Possible role of hyposensitivity of C-fiber afferents at the proximal urethra in the development of urge urinary incontinence in patients with detrusor overactivity.

OBJECTIVE: The aim of the present study was to investigate associations between urethral sensation and urge urinary incontinence (UUI) in patients with and without detrusor overactivity (DO). METHODS: The medical records of 80 consecutive patients who underwent filling cystometry and urethral current perception threshold (CPT) tests were examined retrospectively. Following the exclusion of 4 patients not eligible for analysis, patients were classified into neurogenic DO, idiopathic DO, or DO-negative groups based on neurological and cystometric findings (n = 30, 12, and 34, respectively). Eleven DO-negative patients were defined as normal controls on cystometrograms (CMG) using the following exclusion criteria: bladder compliance <12.5 mL/cmH2 O, volume >275 mL at first filling sensation, and comorbidities possibly affecting lower urinary tract function. Thus, 53 patients were finally included in the study. Proximal urethral CPT was evaluated with intraurethral square-wave stimulation at 3 Hz to activate C-fiber afferents. RESULTS: Median CPT was higher in neurogenic and idiopathic DO than in the normal CMG group (11.3 and 9.0 vs. 2.8 mA, respectively; P < .05), as well as in patients with UUI (n = 19) compared with non-UUI patients (n = 34; 12.5 vs. 5.4 mA, respectively; P < .05). The proportion of UUI patients was significantly greater in the DO-positive groups than in the normal CMG group (P < .05). CPTs were not associated with bladder capacity at the first filling sensation (r = 0.11). CONCLUSION: Hyposensitive C-fibers of the proximal urethra may contribute to the development of urodynamic DO as well as UUI in patients complaining of lower urinary tract symptoms.

Is there a relationship between chronic bladder dysfunction and somatic symptoms in other body regions? 1. Clinical observations.

OBJECTIVE: Investigation of patients with chronic bladder dysfunction regarding associated general symptoms and complaints in the cervico-facial, upper and lower extremity regions. PATIENTS AND METHODS: We retrospectively evaluated history, physical and special neurourological examination and urodynamic studies in 213 patients with non-neurogenic bladder dysfunction. RESULTS: 22 patients out of 213 patients with chronic bladder dysfunction reported reproducible associated symptoms involving the temporo-mandibular joint, the distal forearm/hand or feet and headache. There was an obvious clinical connection regarding the severity of bladder dysfunction and associated symptoms and possible relief of both by successful treatment. CONCLUSION: Symptomatic lower urinary tract dysfunction may accompanied by specific muscular and or sensory disturbances in different areas of the body. These associated pathologies in patients without neurological disease can be explained by functional changes in a complex autonomic peripheral and central nervous network.

Is there a relationship between chronic bladder dysfunction and somatic symptoms in other body regions? 2. An experimental neuroanatomical approach.

OBJECTIVE: Based on clinical description of associated dysfunctional symptoms in patients with non-neurogenic lower urinary tract dysfunction an experimental setup was created in order to investigate the neuroanatomical basis for the clinical phenomena observed. METHODS: Using 24 male adult Sprague-Dawley rats for retrograde mapping of the spinal cord and brain, a pseudorabies virus (PRV) tracer was subsequently injected into four pertinent locations; (a) the trigone, (b) the masseter muscle (c) the forepaw and (d) the hindpaw. RESULTS: PRV tracing demonstrated clearly overlapping of labeled areas in the brain stem, diencephalon and thoracic-lumbar cord, from all injection sites of the rats. CONCLUSION: There is a diffuse overlap within the brain stem and spinal cord, of autonomic innervation to peripheral tissues based on the presented animal experiments. The described autonomic network allows an understanding of the occurrence of symptoms in distant regions of the body associated to chronic bladder dysfunction.

Central autonomic innervation of the kidney. What can we learn from a transneuronal tracing study in an animal model?

PURPOSE: Renal sympathetic innervation is involved in the maintenance of fluid homeostasis, modulation of renal secretion from juxtaglomerular cells, sodium resorption from renal tubular cells and renal hemodynamics. The understanding of central innervation and neuronal connections is important for studying the consequences of renal disease and surgical interventions compromising renal nerves. MATERIALS AND METHODS: A total of 38 individual adult male Sprague-Dawley rats were used for retrograde transneuronal mapping of the spinal cord and brain stem after pseudorabies virus (PRV) injection into the left kidney in 30 and control experiments in 8. After a survival time of 72, 96 or 120 hours the animals were sacrificed. Exploration of the abdominal and pelvic visceral organs was done, and the brain and spinal cord were harvested via dorsal laminectomy. After cutting on a freezing microtome the tissue was immunostained for PRV. RESULTS: After kidney injection inspection of the abdominal and pelvic cavity revealed an enlarged bladder with hemic urine. The urine was sterile and the bladder wall showed signs of neurogenic inflammation. Other organs were not affected. PRV positive cells were primarily found within the ipsilateral nucleus intermediolateralis of thoracic spinal cord segments T6 to T13. At the supraspinal level PRV positive cells were found within certain regions, namely the nuclei raphes, rostral ventromedial and ventrolateral medulla, A5 noradrenergic cell region, locus coeruleus and nucleus paraventricularis of the hypothalamus. CONCLUSIONS: This investigation demonstrates the anatomical basis for broad central sympathetic innervation of the kidney. The neurogenic inflammation within the spinal cord inherent to the PRV tracing method causes an inflammatory reaction within the bladder. This can be due to increased sympathetic nerve activity, followed by peripheral, neurogenically mediated inflammation.

c-Fos expression in the spinal cord after acute sacral segmental nerve stimulation.

