Sympathetic Actions on Detrusor Muscle and Ganglia

During physiologic bladder filling, little or no increase in intravesical pressure is observed, despite large increases in urine volume. This process, called accommodation, is caused primarily by passive elastic and viscoelastic properties of the smooth muscle and connective tissue of the bladder wall. During filling, muscle bundles in the bladder wall undergo reorganization, and the muscle cells are elongated up to four times their length. As bladder filling progresses, at a certain bladder wall tension, a desire to void is felt, although it has not been determined where this sensation is processed in the brain. Mechanoreceptors in the bladder wall are activated (Aδ fibers), and action potentials run with afferents following parasympathetic pelvic nerves to the spinal cord at the S2 to S4 and with afferents following sympathetic nerves to the thoracolumbar cord ( ). As filling increases to a critical intravesical pressure, or with rapid bladder filling, detrusor muscle contractility is inhibited and urethral sphincter muscle enhanced by activation of a spinal sympathetic reflex—one that stays intact with spinal cord lesions above the lumbar level ( ).

The sympathetic preganglionic fibers from thoracolumbar spinal segments form white rami communicantes to synapse in the paravertebral or prevertebral sympathetic pathways, the latter predominating. Preganglionic neurons reach their inferior mesenteric ganglia by the lumbar splanchnic nerves, synapse, and continue as postganglionic nerves through the hypogastric nerves to the presacral fascia, across the upper posterior lateral pelvic wall, 1 to 2 cm behind and below the ureter. This location is ironically the same area where uterosacral sutures are placed for vaginal vault suspension. After these neurons join the pelvic nerves, the pelvic plexus is formed, running below and medial to the internal iliac vessels overlying the anterior lateral lower rectum near the anorectal junction. The plexus spreads in the lateral wall of the upper one-third of the vagina beneath the uterine artery, medial to the ureter and 2 cm inferolateral to the cervix. Within the vesicovaginal space, the plexus supplies the upper vagina, bladder, proximal urethra, and lower ureter. Sympathetic preganglionic neurons generally use acetylcholine neurotransmitter acting on nicotinic receptors. The sympathetic postganglionic fibers are primarily noradrenergic, with norepinephrine being the chief neurotransmitter. Norepinephrine stimulation of β3-adrenergic receptors located in the bladder body causes relaxation of the smooth muscle. Stimulation of α ₁ receptors in bladder base and urethral smooth muscle by norepinephrine causes muscle contraction. In addition, norepinephrine also acts as a neurotransmitter at the parasympathetic ganglia, and α-adrenergic receptors, when stimulated, depress parasympathetic pelvic ganglion transmission by suppression of presynaptic cholinergic neurotransmitter release.

Thus, sympathetic relaxation of detrusor body smooth muscle, contraction of bladder base and urethral smooth muscle, and depression of parasympathetic ganglionic transmission all act to promote urine storage.

Parasympathetic Actions on Detrusor Muscle

The parasympathetic preganglionic fibers arise from nerve roots S3 and S4 and, occasionally, S2, with the cell bodies being in the sacral cord, the conus medullaris. These fibers emerge from the piriformis muscle overlying the sacral foramina and enter the presacral fascia near the ischial spine at the posterior layer of the hypogastric sheath forming the pelvic nerve, where they then contribute to the already described pelvic plexus. The pelvic plexus has freely interconnected nerves in the pelvic fascia that supply the rectum, genitalia, and lower urinary tract. The parasympathetic fibers to the urinary tract terminate in pelvic ganglia located within the wall of the bladder, a location quite vulnerable to end-organ disease, such as overstretch, infection, or fibrosis. At the ganglia, excitatory transmission occurs from activation of nicotinic acetylcholine receptors, with some ganglionic cells having secondary muscarinic receptors. Multiple neuropeptide agents also function at these ganglia including adrenergic, purinergic, and peptidergic modulation. Transmission regulation remains complex, and precise knowledge is not available at present.

