Review| Volume 200, P35-42, October 2016

Download started.


Central control of visceral pain and urinary tract function

Published:February 06, 2016DOI:


      • Central nervous control of bladder function
      • Differential processing of Aδ and C fibre input from the bladder by the central nervous system
      • Regulation of the micturition circuitry during sleep and wakefulness
      • Long term impact of psychosocial stress on bladder function – epigenetic and environmental effects


      Afferent input from Aδ and C-fibres innervating the urinary bladder are processed differently by the brain, and have different roles in signaling bladder sensation. Aδ fibres that signal bladder filling activate a spino-bulbo-spinal loop, which relays in the midbrain periaqueductal grey (PAG) and pontine micturition centre (PMC). The excitability of this circuitry is regulated by tonic GABAergic inhibitory processes. In humans and socialised animals micturition is normally under volitional control and influenced by a host of psychosocial factors. Higher nervous decision-making in a social context to ‘go now’ or ‘do not go’ probably resides in frontal cortical areas, which act as a central control switch for micturition. Exposure to psychosocial stress can have profoundly disruptive influence on the process and lead to maladaptive changes in the bladder. During sleeping the voiding reflex threshold appears to be reset to a higher level to promote urinary continence.
      Under physiological conditions C-fibre bladder afferents are normally silent but are activated in inflammatory bladder states and by intense distending pressure. Following prolonged stimulation visceral nociceptors sensitise, leading to a lowered threshold and heightened sensitivity. In addition, sensitization may occur within the central pain processing circuitry, which outlasts the original nociceptive insult. Visceral nociception may also be influenced by genetic and environmental influences. A period of chronic stress can produce increased sensitivity to visceral pain that lasts for months. Adverse early life events can produce even longer lasting epigenetic changes, which increase the individual's susceptibility to developing visceral pain states in adulthood.

      Graphical abstract


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Autonomic Neuroscience: Basic and Clinical
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Adolphs R.
        Social cognition and the human brain.
        Trends Cogn. Sci. 1999; 3: 469-479
        • An X.
        • Bandler R.
        • Ongür D.
        • Price J.L.
        Prefrontal cortical projections to longitudinal columns in the midbrain periaqueductal gray in macaque monkeys.
        J. Comp. Neurol. 1998; 401: 455-479
        • Beckel J.M.
        • Holstege G.
        The lower urinary tract.
        in: The Rat Nervous System. 4th Ed. Ch 12. Acad. Press, Paxinos G, Sydney - Tokyo2014
        • Bradesi S.
        Role of spinal cord glia in the central processing of peripheral pain perception.
        Neurogastroenterol. Motil. 2010; 22: 499-511
        • Cervero F.
        • Jänig W.
        Visceral nociceptors: a new world order?.
        TINS. 1992; 15: 374-378
        • Chang A.
        • Butler S.
        • Sliwoski J.
        • Valentino R.
        • Canning D.
        • Zderic S.
        Social stress in mice induces voiding dysfunction and bladder wall remodeling.
        Am. J. Physiol. Ren. Physiol. 2009; 29: F1101-F1108
        • Charil A.
        • Zijdenbos A.P.
        • Taylor J.
        • Boelman C.
        • Worsley K.J.
        • Evans A.C.
        • Dagher A.
        Statistical mapping analysis of lesion location and neurological disability in multiple sclerosis: application to 452 patient data sets.
        NeuroImage. 2003; 19: 532-544
        • Clement E.A.
        • Richard A.
        • Thwaites M.
        • Ailon J.
        • Peters S.
        • Dickson C.T.
        Cyclic and sleep-like spontaneous alternations of brain state under urethane anaesthesia.
        PLoS ONE. 2008; 3e2004
        • Conte B.
        • Maggi C.A.
        • Parlani M.
        • Lopez G.
        • Manzini S.
        • Giachetti A.
        Simultaneous recording of vesical and urethral pressure in urethane-anesthetized rats: effect of neuromuscular blocking agents on the activity of the external urethral sphincter.
        J. Pharmacol. Methods. 1991; 26: 161-171
        • Coutinho S.V.
        • Plotsky P.M.
        • Sablad M.
        • Miller J.C.
        • Zhou H.
