Abstract
Stress exacerbates symptoms of bladder dysfunction including overactive bladder and bladder pain syndrome, but the underlying mechanisms are unknown. Bombesin-like peptides and bombesin receptor types 1 and 2 (BB1 and BB2, respectively) in the brain have been implicated in the mediation/integration of stress responses. In this study, we examined effects of centrally administered bombesin on micturition, focusing on their dependence on 1) the sympathoadrenomedullary system (a representative mechanism activated by stress exposure) and 2) brain BB receptors in urethane-anesthetized (1.0–1.2 g/kg, i.p.) male rats. Intracerebroventricularly administered bombesin significantly shortened intercontraction intervals (ICI) at both doses (0.1 and 1 nmol/animal) without affecting maximal voiding pressure. Bombesin at 1 nmol induced significant increments of plasma noradrenaline and adrenaline levels, which were both abolished by acute bilateral adrenalectomy. On the other hand, adrenalectomy showed no effects on the bombesin-induced shortening of ICI. Much lower doses of bombesin (0.01 and 0.03 nmol/animal, i.c.v.) dose-dependently shortened ICI. Pretreatment with either a BB1 receptor antagonist (BIM-23127; d-Nal-cyclo[Cys-Tyr-d-Trp-Orn-Val-Cys]-Nal-NH2; 3 nmol/animal, i.c.v.) or a BB2 receptor antagonist (BEA; H-d-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt; 3 nmol/animal, i.c.v.), respectively, suppressed the BB (0.03 nmol/animal, i.c.v.)–induced shortening of ICI, whereas each antagonist by itself (1 and 3 nmol/animal, i.c.v.) had no significant effects on ICI. Bombesin (0.03 nmol/animal, i.c.v.) significantly reduced voided volume per micturition and bladder capacity without affecting postvoid residual volume or voiding efficiency. These results suggest that brain bombesin and BB receptors are involved in facilitation of the rat micturition reflex to induce bladder overactivity, which is independent of the sympathoadrenomedullary outflow modulation.
Footnotes
- Received November 2, 2015.
- Accepted December 30, 2015.
This research was supported in part by the Japan Society for the Promotion of Science [Grant-in-Aid for Scientific Research (C) 26460909 (to T.S.), Grant-in-Aid for Young Scientists (B) 26861271 (to S.S.), and Grant-in-Aid for Challenging Exploratory Research 15K15583 (to M.S.)], the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK088836 (to N.Y.)], the Department of Defense [Grant W81XWH-12-1-0565 (to N.Y.)], the Smoking Research Foundation in Japan, the Japan Health Foundation, and Kochi University [Discretionary Grant of the President].
Part of this work was previously published in abstract form at the 2015 International Continence Society annual meeting; 2015 Oct 6–9; Montreal, Quebec, Canada.
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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