Psychological/mental stress can influence on urinary function as evidenced by studies in humans and animal models [1].  In addition, a strong correlation has been reported between psychological/mental stressors and symptoms in patients with lower urinary tract dysfunction (LUTD) including overactive bladder (OAB) and bladder pain syndrome/interstitial cystitis (BPS/IC) [1].  Stress-related information is conveyed to the central nervous system (CNS), thereby inducing physical and behavioral responses for adaptation to stress (stress responses), such as the hypothalamus-pituitary-adrenocortical (HPA) axis and the sympatho-adrenomedullary (SA) system.  The HPA axis is more reactive in patients with OAB than in healthy controls, and psychological stress-induced frequent urination is mediated at least by the activation of the SA system in rats.  Therefore, stress responses can provide a link to LUTD.  However, the central mechanisms underlying psychological/mental stress-induced effects on urinary function and LUTD are not fully elucidated
  Corticotropin-releasing factor (CRF) and its receptors [type 1 (CRFR1) and type 2 (CRFR2)] have been recognized as central components to stress.  In fact, central CRF is identified as the master regulator of the HPA axis and induces activation of the SA system.  However, roles of central CRF in regulation of the micturition are still controversial, both facilitatory and inhibitory roles are reported [2,3].  In this study, we investigated the effects of centrally administered CRF on the rat micturition and central mechanisms for the CRF-induced responses, focusing on brain CRFR1 and CRFR2 and glutamatergic receptors.

Urethane anesthetized (0.8 g/kg, ip) male Wistar rats (300-450 g) were used.
(1) A catheter was inserted into the bladder from the dome to perform cystometry (12 ml/h saline infusion).  Two hours after the surgery, continuous cystometry was started to evaluate intercontraction interval (ICI) and maximal voiding pressure (MVP).  One hour after the start, CRF (1 or 3 nmol/rat) or vehicle-1 (10 µl 0.08% AcOH in saline/rat) was intracerebroventricularly (icv) administered.  Evaluations of ICI and MVP were continued 3 h after the administration.
(2) Three hours after the surgery described in (1), single cystometry (12 ml/h saline infusion) was performed.  After 4-5 times of single cystometry, CRF (3 nmol/rat) or vehicle-1 (10 µl 0.08% AcOH in saline/rat) was icv administered, then single cystometry was performed during 60-120 min after the administration.
(3) Effects of central pretreatment with CP154526 [CP, CRFR1 antagonist, 30 or 100 nmol in 3 ul N,N-dimethylformamide (DMF)/rat, icv], K41498 (K, CRFR2 antagonist, 30 nmol in 10 µl in saline/rat, icv), MK-801 [MK, an antagonist of N-methyl-D-aspartate type glutamatergic receptors (NMDA receptors), 3 or 10 nmol in 5 µl saline/rat, icv] or DNQX [an antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate type glutamatergic receptors (AMPA receptors), 1 or 3 nmol in 5 µl saline/rat, icv] on the CRF (3 nmol/rat, icv)-induced responses were also investigated.

(1) Centrally administered CRF dose-dependently shortened ICI without changing MVP (Fig. 1).
(2) Centrally administered CRF significantly reduced single-voided volume (Vv) and bladder capacity (BC) without affecting post-voiding residual volume (Rv) or voiding efficiency (VE) compared to the vehicle-1-treated group (Table 1).
(3) Central pretreatment with CP, MK, and DNQX significantly attenuated the CRF-induced ICI shortening (Fig. 2), while K showed no significant effect on the CRF-induced response (data not shown).  Central administration of each antagonist alone showed no significant effect on ICI or MVP (data not shown).

Our present data indicate that CRF centrally induces facilitation of the micturition as shown by centrally administered CRF-induced ICI shortening and reduction in Vv and BC without changing MVP, Rv or VE.  The CRF-induced ICI shortening was attenuated by centrally pretreated CP, but not by K, indicating that CRF induced facilitation of the micturition via brain CRFR1.  Because in response to centrally administered CRF, urodynamic parameters of bladder efferent activity such as MVP, Rv or VE were not changed, CRF in the brain might induce facilitation of the micturition reflex through facilitation of sensory inputs to the micturition center.  We also investigated central mechanisms for the CRF-induced facilitation of the micturition in relation to the glutamatergic receptors because an interaction between CRFergic and glutamatergic neurotransmission is reported, and glutamatergic nervous system in the CNS is a central component for regulation of the micturition.  In this study, the CRF-induced ICI shortening was attenuated by centrally pretreated MK and DNQX, suggesting that CRF induced facilitation of the micturition via brain NMDA and AMPA receptors.  Each antagonist (MK or DNQX) alone showed no effect on ICI or MVP, indicating that basal activity of the glutamatergic nervous system was partially suppressed by the pretreatment at least under our conditions.  Therefore, stimulation of brain CRFR1 might facilitate the micturition through brain NMDA and AMPA glutamatergic receptors.

Brain CRF induces facilitation of the rat micturition through brain CRFR1 and NMDA and AMPA glutamatergic receptors.  These findings would be useful for understanding the underlying mechanisms of psychological/mental stress-induced effects on LUTD, and CRFR1 might be new therapeutic target for neurogenic bladder overactivity.

Shimizu T, Shimizu S, Higashi Y, et al. Psychological/mental stress-induced effects on urinary function: Possible brain molecules related to psychological/mental stress-induced effects on urinary function. Int J Urol 2021;28:1093-1104.
Wood SK, McFadden K, Griffin T, et al. A corticotropin-releasing factor receptor antagonist improves urodynamic dysfunction produced by social stress or partial bladder outlet obstruction in male rats. Am J Physiol Regul Integr Comp Physiol 2013;304:R940-R950.
Wróbel A, Doboszewska U, Rechberger E, et al. SN003, a CRF1 receptor antagonist, attenuates depressive-like behavior and detrusor overactivity symptoms induced by 13-cis-retinoic acid in rats. Eur J Pharmacol 2017;812:216-224.

Continence 2S2 (2022) 100319
DOI: 10.1016/j.cont.2022.100319