        • Bayati A.I.
        • McRoberts J.A.
        • Mayer E.A.
        Neonatal maternal separation alters stress-induced responses to viscerosomatic nociceptive stimuli in rat.
        Am. J. Physiol. 2002; 282: G307-G316
        • D'Amico S.C.
        • Schuster I.P.
        • Collins 3rd, W.F.
        Quantification of external urethral sphincter and bladder activity during micturition in the intact and spinally transected adult rat.
        Exp. Neurol. 2011; 228: 59-68
        • de Groat W.C.
        A neurologic basis for the overactive bladder.
        Urology. 1997; 50: 36-52
        • de Groat W.C.
        • Wickens C.
        Organization of the neural switching circuitry underlying reflex micturition.
        Acta Physiol. (Oxf.). 2013; 207: 66-84
        • De Wachter S.G.
        • Heeringa R.
        • Van Koeveringe G.A.
        • Winkens B.
        • Van Kerrebroeck P.E.
        • Gillespie J.I.
        “Focused introspection” during naturally increased diuresis: description and repeatability of a method to study bladder sensation non-invasively.
        Neurourol. Urodyn. 2013; 33: 502-506
        • Ding Y.Q.
        • Zheng H.X.
        • Gong L.W.
        • Lu Y.
        • Zhao H.
        • Qin B.Z.
        Direct projections from the lumbosacral spinal cord to Barrington's nucleus in the rat: a special reference to micturition reflex.
        J. Comp. Neurol. 1997; 389: 149-160
        • Drake M.J.
        • Fowler C.J.
        • Griffiths D.
        • Mayer E.
        • Paton J.F.
        • Birder L.
        Neural control of the lower urinary and gastrointestinal tracts: supraspinal CNS mechanisms.
        Neurourol. Urodyn. 2010; 29: 119-127
        • Duong M.
        • Downie J.W.
        • Du H.J.
        Transmission of afferent information from urinary bladder, urethra and perineum to periaqueductal gray of cat.
        Brain Res. 1999; 819: 108-119
        • Floyd N.S.
        • Price J.L.
        • Ferry A.T.
        • Keay K.A.
        • Bandler R.
        Orbitomedial prefrontal cortical projections to distinct longitudinal columns of the periaqueductal gray in the rat.
        J. Comp. Neurol. 2000; 422: 556-578
        • Fowler C.J.
        • Griffiths D.J.
        A decade of functional brain imaging applied to bladder control.
        Neurourol. Urodyn. 2010; 29: 49-55
        • Fowler C.J.
        • Griffiths D.
        • de Groat W.C.
        The neural control of micturition.
        Nat. Rev. Neurosci. 2008; 9: 453-466
        • Gillespie J.
        What determines when you go to the toilet? The concept of cognitive voiding.
        BJOG. 2013; 120: 133-136
        • Gonzalez E.J.
        • Merrill L.
        • Vizzard M.A.
        Bladder sensory physiology: neuroactive compounds and receptors, sensory transducers, and target-derived growth factors as targets to improve function.
        Am. J. Physiol. Regul. Integr. Comp. Physiol. 2014; 306: R869-R878
        • Griffiths D.J.
        • Fowler C.J.
        The micturition switch and its forebrain influences.
        Acta Physiol. 2013; 207: 93-109
        • Holstege G.
        The emotional motor system and micturition control.
        Neurourol. Urodyn. 2010; 29: 42-48
        • Holstege G.
        • Griffiths D.
        • de Wall H.
        • Dalm E.
        Anatomical and physiological observations on supraspinal control of bladder and urethral sphincter muscles in the cat.
        J. Comp. Neurol. 1986; 250: 449-461
        • Hong S.
        • Zheng G.
        • Wiley J.W.
        Epigenetic regulation of genes that modulate chronic stress-induced visceral pain in the peripheral nervous system.
        Gastroenterology. 2015; 148: 148-157
        • Huang T.Y.
        • Belzer V.
        • Hanani M.
        Gap junctions in dorsal root ganglia: possible contribution to visceral pain.
        Eur. J. Pain. 2010; 14: 49e1–11
        • Iggo A.
        Tension receptors in the stomach and the urinary bladder.
        J. Physiol. 1955; 128: 593-607
        • Kiddoo D.A.
