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5-HT3 receptors modulate changes in voiding pattern and bladder contractility in water avoidance stress-induced bladder overactivity in male mice

Published:October 03, 2022DOI:https://doi.org/10.1016/j.autneu.2022.103040

      Highlights

      • Oral administration of 5-HT3 receptor antagonist, ondansetron, attenuates changes in urine voiding pattern in water avoidance stress-induced mice.
      • Enhanced spontaneous tonic and amplitude of contraction to cholinergic stimulation in the urinary bladder of stressed-mice was mediated via 5-HT3 receptors in the urinary bladder.
      • Mice exposed to repeated water avoidance stress showed less sensitivity to 5-HT-induced urinary bladder contraction.

      Abstract

      Purpose

      Chronic psychological stress aggravates painful bladder syndrome symptoms. Previous studies suggest roles of 5-HT3 receptors in regulating micturition and bladder hypersensitivity. This study aimed to investigate the roles of 5-HT3 receptors in modulating voiding patterns and spontaneous bladder contractile properties in water avoidance stress-induced mice.

      Materials and methods

      Voiding patterns in sham stress (SS), water avoidance stress (WS), and water avoidance stress with daily oral gavage of ondansetron (1 mg/kg BW) (WA) groups were analyzed after exposure to repeated water avoidance stress for 10 days. Changes in contractile activity of isolated bladder in response to KCl, carbachol, and 5-hydroxytryptamine were determined. Bladder mast cell quantification was examined using toluidine blue staining.

      Results

      Urine voided area was significantly decreased in WS group after exposure to 10 days of the stress protocol, which was reversed in the WA group. The WS group had a higher number of urine spots than the SS group. Increased mast cell degranulation was observed in the stressed mice. Bladder strips of the WS group showed higher tonic and amplitude of spontaneous contraction than the SS group, which were normalized by ondansetron administration. Increased response to carbachol-induced bladder contraction was observed in the bladder of stressed mice, which was attenuated with ondansetron pre-incubation.

      Conclusions

      Water avoidance stress-induced mice exhibited changes in voiding pattern, which was reversed by oral administration with a 5-HT3 receptor antagonist (ondansetron). Enhanced contractile response to cholinergic stimulation in the urinary bladder of the psychological stress-induced bladder overactivity was mediated through 5-HT3 receptors.

      Abbreviations:

      PBS (painful bladder syndrome), 5-HT (5-hydroxytryptamine), CCh (carbachol), SS (sham stress), WS (water avoidance stress), WA (water avoidance stress with oral administration of ondansetron)

