A central pattern generator in the spinal cord for the central control of micturition: An opportunity for first-in-class drug treatments
Pierre A Guertin
Neuroscience Unit, Laval University Medical Center (CHUL–CHU de Québec); Faculty of Medicine, Department of Psychiatry and Neurosciences, Laval University, Quebec City, Canada
|Date of Submission||20-Dec-2018|
|Date of Acceptance||14-Feb-2019|
|Date of Web Publication||25-Feb-2019|
Pierre A Guertin
Neuroscience Unit, Laval University Medical Center (CHUL–CHU de Québec); Faculty of Medicine, Department of Psychiatry and Neurosciences, Laval University, Quebec City
Source of Support: None, Conflict of Interest: None
For non-neuroscientists, the spinal cord is often considered simply as a relay between the brain and peripheral organs such as the skin, smooth muscles, and skeletal muscles. However, its gray matter has also been shown to play a pivotal role in the control of stereotyped motor behaviors. Neuroscientists have indeed clearly shown recently that the spinal cord contains command centers also known as central pattern generators. Those spinal centers have been found to elicit, inhibit or modulate locomotion, ejaculation, defecation and micturition. This short communication briefly outlines the main characteristics of the central pattern generator for micturition and how it could become a therapeutic target for innovative drugs against micturition-related problems.
Keywords: brainstem; spinal cord; micturition; urinary retention; pharmacology
|How to cite this article:|
Guertin PA. A central pattern generator in the spinal cord for the central control of micturition: An opportunity for first-in-class drug treatments. Asia Pac J Clin Trials Nerv Syst Dis 2019;4:1-2
|How to cite this URL:|
Guertin PA. A central pattern generator in the spinal cord for the central control of micturition: An opportunity for first-in-class drug treatments. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2019 [cited 2019 Mar 25];4:1-2. Available from: http://www.actnjournal.com/text.asp?2019/4/1/1/251477
Micturition depends essentially, for the storage and periodic elimination of urine, on the coordinated activity of smooth and striated muscles of the lower urinary tract system: the urinary bladder, the bladder neck, the urethra and the urethral sphincters. The bladder and urethral sphincters are controlled in a reciprocal and thus coordinated manner to accomplish both urine storage and micturition (also known as voiding or urination). During storage, urine is retained in the bladder in response to sympathetic activation, producing bladder relaxation via adrenergic signaling through the hypogastric nerve, and activation of the somatic pudendal nerve output from the Onuf's nucleus producing a coordinated contraction of the external urethral sphincter. During voiding, the parasympathetic system (preganglionic neurons in S2–4) is activated rhythmically, producing cyclic contraction of the detrusor muscle of the bladder via cholinergic excitation through the pelvic nerve, whereas the urethral sphincters (internal and external elements) are relaxed concomitantly, allowing urine to leave the bladder and flow through the urethra. The control of urination depends therefore upon autonomic, spinal and supraspinal mechanisms. This indicates compelling evidence exists of a central pattern generator (CPG) for micturition –the spinal micturition center –that is localized in the sacral spinal cord. Indeed, experiments have shown that automatic or reflex-like well-coordinated voiding in low-thoracic spinal cord-transected cats as well as in humans (paraplegics) could be induced by intraspinal stimulation at the upper sacral level (Nashold et al., 1971; Friedman et al., 1972).