At the detrusor muscle, postganglionic parasympathetic detrusor nerve fibers diverge and store neurotransmitter agents in axonal varicosities called synaptic vesicles . The agent is diffused to neuromuscular bundles of 12 to 15 smooth muscle fibers enclosed in a collagen capsule that acts similarly to the tendon insertion of a muscle. Stimulating electrical pulses produce two episodes of depolarization, suggesting the release of two neurotransmitters. The chief neurotransmitter is cholinergic, with muscarinic receptors, and a second major neurotransmitter is noncholinergic and nonadrenergic. This observation accounts for detrusor atropine resistance. The studies of demonstrated that adenosine triphosphate (ATP) was the mediator of these noncholinergic, nonadrenergic contractions. Variability is present between species, and some studies suggest that the purine (ATP) pathway responses lead to more rapid bladder contractions, perhaps being useful in animals that use short, quick squirts of urine for geographically marking their territory.

Muscarinic receptors have received much attention by pharmaceutical companies. The receptors are present in the CNS, eye lacrimal glands, salivary glands, heart, gallbladder, stomach, and colon. Five types (M _1–5 ) have been identified. In detrusor muscle, M ₂ and M ₃ predominate. While there are more detrusor M ₂ receptors, the M ₃ are more important for detrusor contractions. Dry mouth, slowed gastrointestinal motility, blurred vision, increased heart rate, heat intolerance, sedation with reductions in memory and attention, delirium, drowsiness, fatigue, and other cognitive functions are side effects related to the various receptors located throughout the body. Anticholinergic medications more selective for M ₃ receptors should have more therapeutic effects against bladder overactivity with fewer side effects.

Cholinergic receptors are more present in the body than in the base of the bladder, whereas adrenergic and neuropeptide receptors are more prevalent in the base of the bladder. Neuropeptide modulators include vasoactive intestinal polypeptide and substance P. Histaminic and purinergic receptors may also be present in detrusor smooth muscle.

Smooth Muscle of Trigone and Urethra

The trigone was originally thought to be of separate embryologic origin from the bladder, however, this idea is being challenged ( ). The idea of a separate origin was attractive because of the different innervation of this area compared to the rest of the bladder. The innervation of the trigone smooth muscle fibers is an almost exclusively adrenergic innervation with chiefly α ₁ receptors. Cholinergic development in the bladder is present at birth, whereas adrenergic development occurs later. Prostaglandins act as intracellular messengers to relax trigonal muscles.

The proximal urethral smooth muscle is rich in α-adrenergic receptors responsive to norepinephrine neurotransmitter. Acetylcholine, substance P, vasoactive intestinal polypeptide, and histamine are all additional potential transmitters in the urethra. Nitric oxide (NO) is prominent in the parasympathetic postganglionic innervation of the urethra, and exogenous NO or parasympathetic nerve stimulation relaxes urethral smooth muscle.

Skeletal Muscle of Lower Urinary Tract: Somatic Innervation

In the lower urinary tract, the somatic system involves skeletal muscle in the lower urinary tract outlet. The neuronal cell bodies for the urethral sphincter and for the distal periurethral striated muscles and pelvic floor muscles are located in Onuf’s (Onufrowicz) somatic nucleus in the lateral aspect of the anterior horn of the gray matter of the sacral spinal cord from S2 to S4. This nucleus gives rise to the pudendal nerve, which is classically thought to provide the efferent innervation of the striated sphincter. has shown that serotonin and norepinephrine enhance the effects of glutamate, the primary excitatory neurotransmitter for pudendal motor neurons. This is the proposed mechanism of action of duloxetine (a serotonin-norepinephrine reuptake inhibitor) in treating stress incontinence. The pudendal nerve, using acetylcholine, activates nicotinic cholinergic receptors to contract the rhabdosphincter. The alpha motor neurons of Onuf’s nucleus are unique in many ways including their resistance to polio and amyotrophic lateral sclerosis (ALS).

The exact neuropathways supplying the urethral sphincter skeletal muscle are controversial. The proximal intramural component of the striated urogenital sphincter muscle (urethral sphincter, rhabdosphincter) is variably innervated by somatic efferent branches of the pelvic nerves, a component of the pelvic plexus. believed this intramural component to have somatic and autonomic (both cholinergic and adrenergic) innervation. However, the more distal periurethral striated muscles (compressor urethrae and urethrovaginal sphincter) are innervated by the pudendal nerve, as is the skeletal muscle of the external anal sphincter and perineal muscles.

Typically, somatic motor activity regulates skeletal muscle contraction by spinal reflexes, with the afferent arm of the reflex originating in muscle spindles, synapses taking place in the spinal cord, and the efferent arm originating in anterior horn cells with the axon going to the muscle. Unlike typical somatic reflex pathways that are regulated by sensory nerves from muscle spindles, the afferent regulation of the urethral sphincter somatic reflex is different because urethral skeletal muscle has no spindles.

