory firing to generate high activity levels when the bladder was empty. They showed activity levels with no bladder filling, comparable to those measured at a bladder filling of 600 ml in the brain-dead individual. A bladder storage volume of 600 ml was thus lost in the paraplegic, due to a too high bladder afferent input to the sacral micturition center, secondary to inflammation and hypertrophy of the detrusor. (3) In a brain-dead human, 2 phase relations existed per oscillation period of 160 ms between the APs of a sphincteric oscillatory firing α 2-motoneuron, a dynamic fusimotor and a secondary muscle spindle afferent fibre. Following stimulation of mainly somatic afferent fibres, the phase relations changed only little. (4) In a paraplegic with dyssynergia of the urinary bladder also 2 phase relations existed per oscillation period of 110 ms in a functional unit between the APs of a sphincteric α-motoneuron, a fusimotor and a secondary spindle afferent fibre. The phase relations changed with time following stimulation of mainly somatic afferents. A second functional unit organized by phase-related interactions was phase related to the first functional unit. (5) Following painful bladder catheter pulling, the parasympathetic division was transiently activated several times in the paraplegic. At times of activation of the parasympathetic division, 3 broad phase relations occurred within and between the two functional units, indicating that the parasympathetic division in the sacral micturition and defecation center channeled an additional input to the somatic oscillatory firing neuronal networks driving motoneurons which innervate the external bladder and/or anal sphinters. (6) It is discussed that the parasympathetic division, activated physiologically for detrusor contraction, may have failed to inhibit the somatic neuronal network driving the external sphincters (detrusor-sphincteric dyssynergia), because the oscillatory firing somatic neuronal networks escaped from the inhibitory action by changing their phase relations of organization. (7) It is conceivable that the mutual inhibitory action of detrusor and external bladder sphincter has the capacity to recover, if the functional neuronal organization of the sacral micturition center is improved in the direction of more stable oscillatory firing neuronal networks by natural afferent inputs from continence organs and supraspinal neurons. For supraspinal control and improvement of neuronal organization some kind of bulbo-spinal-bulbo pathways have to exist or to be reconstructed. (8) In the clinical implications section a case is introduced in which a tetraplegic was made running again by training different spinal pattern generators.

Naloxone Induced Micturition in Unanesthetized Paraplegic Cats

AbstractIn chronic spinal cats 2 to 10 weeks after transection of the spinal cord at the lower thoracic level (T12-T13), the administration of naloxone, an opiate antagonist, (32-500 µg./kg./kg. i.p.). stimulated micturition. The total quantity of urine released after administration of naloxone ranged from 10 to 70 per cent, (mean 39 per cent) of the initial bladder volume. The response to the drug occurred 5 to 10 minutes after injection and was characterized by repeated periodic expulsion of small quantities of urine (5 to 10ml.) which coincided with a pattern of hind-limb movement which resembled walking behavior. The effects of naloxone persisted for about 1 hour. The motor activity following administration of naloxone was dependent upon activation of bladder afferents since it did not occur when the bladder was empty. Naloxone also facilitated the release of urine induced by stimulation of somatic afferents. With repeated administration of naloxone, tolerance developed which was evident for several days. These observations suggest that an endogenous opiate may have a tonic inhibitory role in regulation of micturition. Pharmacologic manipulation of this putative inhibitory mechanism may facilitate management of neurogenic bladder dysfunction.

Effects of urinary bladder afferents on respiration.

The electrical activity of phrenic and recurrent laryngeal motoneurons was recorded during activation of urinary bladder afferents in pentobarbital-anesthetized, paralyzed, artificially ventilated cats. Distension or spontaneous neurogenic contraction of the bladder decreased the amplitude and frequency (bursts/min) of the burst activity in these two nerves. The decrease in frequency was due mainly to a prolongation of the interburst interval (duration of expiration). Similar effects were observed during low-frequency electrical stimulation of pelvic nerve afferents with conduction velocities in the A gamma-A delta range. High-frequency stimulation of pelvic nerve afferents increased the amplitude of the burst activity in these two nerves. These results suggest an action of bladder afferents on the brain stem oscillator controlling respiratory frequency and drive. Some of the excitatory and inhibitory effects of bladder afferents on phrenic motoneurons may be mediated through spinal circuits.