Research Article| Volume 226, 102672, July 2020

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Transecting the hypogastric nerve to uncover the bladder-inhibitory pathways involved with saphenous nerve stimulation in anesthetized rats

  • Karly S. Franz
    Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
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  • Paul B. Yoo
    Corresponding author at: Institute of Biomaterials and Biomedical Engineering (IBBME), University of Toronto, 164 College Street, Room 407, Toronto, ON M5S 3G9, Canada.
    Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada

    Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario, Canada
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      • Saphenous nerve stimulation can inhibit bladder function in anesthetized rats.
      • Complete bladder inhibition can be achieved in saline and acetic acid infused bladder models.
      • Inhibitory effects of saphenous nerve stimulation are not mediated via the hypogastric nerve.
      • The mechanism of action appears to involve an alternative (supraspinal) pathway.


      Saphenous (SAFN) nerve stimulation was recently shown in anesthetized rats to elicit bladder-inhibitory responses in a frequency-dependent manner; however, the mechanism of action is unknown. The goal of this study was to investigate the potential role of the hypogastric nerve (HGN) in this inhibitory pathway by examining stimulation-evoked changes in bladder function under four different experimental conditions: (1) HGN intact, saline infusion (HGNi-s), (2) HGN transected, saline infusion (HGNt-s), (3) HGN intact, acetic acid (AA) infusion (HGNi-a), and (4) HGN transected, AA infusion (HGNt-a). Experiments were conducted in 33 urethane-anesthetized female rats, where continuous bladder infusion was provided through a suprapubic catheter. The experimental protocol involved two, 40-min stimulation trials in which electrical pulses were applied to the SAFN at a set frequency (10 Hz) and two different amplitudes (50 μA and 100 μA). In all experimental groups, SAFN stimulation resulted in complete suppression of bladder activity with an incidence rate of 25% to 50%. However, significant changes in the measured urodynamic changes (e.g., basal pressure, contraction amplitude, and inter-contraction interval) were found only in the HGNt-a animals. Our findings suggest that the HGN does not mediate the inhibitory effects of SAFN stimulation and that bladder inhibition is achieved through a different mechanism of action.



