Bladder overactivity and afferent hyperexcitability induced by prostate‐to‐bladder cross‐sensitization in rats with prostatic inflammation

Abstract

Key points There is clinical evidence showing that prostatic inflammation contributes to overactive bladder symptoms in male patients; however, little is known about the underlying mechanisms In this study, we investigated the mechanism that prostatic inflammation causes detrusor overactivity by using a rat model of chemically induced prostatic inflammation. We observed a significant number of dorsal root ganglion neurons with dichotomized afferents innervating both prostate and bladder. We also found that prostatic inflammation induces bladder overactivity and urothelial NGF overexpression in the bladder, both dependent on activation of the pelvic nerve, as well as changes in ion channel expression and hyperexcitability of bladder afferent neurons. These results indicate that the prostate‐to‐bladder cross‐sensitization through primary afferent pathways in the pelvic nerve, which contain dichotomized afferents, could be an important mechanism contributing to bladder overactivity and afferent hyperexcitability induced by prostatic inflammation. Abstract Prostatic inflammation is reportedly an important factor inducing lower urinary tract symptoms (LUTS) including urinary frequency, urgency and incontinence in patients with benign prostatic hyperplasia (BPH). However, the underlying mechanisms inducing bladder dysfunction after prostatic inflammation are not well clarified. We therefore investigated the effects of prostatic inflammation on bladder activity and afferent function using a rat model of non‐bacterial prostatic inflammation. We demonstrated that bladder overactivity, evident as decreased voided volume and shorter intercontraction intervals in cystometry, was observed in rats with prostatic inflammation versus controls. Tissue inflammation, evident as increased myeloperoxidase activity, and IL‐1α, IL‐1β, and IL‐6 levels inside the prostate, but not in the bladder, following intraprostatic formalin injection induced an increase in NGF expression in the bladder urothelium, which depended on activation of the pelvic nerve. A significant proportion (18–19%) of dorsal root ganglion neurons were double labelled by dye tracers injected into either bladder or prostate. In rats with prostatic inflammation, TRPV1, TRPA1 and P2X2 increased, and Kv1.4, a potassium channel α‐subunit that can form A‐type potassium (KA) channels, decreased at mRNA levels in bladder afferent and double‐labelled neurons vs. non‐labelled neurons, and slow KA current density decreased in association with hyperexcitability of these neurons. Collectively, non‐bacterial inflammation localized in the prostate induces bladder overactivity and enhances bladder afferent function. Thus, prostate‐to‐bladder afferent cross‐sensitization through primary afferents in the pelvic nerve, which contain dichotomized afferents, could underlie storage LUTS in symptomatic BPH with prostatic inflammation.

Long‐lasting bladder overactivity and bladder afferent hyperexcitability in rats with chemically‐induced prostatic inflammation

“…Intraprostatic formalin injection has been recognized as a convenient and qualified method to establish nonbacterial prostatic inflammation. Previous studies including ours showed that a single intraprostatic injection of 5% or 10% formalin could induce prostatic inflammation and result in bladder overactivity for up to 4 weeks, as well as bladder afferent hyperexcitability at 1 week after formalin injection . Our current study further confirmed that formalin‐treated rats exhibit bladder overactivity that lasts for 8 weeks using metabolic cage measurements and continuous CMG recordings.…”

“…Among these models, intraprostatic injection of chemicals (such as formalin, carrageenan, zymosan, or complete Freund adjuvant) is a convenient and effective approach. Our previous studies showed that a rat model of formalin‐induced prostatic inflammation developed molecular changes similar to those identified in human BPH specimens and exhibits 13 at 1 week after intraprostatic formalin injection . Schwartz et al also reported that bladder afferent pathways were sensitized in a 4‐week mouse model of prostatitis induced by intraprostatic zymosan injection possibly due to cross‐organ sensitization between the prostate and bladder.…”

“…Rats were housed in under a 12/12 hours reversed light‐dark cycle. In our previous studies, we utilized 5% formalin solution to induce prostatic inflammation . In this study, we increased the formalin concentration to 10% to examine whether prostatic inflammation induced by injection of 10% formalin solution (50 μL) into each of bilateral ventral lobes of the prostate can induce the long‐lasting effects on bladder function and bladder afferent activity.…”

The role of prostaglandin and E series prostaglandin receptor type 4 receptors in the development of bladder overactivity in a rat model of chemically induced prostatic inflammation

“…The rat model of prostatic inflammation used in the present study is not a direct model of BPH; however, we have shown that this rat model exhibits the upregulation of androgen receptor-responsive genes and TGF-b-related genes in the prostate [16], which is similarly seen in human BPH tissue [19], and that increased interleukin-18 expression induced by inflammasome activation is similarly observed in the formalin-induced rat prostatic inflammation model [20] and in human BPH specimens with inflammatory cell infiltration [21]. Although prostatic inflammation is considered to be involved in development of BOO in patients with BPH [22], changes in voiding function in our model appear to be BOOindependent because we recently reported that there was no significant difference in the prostate weight between vehicleand formalin-injected rats, indicating that prostatic inflammation does not induce prostatic enlargement in the same model of prostatic inflammation [17]. Also, the rat prostate is anatomically positioned apart from the urethra and not surrounded by a capsular tissue [23]; therefore, prostatic enlargement, if any, is not likely to induce the BOO condition in rats; thus, the model of non-bacterial prostatic inflammation used in the present study seems useful to investigate inflammation-related events, other than BOO, in human BPH with tissue inflammation.…”

“…© 2019 The Authors BJU International © 2019 BJU International in rats with formalin-induced prostatic inflammation is dependent on activation of primary afferents in the pelvic nerve, which contain dichotomized afferents, because the transection of the pelvic nerve prevented bladder overactivity as well as upregulation of nerve growth factor in the bladder mucosa following prostatic inflammation [17]. It seems reasonable, therefore, to assume that activation of the pelvic nerve containing dichotomized afferents after prostatic inflammation alters the functional and molecular properties of the PGE2-EP4 system in the urothelium to induce bladder overactivity in the present study.…”