Lower Urinary Tract Irritation Research Articles

Prediction of Adverse Radiotherapeutic Effects in Prostate Cancer Patients Prior to Radiation

It is estimated that there will be 241,740 new Prostate Cancer (PCa) cases diagnosed in the U.S. in 2012 [1]. Radiotherapy is a widely used treatment modality for PCa. A recent review revealed that approximately 48% of patients diagnosed with prostate cancer received some form of radiotherapy for their initial treatment [2]. This amounts to around 100,000 patients per year receiving radiotherapy for PCa in the United States alone with a risk of grade 2 or higher bladder or gastrointestinal toxicity of 7-38% [3-5]. This adds up to 7,000 to 38,000 moderate or worse toxicities and up to 2000 severe toxicities each year. Indeed, most PCa patients have mild to moderate side-effects from radiotherapy, but some patients do have severe Adverse Radiotherapeutic Effects (AREs), such as severe lower urinary tract irritation, erectile dysfunction, and rectal bleeding, ulceration or dysfunction, despite the fact that radiotherapy doses and techniques are generally uniform. These severe side effects cause significant morbidity and require costly intervention.

Initial experience of transurethral enucleation of submucosal bladder leiomyoma

Objective To evaluate the clinical effecacy and safety of transurethral enucleation of submucosal bladder leiomyoma.Methods Analyze retrospectively the clinical data of 6 patients (2 male,4 female) of submucosal bladder leiomyoma. The mean age was 59 years (range 32- 78). The clinical manifestations included dysuresia in 3 cases, irritative bladder in 1 case, gross hematuria in 1 caes, and no clinical symptoms in 1 case. The mean course was 23 months (range 1 week-4 years). All the bladder tumors were indicated by ultrasonography, CT scan and cystoscopy, while 4 cases of bladder filling defects were showed by intravenous urogram. Before the tranaurethral enucleation of the bladder tumor, a deep needle biopsy and pathological examination were carried out to confirm the diagnosis of bladder leiomyoma. For the relatively small lateral leiomyomas, holium laser enucleation was carried out, while for the big ones, resectoscope enucleation was used to remove the mass. Biopsys were performed after complete removal of the tumor.Results Transurethral enucleation of 6 cases of submucosal bladder tumors were successful without any postoperative complication. All patients regained normal urination, and lower urinary tract irritation was relieved obviously and hematuria disappeared. No tumor recurrence or metastasis was found during the follow-up of 4 to 158 months.Conclusions Cystoscopy and transurethral biopsy are the most important methods for the diagnosis of submucosal bladder leiomyoma. The transurethral enucleation is a feasible and safe surgical technique for such patients with excellent results. Key words: Bladder neoplasms; Leiomyoma; Transurethral enucleation

NK(1) receptor and its interaction with NMDA receptor in spinal c-fos expression after lower urinary tract irritation.

The role of neurokinin 1 (NK(1)) receptor and possible interaction between NK(1) and N-methyl-D-aspartic acid (NMDA) glutamatergic receptors were investigated on spinal c-fos expression after lower urinary tract irritation with acetic acid infusion in rats. At both levels of the first (L(1)) and sixth lumbar (L(6)) spinal cord, where most of hypogastric nerve and pelvic nerve afferent terminals project, respectively, the selective NK(1) receptor antagonist CP-99,994 dose dependently reduced the total number of c-fos protein (Fos)-positive cells. However, CP-100,263, the enantiomer of CP-99,994 with a very low affinity for NK(1) receptor, did not have any effect on the total number of Fos-positive cells. Coadministration of a low dose (1 mg/kg) of CP-99,994 and NMDA receptor antagonist (MK-801), either of which alone did not affect c-fos expression, significantly inhibited c-fos expression at both levels of the spinal cord. Regarding regional differences, the number of Fos-positive cells decreased significantly at all regions of the L(6) level, but only at the dorsal horn of the L(1) level. These results indicate that NK(1) receptor is involved in spinal c-fos expression after lower urinary tract irritation and that NK(1) and NMDA receptors have a synergistic interaction in the spinal processing of nociceptive input from the lower urinary tract.

C‐Fos expression in the spinal cord after acute sacral segmental nerve stimulation

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. 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. 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. 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.

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.

Vesicoanal, urethroanal, and urethrovesical reflexes initiated by lower urinary tract irritation in the rat.

Irritation of the urinary bladder causes activation of normally "silent" nociceptive primary afferent fibers. In the present study, it is reported that irritation of the urinary bladder or urethra with infusion of 0.5% acetic acid robustly activates motoneurons that innervate the striated muscle of the external anal sphincter via spinal reflex mechanisms. The activation of anal motoneurons following irritation of the bladder and urethra are termed vesicoanal and urethroanal reflexes, respectively. The reflexes can be mimicked by acute application of capsaicin to the bladder and urethra, and they show desensitization following prolonged topical application of capsaicin or following chronic systemic pretreatment with capsaicin. The reflexes can be demonstrated in chronic spinal cord-transected animals, indicating that the reflex pathways are organized within the spinal cord. The urethroanal reflex is also physiologically activated by urethral distension and/or increases in intraluminal pressure. In addition to activation of anal sphincter activity, slight distension, pressure increases, or instillation of 0.5% acetic acid into the urethra inhibited bladder contractions through activation of an inhibitory urethrovesical reflex. These reflexes are discussed in terms of clinical characteristics of urethritis and prostatitis. Anecdotally, it was discovered that the bladder can buffer acetic acid.

