Patients with chronic prostatitis often exhibit irritative bladder symptoms despite no evidence of bladder inflammation.  Previous studies in animal models demonstrated that prostatic inflammation (PI) can induce bladder overactivity via prostate-to-bladder cross-organ afferent sensitization through activation of the pelvic nerve [1]. However, the underlying mechanisms for PI-induced afferent sensitization are not fully elucidated.  Histamine released from mast cells activated by tissue inflammation has been implicated as an important mediator causing pain and itch sensation, and inhibition of histamine H1 receptors is reportedly effective for the treatment of pain and other bladder symptoms in patients with interstitial cystitis/bladder pain syndrome (IC/BPS).  Thus, the present study examined the effect of a second-generation, anti-histamine H1 receptor antagonist, which has a lesser degree of anticholinergic effects [2] [3], on bladder overactivity, molecular expressions of histamine H1 receptors (HT1R), TRPV1 and cytokines in the bladder, the prostate and pelvic afferent pathways in a rat model of non-bacterial PI.

Male Sprague-Dawley rats were divided into three groups: (1) Sham group; control rats without intraprostatic instillation and with oral administration of an HT1R antagonist (desloratadine), (2) Placebo group; PI rats with oral administration of vehicle (methyl cellulose), (3) Treatment group; PI rats with oral administration of desloratadine.  On day 0, formalin (5%, 50 µl) was injected into each ventral lobe of the prostate to induce PI in Placebo and Treatment groups, for which vehicle and desloratadine at a dose of 3 mg/kg dissolved in methyl cellulose (0.5w/v % , 0.1 ml) was respectively administrated daily by oral gavage for 14 days from day 14.  On day 28, we performed conscious cystometry (CMG) and harvested tissues to evaluate mRNA expressions of HT1R in the bladder, TRPV1, HT1R and inflammation markers (IL-β and IL-18) in the prostate and TRPV1 in L6-S1 dorsal root ganglia (DRG) by RT-PCR.

In CMG, Treatment group had significant longer intercontraction intervals (ICIs) than Placebo group, in which ICIs were significantly reduced compared to Sham group (Fig. 1A, 1B). In other CMG parameters, Placebo group had significantly higher post voided volume (PVR) than Sham group while there were no significant differences in PVR between Treatment and Sham groups (Fig. 1C). In Placebo group, mRNA levels of TRPV1 in the prostate and L6-S1 DRG were significantly increased, and mRNA expression of HT1R in the prostate and the bladder were also significantly increased compared to Sham group (Fig. 2A and 2B). However, these changes were normalized in Treatment group (Fig. 2A and 2B). In addition, mRNA expressions of IL-1β and IL-18 in the prostate of Placebo group were significantly higher compared to Sham group while there were no significant differences between Treatment and Sham groups (Fig. 2C).

These results indicate that PI induces bladder overactivity shown by decreased ICI in association with HT1R upregulation in the bladder and the prostate, and that inhibition of HT1R improved PI-induced cytokine production, bladder overactivity and C-fiber afferent marker (TRPV1) overexpression in L6-S1 DRG that contain bladder and prostate afferent neurons. Thus, it is assumed that HT1R plays a significant role in prostate-to-bladder cross-organ sensitization, which induces bladder overactivity due to enhanced bladder afferent activity, after PI.

Blockade of histamine H1 receptors improved not only prostatic inflammation, but also bladder overactivity in a rat model of PI. Thus, the histamine-H1 receptor mechanism would be a potential target for the treatment of irritative bladder symptoms in patients with chronic prostatitis.  Also, it is possible that second-generation, anti-histamine H1 receptor antagonists such as desloratadine, which have a lesser anticholinergic effect [2] [3], can induce therapeutic effects without affecting PI-associated voiding problems because desloratadine did not increase, but rather improved PVR in PI rats.

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