Integrative control of the lower urinary tract: preclinical perspective

Abstract

Storage and periodic expulsion of urine is regulated by a neural control system in the brain and spinal cord that coordinates the reciprocal activity of two functional units in the lower urinary tract (LUT): (a) a reservoir (the urinary bladder) and (b) an outlet (bladder neck, urethra and striated muscles of the urethral sphincter). Control of the bladder and urethral outlet is dependent on three sets of peripheral nerves: parasympathetic, sympathetic and somatic nerves that contain afferent as well as efferent pathways. Afferent neurons innervating the bladder have A-delta or C-fibre axons. Urine storage reflexes are organized in the spinal cord, whereas voiding reflexes are mediated by a spinobulbospinal pathway passing through a coordination centre (the pontine micturition centre) located in the brainstem. Storage and voiding reflexes are activated by mechanosensitive A-delta afferents that respond to bladder distension. Many neurotransmitters including acetylcholine, norepinephrine, dopamine, serotonin, excitatory and inhibitory amino acids, adenosine triphosphate, nitric oxide and neuropeptides are involved in the neural control of the LUT. Injuries or diseases of the nervous system as well as disorders of the peripheral organs can produce LUT dysfunctions including: (1) urinary frequency, urgency and incontinence or (2) inefficient voiding and urinary retention. Neurogenic detrusor overactivity is triggered by C-fibre bladder afferent axons, many of which terminate in the close proximity to the urothelium. The urothelial cells exhibit 'neuron-like' properties that allow them to respond to mechanical and chemical stimuli and to release transmitters that can modulate the activity of afferent nerves.

Figures

Figure 1

Diagram showing the sympathetic, parasympathetic and somatic innervation of the urogenital tract of the male cat. Sympathetic preganglionic pathways emerge from the lumbar spinal cord and pass to the sympathetic chain ganglia (SCG) and then via the inferior splanchnic nerves (ISN) to the inferior mesenteric ganglia (IMG). Preganglionic and postganglionic sympathetic axons then travel in the hypogastric nerve (HGN) to the pelvic plexus and the urogenital organs. Parasympathetic preganglionic axons that originate in the sacral spinal cord pass in the pelvic nerve to ganglion cells in the pelvic plexus and to distal ganglia in the organs. Sacral somatic pathways are contained in the pudendal nerve, which provides an innervation to the penis, the ischiocavernosus (IC), bulbocavernosus (BC) and external urethral sphincter (EUS) muscles. The pudendal and pelvic nerves also receive postganglionic axons from the caudal sympathetic chain ganglia. These three sets of nerves contain afferent axons from the lumbosacral dorsal root ganglia. Abbreviations: ureter (U), prostate gland (PG), vas deferens (VD).

Figure 2

Combined cystometrograms and sphincter electromyograms (EMG) comparing reflex voiding responses in an infant (a) and in a paraplegic patient (c) with a voluntary voiding response in an adult (b). The abscissa in all records represents bladder volume in millilitres and the ordinates represent bladder pressure in cmH2O and electrical activity of the EMG recording. On the left side of each trace, the arrows indicate the start of a slow infusion of fluid into the bladder (bladder filling). Vertical dashed lines indicate the start of sphincter relaxation which precedes by a few seconds the bladder contraction in (a and b). In part (b) note that a voluntary cessation of voiding (stop) is associated with an initial increase in sphincter EMG followed by a reciprocal relaxation of the bladder. A resumption of voiding is again associated with sphincter relaxation and a delayed increase in bladder pressure. On the other hand, in the paraplegic patient (c), the reciprocal relationship between bladder and sphincter is abolished. During bladder filling, transient uninhibited bladder contractions occur in association with sphincter activity. Further filling leads to more prolonged and simultaneous contractions of the bladder and sphincter (bladder–sphincter dyssynergia). Loss of the reciprocal relationship between bladder and sphincter in paraplegic patients interferes with bladder emptying.