        • Valentino R.J.
        • Zderic S.
        • Ganesh A.
        • Leiser S.C.
        • Hale L.
        • Grigoriadis D.E.
        Impact of state of arousal and stress neuropeptides on urodynamic function in freely moving rats.
        Am. J. Physiol. 2006; 290: R1697-R1706
        • Kitta T.
        • Matsumoto M.
        • Tanaka H.
        • Mitsui T.
        • Yoshioka M.
        • Nonomura K.
        GABAergic mechanism mediated via D receptors in the rat periaqueductal gray participates in the micturition reflex: an in vivo microdialysis study.
        Eur. J. Neurosci. 2008; 27: 3216-3225
        • Klausner A.P.
        • Streng T.
        • Na Y.-G.
        • Raju J.
        • Batts T.W.
        • Tuttle J.B.
        • Andersson K.-E.
        • Steers W.D.
        The role of corticotropin releasing factor and its antagonist, astressin, on micturition in the rat.
        Auton. Neurosci. 2005; 123: 26-35
        • Kuipers R.
        • Mouton L.J.
        • Holstege G.
        Afferent projections to the pontine micturition center in the cat.
        J. Comp. Neurol. 2006; 494: 36-53
        • Latremoliere A.
        • Woolf C.J.
        Central sensitization: a generator of pain hypersensitivity by central neural plasticity.
        J. Pain. 2009; 10: 895-926
        • 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: 541-548
        • Leserman J.
        • Drossman D.A.
        Relationship of abuse history to functional gastrointestinal disorders and symptoms: some possible mediating mechanisms.
        Trauma Violence Abuse. 2008; 8: 331-343
        • Liu Z.
        • Sakakibara R.
        • Nakazawa K.
        • Uchiyama T.
        • Yamamoto T.
        • Itoa T.
        • Hattoria T.
        Micturition-related neuronal firing in the periaqueductal gray area in cats.
        Neuroscience. 2004; 126: 1075-1082
        • Liu P.Y.
        • Lu C.L.
        • Wang C.C.
        • Lee I.H.
        • Hsieh J.C.
        • Chen C.C.
        • Lee H.F.
        • Lin H.C.
        • Chang F.Y.
        • Lee S.D.
        Spinal microglia initiate and maintain hyperalgesia in a rat model of chronic pancreatitis.
        Gastroenterology. 2012; 142: 165-173
        • Maggi C.A.
        • Giuliani S.
        • Santicioli P.
        • Meli A.
        Analysis of factors involved in determining urinary bladder voiding cycle in urethan-anesthetised rats.
        Am. J. Physiol. Regul. Integr. Comp. Physiol. 1986; 251: R250-R257
        • Marson L.
        Identification of central nervous system neurons that innervate the bladder body, bladder base, or external urethral sphincter of female rats: a transneuronal tracing study using pseudorabies virus.
        J. Comp. Neurol. 1997; 389: 584-602
        • Matsumoto S.
        • Levendusky M.C.
        • Longhurst P.A.
        • Levin R.M.
        • Millington W.R.
        Activation of mu opioid receptors in the ventrolateral periaqueductal gray inhibits reflex micturition in anesthetized rats.
        Neurosci. Lett. 2004; 363: 116-119
        • Matsuura S.
        • Allen G.V.
        • Downie J.W.
        Volume-evoked micturition reflex is mediated by the ventrolateral periaqueductal gray in the anesthetized rats.
        Am. J. Physiol. 1998; 275: R2049-R2055
        • Matsuura S.
        • Downie J.W.
        • Allen G.V.
        Micturition evoked by glutamate microinjection in the ventrolateral periaqueductal gray is mediated through Barrington's nucleus in the rat.
        Neuroscience. 2000; 101: 1053-1061
        • Mehnert U.
        • Michels L.
        • Zempleni M.-Z.
        • Schurch B.
        • Kollias S.
        The supraspinal neural correlate of bladder cold sensation—an fMRI study.
        Hum. Brain Mapp. 2011; 32: 835-845
        • Mitsui T.
        • Kakizaki H.
        • Matsuura S.
        • Tanaka H.
        • Yoshioka M.
        • Koyanagi T.