      AA (acetic acid), BP (basal (bladder) pressure), CA (contraction amplitude), EUS (external urethral sphincter), HGN (hypogastric nerve), ICI (inter-contraction interval), OI (overflow incontinence), SAFN (saphenous nerve), SNS (sacral nerve stimulation), TNS (tibial nerve stimulation), VV (voided volume)
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        • Chang H.-Y.
        • Cheng C.-L.
        • Chen J.-J.
        • de Groat W.C.
        Serotonergic drugs and spinal cord transections indicate that different spinal circuits are involved in external urethral sphincter activity in rats.
        Am. J. Physiol. Physiol. 2007; 292: F1044-F1053
        • Choudhary M.
        • van Mastrigt R.
        • van Asselt E.
        Effect of tibial nerve stimulation on bladder afferent nerve activity in a rat detrusor overactivity model.
        Int. J. Urol. 2016; 23: 253-258
        • Conway D.
        • Kamo I.
        • Yoshimura N.
        • Chancellor M.
        • Cannon T.
        Comparison of leak point pressure methods in an animal model of stress urinary incontinence.
        Int. Urogynecol. J. 2005; 16: 359-363
        • Fowler C.J.
        • Griffiths D.
        • de Groat W.C.
        The neural control of micturition.
        Nat. Rev. Neurosci. 2008; 9: 453-466
        • de Groat W.C.
        • Theobald R.J.
        Reflex activation of sympathetic pathways to vesical smooth muscle and parasympathetic ganglia by electrical stimulation of vesical afferents.
        J. Physiol. 1976; 259: 223-237
        • de Groat W.C.
        • Yoshimura N.
        Mechanisms underlying the recovery of lower urinary tract function following spinal cord injury.
        Prog. Brain Res. 2006; 152: 59-84
        • Kadekawa K.
        • Nishijima S.
        • Sugaya K.
        • Miyazato M.
        • Saito S.
        Mechanisms by which the serotonergic system inhibits micturition in rats.
        Life Sci. 2009; 85: 592-596
        • Kadow B.T.
        • Lyon T.D.
        • Zhang Z.
        • Lamm V.
        • Shen B.
        • Wang J.
        • Roppolo J.R.
        • de Groat W.C.
        • Tai C.
        Sympathetic β-adrenergic mechanism in Pudendal inhibition of nociceptive and non-nociceptive reflex bladder activity.
        Am. J. Physiol. Renal Physiol. ajprenal. 2016; 180: 2016
        • Kamo I.
        • Cannon T.W.
        • Conway D.A.
        • Torimoto K.
        • Chancellor M.B.
        • de Groat W.C.
        • Yoshimura N.
        The role of bladder-to-urethral reflexes in urinary continence mechanisms in rats.
        Am. J. Physiol. Physiol. 2004; 287: F434-F441
        • Kovacevic M.
        • Yoo P.B.
        Reflex neuromodulation of bladder function elicited by posterior tibial nerve stimulation in anesthetized rats.
        Am. J. Physiol. Ren. Physiol. 2014; 308: F320-F329
        • LaMotte C.C.
        • Kapadia S.E.
        • Shapiro C.M.
        Central projections of the sciatic, saphenous, median, and ulnar nerves of the rat demonstrated by transganglionic transport of choleragenoid-HRP (B-HRP) and wheat germ agglutinin-HRP (WGA-HRP).
        J. Comp. Neurol. 1991; 311: 546-562
        • Li S.
        • Li X.
        • Theisen K.
        • Browning J.
        • Shen B.
        • Wang J.
        • Roppolo J.R.
        • de Groat W.C.
        • Tai C.
        Saphenous nerve stimulation normalizes bladder underactivity induced by tibial nerve stimulation in cats.
        Am. J. Physiol. Physiol. 2017; 315: F247-F253
        • MacDiarmid S.A.
        • John S.M.
        • Yoo P.B.
        A pilot feasibility study of treating overactive bladder patients with percutaneous saphenous nerve stimulation.
        Neurourol. Urodyn. 2018; 37: 1815-1820
        • Maggi C.A.
        • Conte B.
        • Furio M.
        • Santicioli P.
        • Giuliani S.
        • Meli A.
        Further studies on mechanisms regulating the voiding cycle of the rat urinary bladder.
        Gen. Pharmacol. Vasc. Syst. 1989; 20: 833-838
        • McGee M.J.
        • Danziger Z.C.
        • Bamford J.A.
        • Grill W.M.
        A spinal GABAergic mechanism is necessary for bladder inhibition by pudendal afferent stimulation.
        Am. J. Physiol. Physiol. 2014; 307: F921-F930
        • Mitobe M.
        • Inoue H.
        • Westfall T.D.
        • Higashiyama H.
        • Mizuyachi K.
        • Kushida H.
        • Kinoshita M.
        A new method for producing urinary bladder hyperactivity using a non-invasive transient intravesical infusion of acetic acid in conscious rats.
        J. Pharmacol. Toxicol. Methods. 2008; 57: 188-193
        • Mitsui T.
        • Kakizaki H.
        • Matsuura S.
        • Ameda K.