      Keywords

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      References

        • Abrams P.
        • Cardozo L.
        • Fall M.
        • Griffiths D.
        • Rosier P.
        • Ulmsten U.
        • van Kerrebroeck P.
        • Victor A.
        • Wein A.
        The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the international continence society.
        Urology. 2003; 61: 37-49https://doi.org/10.1016/S0090-4295(02)02243-4
        • Berger M.
        • Gray J.A.
        • Roth B.L.
        The expanded biology of serotonin.
        Annu. Rev. Med. 2009; 60: 355-366https://doi.org/10.1146/annurev.med.60.042307.110802
        • Bradesi S.
        • Schwetz I.
        • Ennes H.S.
        • Lamy C.M.R.
        • Ohning G.
        • Fanselow M.
        • Pothoulakis C.
        • McRoberts J.A.
        • Mayer E.A.
        Repeated exposure to water avoidance stress in rats: a new model for sustained visceral hyperalgesia.
        Am. J. Physiol. Gastrointest. Liver Physiol. 2005; 289: G42-G53https://doi.org/10.1152/ajpgi.00500.2004
        • Bradley C.S.
        • Nygaard I.E.
        • Hillis S.L.
        • Torner J.C.
        • Sadler A.G.
        Longitudinal associations between mental health conditions and overactive bladder in women veterans.
        American Journal of Obstetrics and Gynecology. 2017; 217 (430.e1-430.e8) (10.1016/j.ajog.2017.06.016)
        • Candura S.M.
        • Messori E.
        • Franceschetti G.P.
        • D’Agostino G.
        • Vicini D.
        • Tagliani M.
        • Tonini M.
        Neural 5-HT4 receptors in the human isolated detrusor muscle: effects of indole, benzimidazolone and substituted benzamide agonists and antagonists.
        Br. J. Pharmacol. 1996; 118: 1965-1970https://doi.org/10.1111/j.1476-5381.1996.tb15631.x
        • Charrua A.
        • Pinto R.
        • Taylor A.
        • Canelas A.
        • Ribeiro-da-Silva A.
        • Cruz C.D.
        • Birder L.A.
        • Cruz F.
        Can the adrenergic system be implicated in the pathophysiology of bladder pain syndrome/interstitial cystitis? A clinical and experimental study.
        Neurourol. Urodyn. 2015; 34: 489-496https://doi.org/10.1002/nau.22542
        • Chetty N.
        • Coupar I.M.
        • Chess-Williams R.
        • Kerr K.P.
        Demonstration of 5-HT3 receptor function and expression in the mouse bladder.
        Naunyn Schmiedeberg's Arch. Pharmacol. 2007; 375: 359-368https://doi.org/10.1007/s00210-007-0173-7
      1. Creekmore et al., n.d.Creekmore, A. L., Hong, S., Zhu, S., Xue, J., & Wiley, J. W. (n.d.). Chronic stress-associated visceral hyperalgesia correlates with severity of intestinal barrier dysfunction. Pain, 159(9), 1777–1789. doi:10.1097/j.pain.0000000000001271.