Embryologic speculation is that pelvic caudal muscles (tail waggers), which compose the levator group in humans, are supplied from the pelvic plexus on the pelvic surface side, whereas the sphincter cloacal derivatives are supplied from the perineal aspect by the pudendal nerve.

The pudendal nerve passes between the coccygeus and piriformis muscles, leaves the pelvis through the greater sciatic foramen, crosses the ischial spine, and reenters the pelvis through the lesser sciatic foramen. Here the nerve accompanies the pudendal vessels along the lateral wall of the ischiorectal fossa in a tunnel formed by a splitting of the obturator internus fascia, called Alcock’s canal . At or before the perineal membrane, the nerve divides into the inferior rectal nerve, supplying the external anal sphincter, the perineal nerve, and the dorsal nerve to the clitoris ( Fig. 2.5 ). The perineal nerve splits into a superficial branch to the labia and a deep branch to the periurethral striated muscles. The branching of the pudendal nerve shows considerable variation.

The urethral sphincter muscle is an integral part of the urethral wall and is made up of all slow-twitch (type 1) fibers. The periurethral muscles (compressor urethrae and urethrovaginal sphincter) are composed of mostly slow-twitch fibers with a variable concentration of fast-twitch (type 2) fibers. These fibers combine to provide constant tonus, with emergency reflex activity mainly in the distal half of the urethra.

The response of segmental spinal reflex leading to pudendal nerve function involves several spinal cord segments. Afferent fibers involved in the reflex have both segmental and supraspinal routing. This dual routing explains the bimodal response of pudendal motor neurons when pudendal sensory nerves are stimulated, and it differs from stimulation of pelvic detrusor afferents.

The neurotransmitter at the periurethral skeletal neuromuscular junction is acetylcholine and the receptors are nicotinic type. The intimate adherence of the neuromuscular junction to the striated muscle fibers conveys a resistance to blockade by neuromuscular blocking agents.

Cortical and Subcortical Pathways

The brainstem’s importance in the lower urinary tract function has been known since 1921, when Barrington ablated this area in cats and produced permanent urinary retention. He demonstrated that the middle pons was the level in the brain at which the motor tone of the bladder arises. This region in the pons has been called the pontine micturition center or the M region by . Stimulation results in the decrease in urethral pressure and silence of pelvic floor electromyographic (EMG) signal, followed by a rise in detrusor pressure. Tracing studies reveal direct projections from the M region to the intermediolateral cell column of the sacral cord and the parasympathetic preganglionic bladder motor neurons. Other projections are to sacral cord interneurons that activate GABA inhibition of Onuf’s nucleus neurons, resulting in relaxation of urethral skeletal muscle. The detrusor motor nuclei in the pons receive input from basal ganglia and coordinating afferents from the cerebellum and the PAG. Recall that the PAG receives input from the distension receptors in the bladder via fibers ascending from Gert’s nucleus. The PAG then communicates with the M region to stimulate micturition. In addition to these important supraspinal tracts, there is evidence that spinal reflexes may also facilitate voiding. Electrical stimulation of urethral afferents can stimulate detrusor activity in spinal cord patients. This reflex has been postulated to augment bladder emptying by being activated when urine enters the urethra.

Brainstem neurotransmitters include substance P, GABA, and serotonin, which is produced from tryptophan. Stimulation of the same level of the pons at a more lateral position, the L region, results in contraction of the urethral sphincter by fibers in Onuf’s nucleus. Direct cortical relay to the L region gives voluntary micturition control. These brainstem activities, which are important for continence (L region) and micturition (M region) in adults, are replaced by reemerging pathologic primitive reflexes in disease states. Most important in this respect is the C-fiber–mediated reflex that emerges following disconnection from pontine regulatory influences as a consequence of spinal cord disease. These effects are mediated by sensory neurotransmitters that are prompted to appear by nerve growth factors, as shown by , and that are alleviated by intravesical capsaicinoids. Similar development of C-fiber–afferentation is seen with bladder outlet obstruction and with bladder inflammatory states. In addition, with spinal cord injury it appears that the C fibers become sensitized to mechanical distension, a role reserved for Aδ fibers in the normal bladder. This leads to further activation of primitive, ineffective voiding reflexes, which are further modulated by TRP channels acting on the sensory side.

