Presentation Authors: Takahiro Shimizu*, Suo Zou, Shogo Shimizu, Nankoku, Japan, Naoki Wada, Shun Takai, Nobutaka Shimizu, Pittsburgh, PA, Masaki Yamamoto, Youichirou Higashi, Nankoku, Japan, Naoki Yoshimura, Pittsburgh, PA, Motoaki Saito, Nankoku, Japan
Introduction: Psychological stress exacerbates bladder dysfunction such as overactive bladder (OAB) and bladder pain syndrome/interstitial cystitis (BPS/IC). We previously reported that bombesin (BB), a stress-related neuropeptide, centrally induces facilitation of the rat micturition reflex. Brain BB is reported to activate hypothalamo-pituitary-adrenal axis and sympathetic nerves, as representative responses to stressful conditions, via brain corticotropin-releasing factor (CRF), another stress-related neuropeptide. Therefore, we examined whether brain CRF is involved in the BB-induced frequent urination in rats.
Methods: (1) In urethane anesthetized (0.8 g/kg, ip) male Sprague-Dawley (SD) rats (300-400 g), a catheter was inserted into the bladder to perform cystometry (CMG, 12 ml/h saline infusion). Astressin (a non-selective CRF receptor antagonist, 1 or 3 nmol/rat) was intracerebroventricularly (icv) pretreated 60 min before BB administration (0.03 nmol/rat, icv). CMG was started 60 min before the first icv administration.(2) By using urethane anesthetized (0.8 g/kg, ip) male Wistar rats (300-400 g), similar surgery and CMG experiments described above were performed. Three hours after the surgery, CP154526 (CP, a selective antagonist of CRF receptor type 1 (CRF1 receptor), 3 or 10 nmol/rat) or K41498 (a selective antagonist of CRF receptor type 2, 10 nmol/rat) was icv pretreated 30 min before BB administration (0.03 nmol/rat, icv).
Results: Icv administered BB significantly reduced intercontraction interval (ICI) compared to the pre-treatment values before BB (-10~0 min) (Figs. A-C) without affecting maximal voiding pressure (data not shown) in both SD and Wistar rats. Icv pretreated astressin or CP dose-dependently suppressed the BB-induced ICI reduction (Figs. A-B), but K41498 showed no significant effect on the BB-induced ICI reduction (Fig. C).
Conclusions: Brain BB system is involved in facilitation of the rat micturition reflex via brain CRF1 receptors. These findings would be useful for understanding the underlying brain mechanisms of psychological stress-related exacerbation of lower urinary tract symptoms in OAB and BPS/IC, for which brain CRF1 receptors could be a new therapeutic target.
Source of Funding: JSPS KAKENHI (#17K09303), Narishige Neuroscience Research Foundation in Japan, Smoking Research Foundation in Japan, NIH Grant (DK088836), Grant from the Department of Defense (W81XWH-12-1-0565)