Basic And Clinical Trial On Prostate-bladder Cross-sensitization Associated With Chronic Prostatitis

Background and objective: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common disorder in urological clinics. The cause of CP/CPPS is not clear and no objective measures can help to define the disease, therefore it is diagnosed only on the basis of symptoms, principally pain and/or discomfort in the pelvic region and voiding dysfunction. Several treatment modalities have been used empirically for the management of CP/CPPS with doubtful efficacy.Urinary problems, including urinary urgency and frequency, are often associated with persistent pain in patients with CP/CPPS. However, men seldom complain of voiding symptoms. Although some men diagnosed with CPPS have been found to have bladder outlet obstruction, these symptoms hardly benefit from alpha-adrenergic receptor blockers. Since CP/CPPS is a noninfectious condition, it has been postulated that symptoms associated with CPPS may be caused by dysfunction of the nervous system. The recent research reported that the existence of a prostate-bladder neural reflex may be involved in voiding dysfunction associated with CP/CPPS, however the pathway of reflex is not clear.Neural"cross-talk"within the pelvis is necessary for normal regulation of sexual, bladder, and bowel function, which are likely mediated by the convergence of sensory pathways in the spinal cord. In a previous study, we have demonstrated the convergence of primary sensory afferents in the DRG, which innervate both the prostate and pelvic floor. However, it was not clear if dichotomizing DRG neurons supply the prostate and/or bladder.The present study was designed to tested the hypothesis that prostatic irritation can sensitize bladder sensory function, which is a model of cross-organ sensitization. This study was also designed to investigate whether dichotomizing DRG neurons supply the prostate and bladder using retrograde fluorescence labeling. Moreover, a trial was designed to determine efficacy and long-term benefits of a 6-months-course of the alpha-blocker tamsulosin in the relief of symptoms of CP/CPPS.Methods:With the rat prostatitis model, we observered the alteration of the bladder function through filling cystometry and the alteration of the convergent afferent innervating bladder and prostate after prostatic irritation. We also tested that the alteration of TRPV1 expressing of DRG cell innervating the bladder after the complete Freunds adjunct prostatic injection. At last , we designed a multicenter, randomized, double-blind, placebo-controlled, trial to determine efficacy and long-term benefits of the alpha-blocker tamsulosin in the relief of symptoms of CP/CPPS.Resluts:1. Hematoxylin and eosin staining of the prostatic cross sections revealed visible changes in the structure of the prostate including local haemorrhage and massive infiltration after 7 days post-CFA-treatment. By day 14 after CFA injection, the cytoarchitecture of the prostate did not significantly differ from control tissue and local haemorrhage and massive infiltration in the prostate decreased significantly. Histological sections from the bladder showed no signs of inflammation and no invisible changes of cytoarchitecture on either day 7 or day 14 following CFA injection.2. In rats treated with CFA, prostatic inflammation altered bladder function, whereas in control rats, a saline infusion into the bladder led to filling with a slow pressure increase, eventually triggering a bladder contraction followed by visible micturition. CFA treatment shortened mean micturition interval (p<0.05), decreased mean volume threshold inducing micturition, increased the baseline pressure and threshold pressure (p<0.05), but lowered peak micturition pressure compared with controls (p<0.01). Cystometry parameters of saline and sham operated rats were not statistically different before or after intraprostatic injection3. In the fluorescent labeled study, three groups of labeled cells were observed and counted in the L1 to S2 segment DRG. These cells were PI labeled cells (prostatic afferent neurons), Bb labeled cells (bladder afferent neurons) or PI/Bb double labeled cells (convergent neurons). Distribution of double labeled cells varied from 7.5% to 14% in L1-L2 and L6-S1 ganglia. There were no significant changes in the number of cells labeled with PI or Bb after prostatitis compared to segment-matched controls. Analysis of the size frequency revealed that most of the double labeled cells were small (cell area, 200-600μm2) and medium neurons (cell area, 600-1200μm2), 46.7% and 36.7% respectively. The mean cell profile of double-labeled neurons was 688±60μm2. Surgical denervation of the bladder was performed,the number of bladder-specific neurons and the number of double-labeled neurons (PI/Bb double labeled) were significantly decreased (p<0.05). As expected, the number of prostate-specific was less decreased, however the difference was not significant (p>0.05),which perhaps resulted from cutting some afferents fibers of the prostate when denervating the bladder.4. In the rat model of chronic prostatitis, the express of TRPV1 and NGF in L6～S1 DRG of chronic prostatitis model on day 7 and day14 was significantly higher than that of control group(P<0.01),whereas, the express of TRPV1 on day 7 and day14 has no obvious difference. The express of NGF on day 14 was lower than those on day 7.5. The tamsulosin patients had modest satisfactory improvements compared to the placebo group during treatment. Six months after initiation of treatment, the mean decrement of total NIH-CPSI score in tamsulosin and placebo group were 7.5±1.9 and 4.0±2.3, respectively, P<0.01. After cessation of therapy, the significant difference waned gradually. Two years after cessation of therapy, the mean decrement of total NIH-CPSI score in two groups were 3.0±1.3 and 1.9±0.9, respectively, P>0.05. No differences were observed for data of class III A or III B and data of peak urinary flow rate, PVR and the IIEF during the study period.Conlusions:1. These findings confirmed that nocuous stimulus to the prostate could cause the bladder functions changed in rats, namely prostatitis could induce prostate-bladder cross-organ sensitization, which may be relative with urinary dysfunction associated with prostatitis.2.This study provided neuronal anatomical evidence for prostate-bladder cross-sensitization. That is distribution of convergent afferents innervating bladder and prostate at lumbar-sacral DRG.3.TRPV1 and NGF over expressing in lumbosacral DRG have a key role in prostate-bladder cross-sensitization.4.A 6-month course of tamsulosin ameliorated symptoms of CP/CPPS during treatment. However, these effects decreased gradually after cessation of treatment. This suggests thatα-blockers could not treat prostate-bladder cross-organ sensitization satisfactorily.