The basal ganglia are associated with the production of dopamine, one of the catecholamine neurotransmitters that is largely inhibitory to bladder activity. Seventy-five percent of patients with decreased dopamine resulting from Parkinson’s disease have slowness of movement, gait disturbance, and tremor; 45% to 75% have bladder overactivity. The vast majority of cell bodies of origin for serotonin are in the raphe nuclei. Serotonin acts to inhibit reflex bladder and pelvic nerve activity by suppressing afferent bladder information. The sympathetic autonomic nuclei and the sphincter motor nuclei also receive a serotonergic input from the raphe nucleus. Fibers from the raphe nuclei of the reticular formation may moderate responsiveness to different phases of the sleep–wake cycle or emotional states.

The locus ceruleus is the brainstem’s CNS container of norepinephrine cell bodies. Norepinephrine acts to tonically facilitate continence-related reflexes.

The hypothalamus and midbrain PAG are activated during micturition. The paraventricular nucleus of the hypothalamus has connections to the sacral parasympathetic nucleus (SPN) and the sphincter motor neurons. The anterior hypothalamus and PAG projects to the pons M region and can induce bladder contraction via pontine parasympathetic pathways. The posterior hypothalamus has sympathetic inhibitory pathways. The hypothalamus function, although poorly delineated, is known to involve β-endorphin neurotransmitters, the opioid peptides constituting an entire class of brain neurotransmitters. Interneurons in the lumbosacral cord project strongly to the PAG, which in turn projects to the pons M region, thus making the PAG an important component in bladder reflex activities.

Pudendal cortical pathways affect periurethral striated muscle innervation by direct descending paths originating in the central vertex of the pudendal cerebral cortical area and going to pudendal nuclei in the ventromedial portion of the ventral gray matter of the S1 to S3 cord segments. At this level, the pudendal motor nuclei act as described to affect lower urinary tract skeletal muscle activity.

Ascending axons from periurethral striated muscle go to the pudendal cortical area, possibly synapsing in the nucleus ventralis posterolateralis of the thalamus, the brain’s chief relay station.

Sensory afferents from both pudendal and detrusor pelvic nerves send input to the anterior vermis of the cerebellum, which then originates an axon relay to the cortex in the dentate nucleus. Fibers for both detrusor and pudendal proprioception and exteroception (pain, temperature, and touch) ascend in posterior columns and spinothalamic tracts, respectively.

Neurotransmitters involved in these pathways include acetylcholine and peptides, especially substance P and enkephalin. Neurotransmitter agents are stored in astrocytes, which may also regulate extracellular concentrations.

The limbic system in the temporal lobes exerts controls affecting all autonomic functions and is a favored site for epileptiform activity. Enkephalin is a notable neurotransmitter here as well as in the reticular formation. The cerebellum, where GABA is prominent along with standard neurotransmitters, regulates muscle tone and coordinates movement. Disease in this area produces spontaneous, high-amplitude detrusor overactivity.

The ACG and the prefrontal cortex have rich communications with the brainstem areas concerned with lower urinary tract function. The ACG shows increased activity with imaging studies during filling and voiding ( ). It projects heavily to the PAG, which in turn connects to the M-region in the pons. Depending on the area affected within the ACG, lesions may lead to bladder overactivity or urinary retention ( ). The prefrontal cortex is thought to play a major role in volitional voiding and deciding the social appropriateness of voiding. Lesions here lead to inappropriate bladder overactivity and voiding ( ).

Spinal Cord

By adolescence, disparity in growth of the spinal cord and the vertebral column leads to the cord’s terminating around the first lumbar vertebra. The adult conus medullaris is quite short and contains the entire S1 to S5 segment. Because the spinal cord terminates well above the respective segmental foramina, the cauda equina describes the terminal ventral and dorsal nerve roots as they travel through the spinal canal to exit. The cauda equina is subject to various spinal pathologies including lumbar disk disease, trauma, tethered cord, and spinal stenosis. Although the thoracolumbar levels are important in sympathetic autonomic influence of the lower urinary tract, the conus medullaris has greater significance because autonomic detrusor nuclei and pudendal somatic nuclei are housed in the intermediolateral and ventromedial anterior gray matter, respectively. The conus medullaris also houses neurons involved with defecation and sexual function, with relays for cortical separation of these visceral functions (encephalization) developing after birth.