A key role for sacral S1 has been proposed by Pikov et al. (2007), using intraspinal electrodes, that S2 stimulation produces bladder contractions insufficient for full voiding behavior, whereas stimulation of sacral S1 generates powerful coordinated bladder contractions and external urethral sphincter relaxation leading to voiding of the bladder. Epidural stimulation at low frequency (1 Hz) between L2 and S1 was also shown recently in low-thoracic spinal cord-tansected rats to elicit both locomotion and micturition suggesting interconnections between the two CPGs (Gad et al., 2014). Those findings provide strong evidence that some important elements of a CPG for micturition are localized mainly in sacral segments of the spinal cord. This is also supported by anatomical, electrophysiological and pharmacological data. In rats, spinal interneurons retrogradely-labeled by injection of pseudorabies virus into the urinary bladder were identified in sacral segments receiving afferent input from the bladder (Nadelhaft and Vera, 1995; Sugaya et al., 1997). A comparable distribution was reported by Vizzard et al. (1995) following injections of virus into the urethra or the external urethral sphincter, suggesting also the existence of a CPG for micturition in the sacral segments. In addition, spinal interneurons nearby the dorsal commissure, superficial dorsal horn and sacral parasympathic nucleus receiving afferent input from the lower urinary tract express c-Fos following noxious or non-noxious stimulation of the bladder and urethra in rats (Birder and de Groat, 1993; Birder et al., 1999). Some of them send projections to the brain, whereas others make local connections in the spinal cord.
Altogether, the results described above provide strong evidence of a CPG for urinary function both in the thoracolumbar (T8–9 for urine storage) and sacral (S2–4 for urination) areas of the spinal cord (Beckel and Holstege, 2011). Derjean et al. (2005) reported, using patch-clamp recordings in vitro, the existence of intrinsic cellular properties such as plateau potentials, L-type Ca2+ channel-mediated voltage oscillations and Ih and ICAN dependent pacemaker-like properties (tetrodotoxin-resistant) in rat sacral interneurons that may belong to SMC and/or other CPGs located in that same area (e.g., lumbosacral defecation center). Gamma-aminobutyric acidergic, glycinergic, dopaminergic, serotonergic, neuropeptidergic, glutamatergic, tachykininergic ligands as well as pituitary-adenylate-cyclase-activating polypeptides, nitric oxide or ATP have been shown to act peripherally or centrally on micturition in different animal models (Mallory et al., 1991; de Groat et al., 1993; Andersson and Pehrson, 2003; Yoshiyama and de Groat, 2005; Chang et al., 2006; Füllhase et al., 2011; Gu et al., 2012; Sugaya et al., 2014). For instance, gamma-aminobutyric acid, glycine and enkephalins were reported to inhibit pontine micturition center activity that regulates bladder capacity whereas 5-hydroxytryptamine, norepinephrine, and acetylcholine have either inhibitory or excitatory effects on micturition, depending on the type and location of activated receptors, e.g., Naftopidil, an alpha-1/5-hydroxytryptamine 1A receptor agonist, administered intrathecally inhibits micturition in rats but 8-hydroxy-2-(di-n-propylamino)-tetralin, a 5-hydroxytryptamine 1A/7 receptor agonist, intravenously administered promotes micturition whereas beta-adrenoceptor activation using BRL 3744 administered intrathecally also induces pro-micturition effects.
| Conclusion|| |
Micturition is partially controlled by spinal micturition center neurons located in sacral segments with key elements in S1. Although many target mechanisms (e.g., transmembrane 5-hydroxytryptamine 1A receptors, Ih currents, and L-type calcium channels) have recently been identified, no pharmacological approaches centrally acting upon SMC neurons have yet been proposed as treatment against urinary problems (such as urinary retention, overactive bladder syndrome, detrusor sphincter dyssynergia, and incontinence). Selective pharmacological activation of the SMC may possibly yield the identification and development of alternative non-invasive pharmacological approaches for patients with spinal cord injury experiencing bladder control problems and specifically urinary retention (Guertin, 2014; Andersson, 2016).
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C-Editors: Zhao M, Li JY; T-Editor: Jia Y
| References|| |
Andersson KE (2016) Potential future pharmacological treatment of bladder dysfunction. Basic Clin Pharmacol Toxicol 119:75-85.
Andersson KE, Pehrson R (2003) CNS involvement in overactive bladder: pathophysiology and opportunities for pharmacological intervention. Drugs 63:2595-2611.
Beckel JM, Holstege G (2011) Neurophysiology of the lower urinary tract. In: Handbook of Experimental Pharmacology (Andersson KE and Michel MC, eds), pp149-169. Berlin Heidelberg: Springer.