        • D’Agostino G.
        • Condino A.M.
        • Gallinari P.
        • Franceschetti G.P.
        • Tonini M.
        Characterization of prejunctional serotonin receptors modulating [3H]acetylcholine release in the human detrusor.
        J. Pharmacol. Exp. Ther. 2006; 316: 129-135https://doi.org/10.1124/jpet.105.092551
        • Davila G.W.
        • Bernier F.
        • Franco J.
        • Kopka S.L.
        Bladder dysfunction in sexual abuse survivors.
        J. Urol. 2003; 170: 476-479https://doi.org/10.1097/01.ju.0000070439.49457.d9
        • Dougherty J.J.
        • Nichols R.A.
        Cross-regulation between colocalized nicotinic acetylcholine and 5-HT 3 serotonin receptors on presynaptic nerve terminals.
        Acta Pharmacol. Sin. 2009; 30: 788-794https://doi.org/10.1038/aps.2009.62
        • Espey M.J.
        • Du H.J.
        • Downie J.W.
        Serotonergic modulation of spinal ascending activity and sacral reflex activity evoked by pelvic nerve stimulation in cats.
        Brain Res. 1998; 798: 101-108https://doi.org/10.1016/s0006-8993(98)00401-6
        • Fuentes I.M.
        • Pierce A.N.
        • di Silvestro E.R.
        • Maloney M.O.
        • Christianson J.A.
        Differential influence of early life and adult stress on urogenital sensitivity and function in male mice.
        Front. Syst. Neurosci. 2018; 11: 97https://doi.org/10.3389/fnsys.2017.00097
        • Gershon M.D.
        • Tack J.
        The serotonin signaling system: from basic understanding to drug development for functional GI disorders.
        Gastroenterology. 2007; 132: 397-414https://doi.org/10.1053/j.gastro.2006.11.002
        • Gobert A.
        • Lejeune F.
        • Rivet J.M.
        • Audinot V.
        • Newman-Tancredi A.
        • Millan M.J.
        Modulation of the activity of central serotoninergic neurons by novel serotonin1A receptor agonists and antagonists: a comparison to adrenergic and dopaminergic neurons in rats.
        J. Pharmacol. Exp. Ther. 1995; 273: 1032-1046
        • Hall J.D.
        • DeWitte C.
        • Ness T.J.
        • Robbins M.T.
        Serotonin enhances urinary bladder nociceptive processing via a 5-HT3 receptor mechanism.
        Neurosci. Lett. 2015; 604: 97-102https://doi.org/10.1016/j.neulet.2015.07.048
        • Herat L.
        • Schlaich M.
        • Matthews V.
        Sympathetic stimulation with norepinephrine may come at a cost.
        Neural Regen. Res. 2019; 14: 977-978https://doi.org/10.4103/1673-5374.250576
        • Imamura T.
        • Ishizuka O.
        • Ogawa T.
        • Yamagishi T.
        • Yokoyama H.
        • Minagawa T.
        • Nakazawa M.
        • Gautam S.S.
        • Nishizawa O.
        Muscarinic receptors mediate cold stress-induced detrusor overactivity in type 2 diabetes mellitus rats.
        Int. J. Urol. 2014; 21: 1051-1058https://doi.org/10.1111/iju.12475
        • Ishizuka O.
        • Gu B.
        • Igawa Y.
        • Nishizawa O.
        • Pehrson R.
        • Andersson K.E.
        Role of supraspinal serotonin receptors for micturition in normal conscious rats.
        Neurourol. Urodyn. 2002; 21: 225-230https://doi.org/10.1002/nau.10043
        • Joels M.
        • Hesen W.
        • de Kloet E.R.
        Mineralocorticoid hormones suppress serotonin-induced hyperpolarization of rat hippocampal CA1 neurons.
        J. Neurosci. 1991; 11: 2288-2294https://doi.org/10.1523/jneurosci.11-08-02288.1991
        • Konthapakdee N.
        • Grundy L.
        • O’Donnell T.
        • Garcia-Caraballo S.
        • Brierley S.M.
        • Grundy D.
        • Daly D.M.
        Serotonin exerts a direct modulatory role on bladder afferent firing in mice.
        J. Physiol. 2019; 597: 5247-5264https://doi.org/10.1113/JP278751
        • Kummer W.
        • Wiegand S.
        • Akinci S.
        • Wessler I.
        • Schinkel A.H.
        • Wess J.
        • Koepsell H.
        • Haberberger R.v.
        • Lips K.S.
        Role of acetylcholine and polyspecific cation transporters in serotonin-induced bronchoconstriction in the mouse.