Increased c- fos expression in spinal lumbosacral projection neurons and preganglionic neurons after irritation of the lower urinary tract in the rat

Chemical irritation of the lower urinary tract (LUT) induces c- fos expression in neurons in the lumbosacral (L 6 and S 1) spinal cord. This study used axonal tracing with fluorescent dyes to identify the types of spinal neurons expressing Fos immunoreactivity (IR) after LUT irritation in the rat. Fos-IR was detected in lateral and medial superficial dorsal horn, the sacral parasympathetic nucleus (SPN) and lamina X around the central canal. Fos-IR was detected in spinal neurons projecting to supraspinal sites (brainstem and hypothalamus), in preganglionic neurons (PGN) and in unlabeled segmental interneurons. A substantial percentage (20%) of dye labeled PGN exhibited Fos-IR after LUT irritation; and a larger percentage (36%) exhibited Fos-IR after electrical stimulation of the pelvic nerve which contains afferent pathways from all of the pelvic organs. The majority (average 55%) of Fos-positive neurons projecting to supraspinal sites were also located in the region of the SPN. A selective distribution of different types of neurons was detected in this region: PGN were located ventral to the spinal projection neurons which in turn were located ventral to the majority of unidentified Fos-positive neurons. The distribution of Fos-positive PGN and projection neurons was similar in spinal intact and spinal transected animals indicating that c- fos expression was mediated by monosynaptic afferent input or input from segmental interneurons and was not due to activation of supraspinal micturition reflex pathways.

Contribution of C-fiber afferent nerves and autonomic pathways in the urinary bladder to spinal c-fos expression induced by bladder irritation

Previous studies have revealed that chemical irritation of the urinary bladder and urethral mucosa increases the expression of the immediate-early gene, c-fos, in the lumbosacral spinal cord of the rat. The present experiments were undertaken to determine whether drugs known to suppress bladder reflex pathways or spinal nociceptive mechanisms would influence c-fos expression induced by chemical irritation of the lower urinary tract (LUT). Capsaicin (100 mg/kg subcutaneous (sc), 7 days prior to the experiment) which does not block bladder reflexes but does desensitize C-fiber afferents, reduced (89%) the number of Fos-positive cells in the lumbosacral spinal cord induced by acetic acid-induced irritation of the LUT. Morphine (2.5 mg/kg, intravenous (iv)) or a low dose of baclofen, a GABAB agonist, both of which markedly suppressed reflex bladder activity, did not alter spinal c-fos expression induced by LUT irritation. However, a larger dose of baclofen (10 mg/kg, iv) reduced by 45% the number of Fos-positive cells. Clonidine (200 mug/kg, iv), an alpha2 adrenergic agonist, depressed bladder reflexes but produced only a small decrease (25%) in c-fos expression in lateral laminae V-VII of the cord. The ganglionic blocking agent, hexamethonium, which blocks autonomic but not afferent pathways to the LUT, decreased c-fos expression by 50%. The results indicate that certain drugs can differentially affect reflex bladder activity and c-fos expression and that analgesic drugs which suppress somatic nociceptive pathways do not necessarily affect the c-fos expression induced by visceral nociceptive input.

Role of NMDA and AMPA glutamatergic transmission in spinal c-fos expression after urinary tract irritation.

Chemical irritation of the lower urinary tract (LUT) of the rat increases the expression of the immediate early gene c-fos within neurons in the dorsal horn (DH), dorsal commissure (DCM), and intermediolateral region, including sacral parasympathetic nucleus (SPN) of the spinal cord (L6-S1). A previous study indicated the involvement of the N-methyl-D-aspartic acid (NMDA) receptor in this c-fos expression after LUT irritation. The role of glutamatergic synapses was further investigated using a selective and competitive alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist (LY-215490). Systemic administration of LY-215490 produced a dose-dependent decrease in the number of Fos-positive cells after LUT irritation in the DCM and SPN areas, whereas in the DH only the highest dose (10 mg/kg) of LY-215490 decreased the number of Fos-positive cells. A low dose (1 mg/kg) of either MK-801 (an NMDA antagonist) or LY-215490 alone did not alter c-fos expression. However, a combined administration of low doses of MK-801 and LY-215490 significantly decreased the number of Fos-positive cells in all regions of the spinal cord. These results indicate that AMPA as well as NMDA receptors are involved in the spinal processing of nociceptive input from the LUT and that these glutamatergic receptors play a synergistic role in visceral nociceptive processing.