Birder LA, de Groat WC (1993) Induction of c-fos expression in spinal neurons by nociceptive and nonnociceptive stimulation of LUT. Am J Physiol 265:326-333.
Birder LA, Roppolo JR, Erickson VL, de Groat WC (1999) Increased c-fos expression in spinal lumbosacral projection neurons and preganglionic neurons after irritation of the lower urinary tract in the rat. Brain Res 834:55-65.
Chang HY, Cheng CL, Chen JJ, de Groat WC (2006) Roles of glutamatergic and serotonergic mechanisms in reflex control of the external urethral sphincter in urethane-anesthetized female rats. Am J Physiol Regul Integr Comp Physiol 291:224-234.
de Groat WC, Booth AM, Yoshimura N (1993) Neurophysiology of micturition and its modifications in animal models of human disease. In: Nervous Control of the Urogenital System (Autonomic Nervous System) (Maggi CA, ed), pp 227-289. London, UK: Harwood Academic Publishers.
Derjean D, Bertrand S, Nagy F, Shefchyk SJ (2005) Plateau potentials and membrane oscillations in parasympathetic preganglionic neurones and intermediolateral neurones in the rat lumbosacral spinal cord. J Physiol 563:583-596.
Friedman H, Nashold BS, Senechal P
(1972) Spinal cord stimulation and bladder function in normal and paraplegic animals. J Neurosurg 36:430-437.
Füllhase C, Soler R, Westerling-Andersson K, Andersson KE (2011) Beta3-adrenoceptors in the rat sacral spinal cord and their functional relevance in micturition under normal conditions and in a model of partial urethral obstruction. Neurourol Urodyn 30:1382-1387.
Gad PN, Roy RR, Zhong H, Lu DC, Gerasimenko YP, Edgerton VR (2014) Initiation of bladder voiding with epidural stimulation in paralyzed, step trained rats. PLoS One 9:e108184.
Gu B, Wu G, Si J, Xu Y, Andersson KE (2012) Improving voiding efficiency in the diabetic rat by a 5-HT1A serotonin receptor agonist. Neurourol Urodyn 31:168-173.
Guertin PA (2014) Preclinical evidence supporting the clinical development of central pattern generator-modulating therapies for chronic spinal cord-injured patients. Front Hum Neurosci 8:272.
Mallory BS, Roppolo JR, de Groat WC (1991) Pharmacological modulation of the pontine micturition center. Brain Res 546:310-320.
Nadelhaft I, Vera PL (1995) Central nervous system neurons infected by pseudorabies virus injected into the rat urinary bladder following unilateral transection of the pelvic nerve. J Comp Neurol 359:443-456.
Nashold BS, Friedman H, Boyarsky S (1971) Electrical activation of micturition by spinal cord stimulation. J Surg Res 11:144-147.
Pikov V, Bullara L, McCreery DB (2007) Intraspinal stimulation for bladder voiding in cats before and after chronic spinal cord injury. J Neural Eng 4:356-368.
Sugaya K, Nishijima S, Kadekawa K, Ashitomi K, Ueda T, Yamamoto H (2014) Spinal mechanism of micturition reflex inhibition by naftopidil in rats. Life Sci 116:106-111.
Sugaya K, Roppolo JR, Yoshimura N, Card JP, de Groat WC (1997) The central neural pathways involved in micturition in the neonatal rat as revealed by the injection of pseudorabies virus into the urinary bladder. Neurosci Lett 223:197-200.
Vizzard MA, Erickson VL, Card JP, Roppolo JR, de Groat WC (1995) Transneuronal labeling of neurons in the adult rat brainstem and spinal cord after injection of pseudorabies virus into the urethra. J Comp Neurol 355;629-640.
Yoshiyama M, de Groat WC (2005) Supraspinal and spinal α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and N-methyl-D-aspartate glutamatergic control of the micturition reflex in the urethane anesthetized rat. Neuroscience 132:1017-1026.