        Respiratory Research. 2006; 7https://doi.org/10.1186/1465-9921-7-65
        • Lai H.H.
        • Morgan C.D.
        • Vetter J.
        • Andriole G.L.
        Impact of childhood and recent traumatic events on the clinical presentation of overactive bladder.
        Neurourol. Urodyn. 2016; 35: 1017-1023https://doi.org/10.1002/nau.22872
        • Lanfumey L.
        • Mongeau R.
        • Cohen-Salmon C.
        • Hamon M.
        Corticosteroid–serotonin interactions in the neurobiological mechanisms of stress-related disorders.
        Neurosci. Biobehav. Rev. 2008; 32: 1174-1184https://doi.org/10.1016/j.neubiorev.2008.04.006
        • Lanfumey L.
        • Pardon M.C.
        • Laaris N.
        • Joubert C.
        • Hanoun N.
        • Hamon M.
        • Cohen-Salmon C.
        5-HT1A autoreceptor desensitization by chronic ultramild stress in mice.
        Neuroreport. 1999; 10: 3369-3374https://doi.org/10.1097/00001756-199911080-00021
        • Lee J.Y.
        • Kim N.
        • Kim Y.S.
        • Nam R.H.
        • Ham M.H.
        • Lee H.S.
        • Jo W.
        • Shim Y.
        • Choi Y.J.
        • Yoon H.
        • Shin C.M.
        • Lee D.H.
        Repeated water avoidance stress alters mucosal mast cell counts, interleukin-1β levels with sex differences in the distal colon of wistar rats.
        J. Neurogastroenterol. Motil. 2016; 22: 694-704https://doi.org/10.5056/jnm16007
        • Lee U.J.
        • Ackerman A.L.
        • Wu A.
        • Zhang R.
        • Leung J.
        • Bradesi S.
        • Mayer E.A.
        • Rodríguez L.
        • v.
        Chronic psychological stress in high-anxiety rats induces sustained bladder hyperalgesia.
        Physiol. Behav. 2015; 139: 541-548https://doi.org/10.1016/j.physbeh.2014.11.045
        • Lutgendorf S.K.
        • Kreder K.J.
        • Rothrock N.E.
        • Ratliff T.L.
        • Zimmerman B.
        Female urology stress and symptomatology in patients with interstitial cystitis: a laboratory stress model.
        J. Urol. 2000; 164: 1265-1269https://doi.org/10.1016/s0022-5347(05)67152-2
        • Matos R.
        • Serrão P.
        • Rodriguez L.
        • Birder L.A.
        • Cruz F.
        • Charrua A.
        The water avoidance stress induces bladder pain due to a prolonged alpha1A adrenoceptor stimulation.
        Naunyn Schmiedeberg's Arch. Pharmacol. 2017; 390: 839-844https://doi.org/10.1007/s00210-017-1384-1
        • Matsumoto-Miyai K.
        • Yamada E.
        • Shinzawa E.
        • Koyama Y.
        • Shimada S.
        • Yoshizumi M.
        • Kawatani M.
        Serotonergic regulation of distention-induced ATP release from the urothelium.
        Am. J. Physiol. Ren. Physiol. 2016; 310: F646-F655https://doi.org/10.1152/ajprenal.00024.2015
        • Messori E.
        • Rizzi C.A.
        • Candura S.M.
        • Lucchelli A.
        • Balestra B.
        • Tonini M.
        5-hydroxytryptamine receptors that facilitate excitatory neuromuscular transmission in the Guinea-pig isolated detrusor muscle.
        Br. J. Pharmacol. 1995; 115: 677-683https://doi.org/10.1111/j.1476-5381.1995.tb14986.x
        • Peng H.Y.
        • Hsieh M.C.
        • Lai C.Y.
        • den Chen G.
        • Huang Y.P.
        • Lin T.
        • <check>bin. </check>
        Glucocorticoid mediates water avoidance stress-sensitized colon-bladder cross-talk via RSK2/PSD-95/NR2B in rats.
        Am. J. Physiol. Endocrinol. Metab. 2012; 303: 1094-1106https://doi.org/10.1152/ajpendo.00235.2012
        • Ramage A.G.
        The role of central 5-hydroxytryptamine (5-HT, serotonin) receptors in the control of micturition.
        Br. J. Pharmacol. 2006; 147: S120-S131https://doi.org/10.1038/sj.bjp.0706504
        • Ritter K.E.
        • Wang Z.
        • Vezina C.M.
        • Bjorling D.E.
        • Southard-Smith E.M.
        Serotonin receptor 5-HT3A affects development of bladder innervation and urinary bladder function.
        Front. Neurosci. 2017; 11: 690https://doi.org/10.3389/fnins.2017.00690
