The neural control of micturition

Abstract

Micturition, or urination, occurs involuntarily in infants and young children until the age of 3 to 5 years, after which it is regulated voluntarily. The neural circuitry that controls this process is complex and highly distributed: it involves pathways at many levels of the brain, the spinal cord and the peripheral nervous system and is mediated by multiple neurotransmitters. Diseases or injuries of the nervous system in adults can cause the re-emergence of involuntary or reflex micturition, leading to urinary incontinence. This is a major health problem, especially in those with neurological impairment. Here we review the neural control of micturition and how disruption of this control leads to abnormal storage and release of urine.

Figure 1. Efferent pathways of the lower urinary tract

a | Innervation of the female lower urinary tract. Sympathetic fibres (shown in blue) originate in the T11–L2 segments in the spinal cord and run through the inferior mesenteric ganglia (inferior mesenteric plexus, IMP) and the hypogastric nerve (HGN) or through the paravertebral chain to enter the pelvic nerves at the base of the bladder and the urethra. Parasympathetic preganglionic fibres (shown in green) arise from the S2–S4 spinal segments and travel in sacral roots and pelvic nerves (PEL) to ganglia in the pelvic plexus (PP) and in the bladder wall. This is where the postganglionic nerves that supply parasympathetic innervation to the bladder arise. Somatic motor nerves (shown in yellow) that supply the striated muscles of the external urethral sphincter arise from S2–S4 motor neurons and pass through the pudendal nerves. b | Efferent pathways and neurotransmitter mechanisms that regulate the lower urinary tract. Parasympathetic postganglionic axons in the pelvic nerve release acetylcholine (ACh), which produces a bladder contraction by stimulating M₃ muscarinic receptors in the bladder smooth muscle. Sympathetic postganglionic neurons release noradrenaline (NA), which activates β₃ adrenergic receptors to relax bladder smooth muscle and activates α₁ adrenergic receptors to contract urethral smooth muscle. Somatic axons in the pudendal nerve also release ACh, which produces a contraction of the external sphincter striated muscle by activating nicotinic cholinergic receptors. Parasympathetic postganglionic nerves also release ATP, which excites bladder smooth muscle, and nitric oxide, which relaxes urethral smooth muscle (not shown). L₁, first lumbar root; S₁, first sacral root; SHP, superior hypogastric plexus; SN, sciatic nerve; T₉, ninth thoracic root. Part a modified, with permission, from REF. 144 © (1996) W. B. Saunders Company.

Figure 2. A model illustrating possible chemical interactions between urothelial cells, afferent nerves, efferent nerves and myofibroblasts in the urinary bladder

Urothelial cells, myofibroblasts and afferent nerves express common receptors, including purinergic receptors (P2X and P2Y) and transient-receptor-potential receptors (TRPs), such as the capsaicin receptor (TRPV1). Urothelial cells also express TRPV2, TRPV4 and TRMP8. Activation of receptors and ion channels in urothelial cells by bladder distension or chemical stimuli can release mediators, such as ATP, nitric oxide (NO), neurokinin A (NKA), acetylcholine (ACh) and nerve growth factor (NGF), that target adjacent nerves or myofibroblasts and might also act in an autocrine or paracrine manner on urothelial cells. Neuropeptides (including NKA) released from sensory nerves and the urothelium can act on the neurokinin 2 receptor (NK2) to sensitize the mechanoreceptive afferent nerve endings. NGF released from muscle or the urothelium can exert an acute and chronic influence on the excitability of sensory nerves through an action on tyrosine kinase A (TrkA) receptors. ATP released from efferent nerves or from the urothelium can regulate the excitability of adjacent nerves through purinergic P2X receptors. ACh released from efferent nerves or from the urothelium regulates the excitability of adjacent nerves through nicotinic or muscarinic ACh receptors (nAChR and mAChR). Figure modified, with permission, from REF. 145 © (2007) Macmillan Publishers Ltd.

Figure 3. Primary afferent and spinal interneuronal pathways involved in micturition

a | Primary afferent pathways to the L6 spinal cord of the rat project to regions of the dorsal commissure (DCM), the superficial dorsal horn (DH) and the sacral parasympathetic nucleus (SPN) that contain parasympathetic preganglionic neurons. The afferent nerves consist of myelinated (Aδ) axons, which respond to bladder distension and contraction, and unmyelinated (C) axons, which respond to noxious stimuli. b | Spinal interneurons that express c-fos following the activation of bladder afferents by a noxious stimulus (acetic acid) to the bladder are located in similar regions of the L6 spinal segment. c | Spinal interneurons involved in bladder reflexes (labelled by transneuronal transport of pseudorabies virus injected into the urinary bladder) are localized to the regions of the spinal cord that contain primary afferents and c-fos. Some of these interneurons provide excitatory and inhibitory inputs to the parasympathetic preganglionic neurons located in the SPN. d | The laminar organization of the cat sacral spinal cord, showing the location of parasympathetic preganglionic neurons in the intermediolateral region of laminae V and VII (shaded area). CC, central canal; IL, intermediolateral nucleus; LT, Lissauer's tract; VM, ventromedial nucleus (Onuf's nucleus).