        Chemical bladder irritation provokes c-fos expression in the midbrain periaqueductal gray matter of the rat.
        Brain Res. 2003; 967: 81-88
        • Moloney R.D.
        • O'Mahony S.M.
        • Dinan T.G.
        • Cryan J.F.
        Stress-induced visceral pain: toward animal models of irritable-bowel syndrome and associated comorbidities.
        Front Psychiatry. 2015; 6: 15
        • Negoro H.
        • Kanematsu A.
        • Doi M.
        • Suadicani S.O.
        • Matusuo M.
        • Imamura M.
        • Okinami T.
        • Nishikawa N.
        • Oura T.
        • Matsui S.
        • Seo K.
        • Tainaka M.
        • Urabe S.
        • Kiyokage E.
        • Todo T.
        • Okamura H.
        • Tabata Y.
        • Ogawa O.
        Involvement of urinary bladder connexin43 and the circadian clock in coordination of diurnal micturition rhythm.
        Nat. Commun. 2012; 3: 809
        • Negoro H.
        • Kanematsu A.
        • Yoshimura K.
        • Ogawa O.
        Chronobiology of micturition: putative role of the circadian clock.
        J. Urol. 2013; 190: 843-849
        • Nishijima S.
        • Sugaya K.
        • Kadekawa K.
        • Ashitomi K.
        • Yamamoto H.
        Effect of chemical stimulation of the medial frontal lobe on the micturition reflex in rats.
        J. Urol. 2012; 187: 1116-1120
        • Olango W.M.
        • Finn D.P.
        Neurobiology of stress-induced hyperalgesia.
        Curr. Top. Behav. Neurosci. 2014; 20: 251-280
        • Pavcovich L.A.
        • Valentino R.J.
        Central regulation of micturition in the rat the corticotropin-releasing hormone from Barrington's nucleus.
        Neurosci. Lett. 1995; 196: 185-188
        • Pedersen K.V.
        • Asbjørn Mohr Drewes A.M.
        • Frimodt-Møller P.C.
        • Osther P.J.S.
        Visceral pain originating from the upper urinary tract.
        Urol. Res. 2010; 38: 345-355
        • Quintino-dos-Santos J.W.
        • Müller C.J.
        • Bernabé C.S.
        • Rosa C.A.
        • Tufik S.
        • Schenberg L.C.
        Evidence that the periaqueductal gray matter mediates the facilitation of panic-like reactions in neonatally-isolated adult rats.
        PLoS ONE. 2014; 9e90726
        • Rickenbacher E.
        • Baez M.A.
        • Hale L.
        • SC Leiser
        • SA Zderic
        • RJ Valentino
        Impact of overactive bladder on the brain: central sequelae of a visceral pathology.
        Proc. Natl. Acad. Sci. U. S. A. 2008; 105: 10589-10594
        • Ringel Y.
        • Drossman D.A.
        • Leserman J.L.
        • Suyenobu B.Y.
        • Wilber K.
        • Lin W.
        • Whitehead W.E.
        • Naliboff B.D.
        • Berman S.
        • Mayer E.A.
        Effect of abuse history on pain reports and brain responses to aversive visceral stimulation: an FMRI study.
        Gastroenterology. 2008; 134: 396-404
        • Sakakibara R.
        • Nakazawa K.
        • Shiba K.
        • Nakajima Y.
        • Uchiyama T.
        • Yoshiyama M.
        • Yamanishi T.
        • Hattori T.
        Firing patterns of micturition-related neurons in the pontine storage centre in cats.
        Auton. Neurosci. 2002; 99: 24-30
        • Smith P.P.
        • DeAngelis A.M.
        • GA Kuchel
        Evidence of central modulation of bladder compliance during filling phase.
        Neurourol. Urodyn. 2012; 31: 30-35
        • Stone E.
        • Coote J.H.
        • Allard J.
        • TA Lovick
        GABAergic control of micturition within the periaqueductal grey matter of the rat.
        J. Physiol. 2011; 589: 2065-2078
        • Sugaya K.
        • Ogawa Y.
        • Hatano T.
        • Nishijima S.
        • Matsuyama K.
        • Mori S.
        Ascending and descending brainstem neuronal activity during cystometry in decerebrate cats.