        • Rothrock N.E.
        • Lutgendorf S.K.
        • Kreder K.J.
        • Ratliff T.
        • Zimmerman B.
        Stress and symptoms in patients with interstitial cystitis: a life stress model.
        Urology. 2001; 57: 422-427https://doi.org/10.1016/s0090-4295(00)00988-2
        • Segieth J.
        • Pearce B.
        • Fowler L.
        • Whitton P.S.
        Regulatory role of nitric oxide over hippocampal 5-HT release in vivo.
        Naunyn Schmiedeberg's Arch. Pharmacol. 2001; 363: 302-306https://doi.org/10.1007/s002100000370
        • Shi L.
        • Maser-Gluth C.
        • Remer T.
        Daily urinary free cortisol and cortisone excretion is associated with urine volume in healthy children.
        Steroids. 2008; 73: 1446-1451https://doi.org/10.1016/j.steroids.2008.08.002
        • Shimizu T.
        • Shimizu S.
        • Higashi Y.
        • Saito M.
        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: 1093-1104https://doi.org/10.1111/iju.14663
        • Smith A.L.
        • Leung J.
        • Kun S.
        • Zhang R.
        • Karagiannides I.
        • Raz S.
        • Lee U.
        • Glovatscka V.
        • Pothoulakis C.
        • Bradesi S.
        • Mayer E.A.
        • Rodríguez L.v.
        The effects of acute and chronic psychological stress on bladder function in a rodent model.
        Urology. 2011; 78 (967.e1–967.e7)https://doi.org/10.1016/j.urology.2011.06.041
        • Theoharides T.C.
        • Alysandratos K.D.
        • Angelidou A.
        • Delivanis D.A.
        • Sismanopoulos N.
        • Zhang B.
        • Asadi S.
        • Vasiadi M.
        • Weng Z.
        • Miniati A.
        • Kalogeromitros D.
        Mast cells and inflammation.
        Biochim. Biophys. Acta. 2012; 1822: 21-33https://doi.org/10.1016/j.bbadis.2010.12.014
        • Theoharides T.C.
        • Kempuraj D.
        • Sant G.R.
        Mast cell involvement in interstitial cystitis: a review of human and experimental evidence.
        Urology. 2001; 57: 47-55https://doi.org/10.1016/s0090-4295(01)01129-3
        • Wang Z.
        • Chang H.H.
        • Gao Y.
        • Zhang R.
        • Guo Y.
        • Holschneider D.P.
        • Rodriguez L.
        • v.
        Effects of water avoidance stress on peripheral and central responses during bladder filling in the rat: a multidisciplinary approach to the study of urologic chronic pelvic pain syndrome (MAPP) research network study.
        PLoS One. 2017; 12e0182976https://doi.org/10.1371/journal.pone.0182976
        • Wegner K.A.
        • Abler L.L.
        • Oakes S.R.
        • Mehta G.S.
        • Ritter K.E.
        • Hill W.G.
        • Zwaans B.M.
        • Lamb L.E.
        • Wang Z.
        • Bjorling D.E.
        • Ricke W.A.
        • Macoska J.
        • Marker P.C.
        • Southard-Smith E.M.
        • Eliceiri K.W.
        • Vezina C.M.
        Void spot assay procedural optimization and software for rapid and objective quantification of rodent voiding function, including overlapping urine spots.
        Am. J. Physiol. Ren. Physiol. 2018; 315: F1067-F1080https://doi.org/10.1152/ajprenal.00245.2018
        • West E.G.
        • Sellers D.J.
        • Chess-Williams R.
        • McDermott C.
        Bladder overactivity induced by psychological stress in female mice is associated with enhanced bladder contractility.
        Life Sci. 2021; 265118735https://doi.org/10.1016/j.lfs.2020.118735
        • Wood S.K.
        • Baez M.A.
        • Bhatnagar S.
        • Valentino R.J.
        Social stress-induced bladder dysfunction: potential role of corticotropin-releasing factor.
        Am. J. Physiol. Regul. Integr. Comp. Physiol. 2009; 296: R1671-R1678https://doi.org/10.1152/ajpregu.91013.2008
        • Zheng G.
        • Wu S.P.
        • Hu Y.
        • Smith D.E.
        • Wiley J.W.
        • Hong S.
        Corticosterone mediates stress-related increased intestinal permeability in a region-specific manner.
        Neurogastroenterol. Motil. 2013; 25: e127-e139https://doi.org/10.1111/nmo.12066