AIMS: Sacral nerve stimulation (SNS) can provide subjective and objective relief of pelvic pain and chronic voiding symptoms, but its mechanism is poorly understood. It is well known that a noxious stimulus applied to one part of the body can reduce the response to a subsequent stimulus elsewhere in the body. This phenomenon, known as diffuse noxious inhibitory controls (DNIC), seems to be the mechanism by which pain can be reduced by concurrent noxious stimulation. METHODS: On the basis of the DNIC concept, we investigated the expression of a protein product of proto-oncogene c-Fos (c-Fos) in the rat spinal cord after acute electrical stimulation of the sacral segmental nerve with or without lower urinary tract irritation. Adult male Sprague-Dawley rats were treated either by sacral nerve stimulation (SNS) from the S1 sacral foramen or chemical irritation of the lower urinary tract (LUT) or both. Rats were perfused transcardially, and spinal cords were removed and processed for c-Fos immunohistochemistry. c-Fos expression in the central nervous system was detected by immunohistochemistry by using the avidin-biotin technique. The number of c-Fos-positive cells and their locations in the spinal cord were evaluated. RESULTS: SNS and LUT irritation resulted in significant increases in c-Fos-positive cells in L6 and S1 spinal segments. In the animals treated by SNS and LUT irritation, counts of c-Fos-positive cells in L6 and S1 segments were significantly smaller than expected. Distribution and number of c-Fos-positive cells in rats that received SNS and LUT irritation were almost the same as those induced by SNS alone in the S1 segment. CONCLUSIONS: SNS alone caused a near maximal response in c-Fos expression such that adding LUT irritation did not cause a linear increase in c-Fos. Subsequent LUT irritation could not induce additional expression of c-Fos within the spinal cord.

Relationship between the shape of passive urethral resistance relation and prostatic histology in patients with benign prostatic hyperplasia.

We assessed the relationship between the type of passive urethral resistance relation (PURR) and prostatic histology in 28 patients with benign prostatic hyperplasia (BPH), who underwent transurethral resection of the prostate. PURR was classified into three types according to pressure-flow plots, and resected specimens were analyzed by quantitative morphometry. Patient age, prostatic volume and the area densities of each histological component did not show significant differences among the three groups. However, there was a trend to correlation between prostates with a high glandular component and urethral compliance. Further studies of larger populations are needed to validate this assumption.

Spinal substance P immunoreactivity is enhanced by acute chemical stimulation of the rat prostate.

OBJECTIVES: To investigate the role substance P (SP) plays in prostatic inflammation, we evaluated SP immunoreactivity within the spinal cord after irritation of the prostate. Because alpha-adrenergic blockade attenuates nociceptor-induced pain, the effects of an alpha-adrenergic blocker on SP immunoreactivity were also evaluated. SP is considered a mediator of nociception in the spinal cord. Immunoreactivity of SP is enhanced after acute chemical stimulation of somata. METHODS: Rats received chemical irritation of the prostate with or without pretreatment with tamsulosin. They were killed after 1 hour, and immunohistochemical staining for SP was performed. SP immunoreactive areas were quantified in the dorsal spinal cord of the L5 to S2 segments. RESULTS: Chemical irritation of the prostate increased SP immunoreactive areas in the L6 to S2 segments. Enhancement was observed in the whole dorsal spinal cord regions. This enhancement was significantly attenuated by tamsulosin in the L6 and S1 segments. CONCLUSIONS: SP probably plays a significant role in mediating nociceptive processing from the prostate. Tamsulosin can attenuate nociception-induced SP upregulation within the spinal cord.

Spinal NK1 receptor is upregulated after chronic bladder irritation.

It has been suggested that there is a significant upregulation of the NK1 receptor (NK1R) on neurons in the dorsal spinal cord after long-term somatic inflammation. This upregulation appears to play a significant role in central sensitization in chronic pain states. However, it is not clear whether such a change is also observed after chronic visceral (bladder) inflammation. Changes in NK1R immunoreactivity after chronic bladder irritation were investigated in order to evaluate the existence of hypersensitive states in the spinal cord after chronic bladder irritation. Experiments were performed on a total of 12 adult female Sprague-Dawley rats. In six animals, cyclophosphamide (CPA) was administered intraperitoneally for 2 weeks. Another six animals were given intraperitoneal saline injections and served as the control group. After these treatments, immunohistochemical staining for NK1Rs and substance P in rat lumbosacral spinal cord was performed. In CPA-treated animals, NK1R-positive areas and staining intensity within the dorsal spinal cord were significantly increased in the L5 to S2 spinal cord areas, especially in the L6 and S1 segments. In the L6 spinal segment, CPA-treatment enhanced NK1R immunostaining in the medial and the lateral dorsal horn, as well as in the lateral laminae including the sacral parasympathetic nucleus to a lesser extent. In CPA-treated animals, substance P staining intensity increased in the same regions in which NK1R immunoreactivity was increased. This finding probably implies the upregulation of spinal NK1R and the occurrence of central sensitization within the spinal cord after chronic visceral inflammation.