        Neurourol. Urodyn. 2003; 22: 343-350
        • Tai C.
        • Wang J.
        • Jin T.
        • Wang P.
        • Kim S.-G.
        • Roppolo J.R.
        • de Groat W.C.
        Brain switch for reflex micturition control detected by fMRI in rats.
        J. Neurophysiol. 2009; 102: 2719-2730
        • Tanaka Y.
        • Koyama Y.
        • Kayama Y.
        • Kawauchi A.
        • Ukimura O.
        • Miki T.
        Firing of micturition center neurons in the rat mesopontine tegmentum during urinary bladder contraction.
        Brain Res. 2003; 965: 146-154
        • Tran L.
        • Chaloner A.
        • AH Sawalha
        • Greenwood Van-Meerveld B.
        Importance of epigenetic mechanisms in visceral pain induced by chronic water avoidance stress.
        Psychoneuroendocrinology. 2013; 38: 898-906
        • Valentino R.J.
        • Chen S.
        • Zhu Y.
        • Aston-Jones G.
        Evidence for divergent projections of corticotropin-releasing hormone neurons of Barrington's nucleus to the locus coeruleus and spinal cord.
        Brain Res. 1996; 732: 1-15
        • Valentino R.J.
        • Wood S.K.
        • Wein A.J.
        • Zderic S.A.
        The bladder-brain connection: putative role of corticotropin releasing factor.
        Nat. Rev. Urol. 2011; 8: 19-28
        • van den Wijngaard R.M.
        • Stanisor O.I.
        • van Diest S.A.
        • Selting O.
        • Wouters M.M.
        • Cailotto C.
        • de Jonge W.J.
        • Boeckxstaens G.E.
        Susceptibility to stress induced visceral hypersensitivity in maternally separated rats is transferred across generations.
        Neurogastroenterol. Motil. 2013; 25: e780-e790
        • Vanderhorst V.G.
        • Mouton L.J.
        • Blok B.F.
        • Holstege G.
        Distinct cell groups in the lumbosacral cord of the cat project to different areas in the periaqueductal gray.
        J. Comp. Neurol. 1996; 376: 361-385
        • Wager T.D.
        • van Ast V.A.
        • Hughes B.L.
        • Davidson M.L.
        • Lindquist M.A.
        • Ochsner K.N.
        Brain mediators of cardiovascular responses to social threat, part II: prefrontal-subcortical pathways and relationship with anxiety.
        NeuroImage. 2009; 47: 836-851
        • Wood S.K.
        • McFadden K.
        • Griffin T.
        • JH Wolfe
        • Zderic S.
        • RJ Valentino
        A corticotropin-releasing factor receptor antagonist improves urodynamic dysfunction produced by social stress or partial bladder outlet obstruction in male rats.
        Am. J. Physiol. 2013; 304: R940-R950
        • Wouters M.M.
        • Van Wanrooy S.
        • Casteels C.
        • Nemethova A.
        • de Fries A.
        • van Oudenhove L.
        • den Wijngaard RM van
        • van Laere K.
        • Boeckxstaens G.
        Altered brain activation to colorectal distention in visceral hypersensitive maternal separated rats.
        Neurogastroenterol. Motil. 2012; 24: 85-6786
        • Xiang B.
        • Biji S.
        • Liu J.X.
        • Chu W.C.
        • Yeung D.K.
        • Yeung C.K.
        Functional brainstem changes in response to bladder function alteration elicited by surgical reduction in bladder capacity: a functional magnetic resonance imaging study.
        J. Urol. 2010; 184: 2186-2191
        • Yaguchi H.
        • Soma H.
        • Miyazaki Y.
        • Tashiro J.
        • Yabe I.
        • Kikuchi S.
        • Sasaki H.
        • Kakizaki H.
        • Moriwaka F.
        • Tashiro K.
        A case of acute urinary retention caused by periaqueductal grey lesion.
        J. Neurol. Neurosurg. Psychiatry. 2004; 75: 1202-1203
        • Zagorodnyuk V.P.
        • Gibbins I.L.
        • Costa M.
        • Brookes S.J.H.
        • SJ Gregory
        Properties of the major classes of mechanoreceptors in the guinea pig bladder.
        J. Physiol. 2007; 585: 147-163