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

1 Neuroscience Unit, Laval University Medical Center (CHUL-CHU de Québec), Quebec City, Canada

2 Faculty of Medicine, Department of Psychiatry and Neurosciences, Laval University, Quebec City, Canada

Abstract

Key words:brainstem; spinal cord; micturition; urinary retention; pharmacology

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 relaxationviaadrenergic 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 bladderviacholinergic 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 nonnoxious 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 recordingsin vitro, the existence of intrinsic cellular properties such as plateau potentials, L-type Ca2+channel-mediated voltage oscillations andIhandICANdependent 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, gammaaminobutyric 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,Ihcurrents, 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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