Figure 4. Connections between the lumbosacral spinal cord and brain areas involved in bladder control

The central pathways that are involved in controlling the urinary bladder can be visualized in rats using transneuronal virus tracing. Injection of pseudorabies virus into the wall of the urinary bladder leads to retrograde transport of the virus (indicated by the dashed arrows) and the sequential infection of postganglionic neurons, preganglionic neurons, spinal interneurons and then various supraspinal neural circuits that are synaptically linked to the spinal preganglionic neurons and interneurons. The supraspinal sites that are labelled by the virus transport include the pontine micturition centre (also known as Barrington's nucleus), the cerebral cortex, the paraventricular nucleus (PVN), the medial preoptic area (MPOA) and periventricular nucleus (PeriVN) of the hypothalamus, the periaqueductal grey (PAG), the locus coeruleus (LC) and subcoeruleus, the red nucleus (Red N.), the raphe nuclei and the A5 noradrenergic cell group. Synaptic connections are indicated by solid arrows. Synaptic inputs from supraspinal neurons can project to spinal preganglionic neurons or interneurons, as indicated by the bracket. Figure reproduced, with permission, from REF. 21 © (2006) Macmillan Publishers Ltd.

Figure 5. Neural circuits that control continence and micturition

a | Urine storage reflexes. During the storage of urine, distention of the bladder produces low-level vesical afferent firing. This in turn stimulates the sympathetic outflow in the hypogastric nerve to the bladder outlet (the bladder base and the urethra) and the pudendal outflow to the external urethral sphincter. These responses occur by spinal reflex pathways and represent guarding reflexes, which promote continence. Sympathetic firing also inhibits contraction of the detrusor muscle and modulates neurotransmission in bladder ganglia. A region in the rostral pons (the pontine storage centre) might increase striated urethral sphincter activity. b | Voiding reflexes. During the elimination of urine, intense bladder-afferent firing in the pelvic nerve activates spinobulbospinal reflex pathways (shown in blue) that pass through the pontine micturition centre. This stimulates the parasympathetic outflow to the bladder and to the urethral smooth muscle (shown in green) and inhibits the sympathetic and pudendal outflow to the urethral outlet (shown in red). Ascending afferent input from the spinal cord might pass through relay neurons in the periaqueductal grey (PAG) before reaching the pontine micturition centre. Note that these diagrams do not address the generation of conscious bladder sensations, nor the mechanisms that underlie the switch from storage to voiding, both of which presumably involve cerebral circuits above the PAG. R represents receptors on afferent nerve terminals.

Figure 6. Brain areas involved in the regulation of urine storage

a | A meta-analysis of positron-emission tomography and functional MRI studies that investigated which brain areas are involved in the regulation of micturition reveals that the thalamus, the insula, the prefrontal cortex, the anterior cingulate, the periaqueductal grey (PAG), the pons, the medulla and the supplementary motor area (SMA) are activated during the urinary storage. b | A preliminary conceptual framework, based on functional brain-imaging studies, suggesting a scheme for the connections between various forebrain and brainstem structures that are involved in the control of the bladder and the sphincter in humans. Arrows show probable directions of connectivity but do not preclude connections in the opposite direction. Part a reproduced, with permission, from REF. 64 © (2007) Backwell Science. Part b modified, with permission, from REF. 63 © (2005) Wiley-Liss.

Figure 7. Reflex voiding responses in an infant, a healthy adult and a paraplegic patient

Combined cystometrograms and sphincter electromyograms (EMGs, recorded with surface electrodes), allowing a schematic comparison of reflex voiding responses in an infant (a) and in a paraplegic patient (c) with a voluntary voiding response in a healthy adult (b). The abscissa in all recordings represents bladder volume in millilitres; the ordinates represent electrical activity of the EMG recording and detrusor pressure (the component of bladder pressure that is generated by the bladder itself) in cm H₂O. On the left side of each trace (at 0 ml), a slow infusion of fluid into the bladder is started (bladder filling). In part b the start of sphincter relaxation, which precedes the bladder contraction by a few seconds, is indicated (‘start’). Note that a voluntary cessation of voiding (‘stop’) is associated with an initial increase in sphincter EMG and detrusor pressure (a myogenic response). A resumption of voiding is associated with sphincter relaxation and a decrease in detrusor pressure that continues as the bladder empties and relaxes. In the infant (a) sphincter relaxation is present but less complete. On the other hand, in the paraplegic patient (c) the reciprocal relationship between bladder and sphincter is abolished. During bladder filling, involuntary bladder contractions (detrusor overactivity) occur in association with sphincter activity. Each wave of bladder contraction is accompanied by simultaneous contraction of the sphincter (detrusor–sphincter dyssynergia), hindering urine flow. Loss of the reciprocal relationship between the bladder and the sphincter in paraplegic patients thus interferes with bladder emptying.

Figure 8. Organization of the parasympathetic excitatory reflex pathway to the detrusor muscle

This scheme is based on results from electrophysiological studies in cats. Micturition is initiated by a supraspinal reflex pathway that passes through a centre in the brainstem. The pathway is triggered by myelinated afferents (Aδ-fibres), which are connected to the tension receptors in the bladder wall. Injury to the spinal cord above the sacral segments interrupts the connections between the brain and spinal autonomic centres and initially blocks micturition. However, following cord injury a spinal reflex mechanism (shown in green) emerges that is triggered by unmyelinated vesical afferents (C-fibres); the A-fibre afferent inputs are ineffective. The C-fibre reflex pathway is usually weak or undetectable in animals with an intact nervous system. Stimulation of the C-fibre bladder afferents by installation of ice water into the bladder (cold stimulation) activates voiding responses in patients with spinal cord injury. Capsaicin (20–30 mg subcutaneously) blocks the C-fibre reflex in cats with spinal lesions but does not block micturition reflexes in intact cats. Intravesical capsaicin also suppresses detrusor hyperreflexia and cold-evoked reflexes in patients with neurogenic bladder dysfunction.