Figure 3

Diagram showing neural circuits controlling continence and micturition. (a) Urine storage reflexes. During the storage of urine, distention of the bladder produces low-level vesical afferent firing, which in turn stimulates (1) the sympathetic outflow to the bladder outlet (base and urethra) and (2) 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 detrusor muscle and modulates transmission in bladder ganglia. A region in the rostral pons (the pontine storage centre) increases external urethral sphincter activity. (b) Voiding reflexes. During elimination of urine, intense bladder afferent firing activates spinobulbospinal reflex pathways passing through the pontine micturition center (PMC), which stimulate the parasympathetic outflow to the bladder and urethral smooth muscle and inhibit the sympathetic and pudendal outflow to the urethral outlet. Ascending afferent input from the spinal cord may pass through relay neurones in the periaqueductal grey (PAG) before reaching the PMG.

Figure 4

Transneuronal virus tracing of the central pathways controlling the urinary bladder of the rat. Injection of PRV into the wall of the urinary bladder leads to retrograde transport of virus (dashed arrows) and sequential infection of postganglionic neurones, preganglionic neurones, and then various central neural circuits synaptically linked to the preganglionic neurones. Normal synaptic connections are indicated by solid arrows. At long survival times, virus can be detected with immunocytochemical techniques in neurones at specific sites throughout the spinal cord and brain, extending to the PMC in the pons (i.e. Barrington's nucleus) and to the cerebral cortex. Other sites in the brain labelled by virus are (1) the paraventricular nucleus (PVN), medial preoptic area (MPOA) and periventricular nucleus (Peri V.N.) of the hypothalamus; (2) periaqueductal grey (PAG); (3) locus coeruleus (LC) and subcoeruleus; (4) red nucleus; (5) medullary raphe nuclei and (6) the noradrenergic cell group designated A5. L6 Spinal-cord section, showing on the left-hand side the distribution of virus-labelled parasympathetic preganglionic neurones (□) and interneurones (•) in the region of the parasympathetic nucleus, the dorsal commissure (DCM) and the superficial laminae of the dorsal horn (DH), 72 h after injection of the virus into the bladder. The right-hand side shows the entire population of preganglionic neurones (PGN) (□) labelled by axonal tracing with the fluorescent dye (fluorogold), injected into the pelvic ganglia and the distribution of virus-labelled bladder PGN (▪). Composite diagram of neurones in 12 spinal sections (42 μm).

Figure 5

Comparison of the distribution of bladder afferent projections to the L6 spinal cord of the rat (a), with the distribution of c-fos-positive cells in the L6 spinal segment following chemical irritation of the LUT of the rat (b), and the distribution of interneurones in the L6 spinal cord labelled by transneuronal transport of PRV injected into the urinary bladder (c). Afferents labelled by WGA-HRP injected into the urinary bladder. C-fos immunoreactivity is present in the nuclei of cells. DH, dorsal horn; SPN, sacral parasympathetic nucleus; CC central canal. Calibration represents 500 μm. (d) The laminar organization of the cat spinal cord. These data show that spinal interneurones involved in the reflex control of the urinary bladder are concentrated in specific regions of the spinal cord that receive afferent input from the LUT. Some of these interneurones provide excitatory input to the parasympathetic preganglionic neurones and represent an essential component of the spinal micturition reflex pathway.

Figure 6

Diagram showing the organization of the parasympathetic excitatory reflex pathway to the detrusor muscle. Scheme is based on electrophysiologic studies in cats. In animals with an intact spinal cord, micturition is initiated by a supraspinal reflex pathway passing through a centre in the brain stem. The pathway is triggered by myelinated afferents (A-δ 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, over a period of several weeks following cord injury, a spinal reflex mechanism emerges, which 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 instillation of ice water into the bladder (cold stimulation) activates voiding responses in patients with SCI. Capsaicin (20–30 mg, subcutaneously) blocks the C-fibre reflex in chronic spinal cats, but does not block micturition reflexes in intact cats. Intravesical capsaicin also suppresses detrusor hyper-reflexia and cold-evoked reflexes in patients with neurogenic bladder dysfunction.