        • Yoshioka M.
        • Koyanagi T.
        Afferent fibers of the Hypogastric nerves are involved in the facilitating effects of chemical bladder irritation in rats.
        J. Neurophysiol. 2001; 86: 2276-2284
        • 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
        • Moazzam Z.
        • Yoo P.B.
        Frequency-dependent inhibition of bladder function by saphenous nerve stimulation in anesthetized rats.
        Neurourol. Urodyn. 2018;
        • Morikawa K.
        • Kakiuchi M.
        • Fukuoka M.
        • Kato H.
        • Ito Y.
        • Gomi Y.
        Effects of various drugs on bladder function in conscious restrained-denervated rats placed in a restraining cage and produced by transection of the hypogastric nerve.
        Jpn. J. Pharmacol. 1990; 52: 405-411
        • Moss N.G.
        • Harrington W.W.
        • Tucker M.S.
        Pressure, volume, and chemosensitivity in afferent innervation of urinary bladder in rats.
        Am. J. Physiol. Integr. Comp. Physiol. 1997; 272: R695-R703
        • Neuhuber W.
        The central projections of visceral primary afferent neurons of the inferior mesenteric plexus and hypogastric nerve and the location of the related sensory and preganglionic sympathetic cell bodies in the rat.
        Anat. Embryol. (Berl). 1982; 164: 413-425
        • Paquette J.P.
        • Yoo P.B.
        Recruitment of unmyelinated C fibers mediates the bladder-inhibitory effects of tibial nerve stimulation in a continuous-fill anesthetized rat model.
        Am. J. Physiol. Physiol. ajprenal. 2019; (00502.2018)
        • Persyn S.
        • Gillespie J.
        • Eastham J.
        • De Wachter S.
        Possible role of the major pelvic ganglion in the modulation of non-voiding activity in rats.
        Auton. Neurosci. Basic Clin. 2016; 198: 33-37
        • Su X.
        • Nickles A.
        • Nelson D.E.
        Comparison of neural targets for neuromodulation of bladder micturition reflex in the rat.
        Am. J. Physiol. Physiol. 2012; 303: F1196-F1206
        • Sugaya K.
        • Nishijima S.
        • Tasaki S.
        • Kadekawa K.
        • Miyazato M.
        • Ogawa Y.
        Effects of propiverine and naftopidil on the urinary ATP level and bladder activity after bladder stimulation in rats.
        Neurosci. Lett. 2007; 429: 142-146
        • Tai C.
        • Larson J.A.
        • Ogagan P.D.
        • Chen G.
        • Shen B.
        • Wang J.
        • Roppolo J.R.
        • de Groat W.C.
        Differential role of opioid receptors in tibial nerve inhibition of nociceptive and nonnociceptive bladder reflexes in cats.
        Am. J. Physiol. Physiol. 2012; 302: F1090-F1097
        • Walter J.S.
        • Wheeler J.S.
        • Robinson C.J.
        • Wurster R.D.
        Inhibiting the hyperreflexic bladder with electrical stimulation in a spinal animal model.
        Neurourol. Urodyn. 1993; 12: 241-252
        • Wang Z.
        • Liao L.
        • Deng H.
        • Li X.
        • Chen G.
        • Liao X.
        The different roles of opioid receptors in the inhibitory effects induced by sacral dorsal root ganglion stimulation on nociceptive and nonnociceptive conditions in cats.
        Neurourol. Urodyn. 2018; 37: 2462-2469
        • Woods M.
        • Carson N.
        • Norton N.W.
        • Sheldon J.H.
        • Argentieri T.M.
        Efficacy of the β3-adrenergic receptor agonist CL-316243 on experimental bladder hyperreflexia and detrusor instability in the rat.
        J. Urol. 2001; 166: 1142-1147
        • Xiao Z.
        • Reese J.
        • Schwen Z.
        • Shen B.
        • Wang J.
        • Roppolo J.R.
        • de Groat W.C.
        • Tai C.
        Role of spinal GABAA receptors in pudendal inhibition of nociceptive and nonnociceptive bladder reflexes in cats.
        Am. J. Physiol. Physiol. 2014; 306: F781-F789
        • Xiao Z.
        • Rogers M.J.
        • Shen B.
        • Wang J.
        • Schwen Z.
        • Roppolo J.R.
        • de Groat W.C.
        • Tai C.
        Somatic modulation of spinal reflex bladder activity mediated by nociceptive bladder afferent nerve fibers in cats.
        Am. J. Physiol. Physiol. 2014; 307: F673-F679
        • Yoshiyama M.
        • de Groat W.C.
        Effect of bilateral Hypogastric nerve transection on voiding dysfunction in rats with spinal cord injury.
        Exp. Neurol. 2002; 175: 191-197
        • Zhang Z.
        • Bandari J.
        • Bansal U.
        • Shen B.
        • Wang J.
        • Vladimir L.
        • Roppolo J.R.
        • de Groat W.C.
        • Tai C.
        Sacral neuromodulation of nociceptive bladder overactivity in cats.
        Neurourol. Urodyn. 2016; 36: 1270-1277