Sacral Parasympathetic Pathways

The sacral parasympathetic nerves, which in humans originate from the S2 to S4 segments of the spinal cord, provide most excitatory input to the bladder. Cholinergic preganglionic neurons located in the intermediolateral region of the sacral spinal cord send axons to ganglionic cells in the pelvic plexus and the bladder wall (see Fig. 3-1). Transmission in bladder ganglia is mediated by a nicotinic cholinergic mechanism. In some species (e.g., cats, rabbits) ganglionic synapses act like gating circuits, exhibiting marked facilitation during repetitive preganglionic activity and modulation by various transmitter systems, including muscarinic, adrenergic, purinergic, and enkephalinergic (Table 3-1).^6,7 The ganglia can have an important role in regulating neural input to the bladder. Whether bladder ganglia in humans have similar properties is not known. Ganglion cells excite the bladder smooth muscle. Histochemical studies of the ganglia and nerves supplying the human lower urinary tract have shown that many ganglion cells contain choline acetyltransferase, acetylcholinesterase, and the vesicular acetylcholine transporter and therefore are cholinergic. Choline acetyltransferase–, acetylcholinesterase-, and acetylcholine transporter– positive nerves are abundant in all parts of the bladder but are less extensive in the urethra.^1,2,5 Neuropeptide Y and nitric oxide synthase also have been identified in 40% to 95% of intramural ganglia of the human bladder. Several populations of axonal varicosities have been detected close to intramural ganglion cells, including substance P–, vasoactive intestinal polypeptide (VIP)–, and calcitonin gene–related peptide (CGRP)–positive axons, which are presumably collaterals of extrinsic sensory nerves; tyrosine hydroxylase and neuropeptide Y axons, which are likely to be sympathetic axons; and galanin- and neuropeptide Y–containing axons.

Table 3-1 Receptors for Putative Transmitters in the Lower Urinary Tract

Parasympathetic neuroeffector transmission in the bladder is mediated by acetylcholine acting on postjunctional muscarinic receptors.^8–11 M₂ and M₃ muscarinic receptors subtypes are expressed in bladder smooth muscle; however, examination of subtype-selective muscarinic receptor antagonists and studies of muscarinic receptor–knockout mice have revealed that the M₃ subtype is the principal receptor involved in excitatory transmission.^8–11 Activation of M₃ receptors triggers intracellular Ca²⁺ release, whereas activation of M₂ receptors inhibits adenylate cyclase.¹⁰ The latter may contribute to bladder contractions by suppressing adrenergic inhibitory mechanisms that are mediated by β₃-adrenergic receptors and stimulation of adenylate cyclase.

In bladders of various animals, stimulation of parasympathetic nerves produces a noncholinergic contraction that is resistant to atropine and other muscarinic receptor–blocking agents. Adenosine triphosphate (ATP) (see Table 3-1) has been identified as the excitatory transmitter mediating the noncholinergic contractions.^10–13 ATP excites the bladder smooth muscle by acting on P2X receptors, which are ligand-gated ion channels. Among the seven types of P2X receptors that have been identified in the bladder, P2X₁ is the major subtype expressed in the rat and in human bladder smooth muscle.^12,13 Purinergic agonists also modulate transmission in bladder ganglia.^6,14,15 Although purinergic excitatory transmission is not important in the normal human bladder, it appears to be involved in bladders from patients with pathologic conditions such as detrusor overactivity, chronic urethral outlet obstruction, or interstitial cystitis.^12,16,17

Parasympathetic pathways to the urethra induce relaxation during voiding.^{1,10,11,18–20} In various species, the relaxation is not affected by muscarinic antagonists and therefore is not mediated by acetylcholine. However, inhibitors of nitric oxide synthase block the relaxation in vivo during reflex voiding or block the relaxation of urethral smooth muscle strips induced in vitro by electrical stimulation of intramural nerves, indicating that nitric oxide is the inhibitory transmitter involved in relaxation.^1,2,11,18,19 In some species, neurally evoked contractions of the urethra are reduced by muscarinic receptor antagonists or by desensitization of P2X purinergic receptors, indicating that acetylcholine or ATP are involved in excitatory transmission to urethral smooth muscle.²¹

Thoracolumbar Sympathetic Pathways

Sympathetic preganglionic pathways that arise from the T11 to L2 spinal segments pass to the sympathetic chain ganglia and then to prevertebral ganglia in the superior hypogastric and pelvic plexus and to short adrenergic neurons in the bladder and urethra. Sympathetic postganglionic nerves that release norepinephrine provide excitatory input to smooth muscle of the urethra and bladder base, inhibitory input to smooth muscle in the body of the bladder, and inhibitory and facilitatory input to vesical parasympathetic ganglia.^1,7,11 Radioligand receptor binding studies showed that α-adrenergic receptors are concentrated in the bladder base and proximal urethra, whereas β-adrenergic receptors are most prominent in the bladder body.^1,10 These observations are consistent with pharmacologic studies showing that sympathetic nerve stimulation or exogenous catecholamines produce β-adrenergic receptor–mediated inhibition of the body and α-adrenergic receptor–mediated contraction of the base, dome, and urethra. Molecular and contractility studies have shown that β₃-adrenergic receptors elicit inhibition and α₁-adrenergic receptors elicit contractions in the human bladder.¹⁰ The α_1A-adrenergic receptor subtype is most prominent in the normal bladders, but the α_1D-adrenergic receptor subtype is upregulated in bladders from patients with outlet obstruction, raising the possibility that α₁-adrenergic receptor excitatory mechanisms in the bladder may contribute to irritative lower urinary tract symptoms in patients with benign prostatic hyperplasia.¹⁰

Sacral Somatic Pathways

Somatic efferent pathways to the external urethral sphincter are carried in the pudendal nerve from anterior horn cells in the third and fourth sacral segments. Branches of the pudendal nerve and other sacral somatic nerves also carry efferent impulses to muscles of the pelvic floor and proprioceptive afferent signals from these muscles, as well as sensory information from the urethra.^2,22–24 Analysis of urethral closure mechanisms in the female rat during bladder distention or sneeze-induced stress conditions revealed that the major rise in urethral pressure occurred in the middle urethra and was mediated by efferent pathways in the pudendal nerve to the external urethral sphincter and by pathways in nerves to the iliococcygeus and pubococcygeus muscles, although not by pathways in the sympathetic or parasympathetic nerves.²⁵

Neural Modulation

Postganglionic nerve terminals are sites of “cross-talk” between sympathetic and parasympathetic nerves and possible sites of gating mechanisms.^26–30 For example, in the rat lower urinary tract, activation of M₂/₄ (muscarinic) cholinergic receptors on nerve terminals suppresses acetylcholine and norepinephrine release,³⁰ whereas activation of M₁ cholinergic receptors or α₁-adrenergic receptors enhances acetylcholine release (see Table 3-1).^26–29 Inhibitory M₂/₄ mechanisms are dominant at low frequencies of nerve activity and therefore may contribute to urine storage, whereas M₁ facilitatory mechanisms are dominant at high frequencies of nerve stimulation and may contribute to an enhancement of neurally evoked bladder contractions during micturition to induce complete bladder emptying.

Other putative transmitters that have been identified in efferent pathways to the lower urinary tract of animals and humans may modulate neuroeffector transmission (see Table 3-1).^3,31,32 Neuropeptide Y is present in adrenergic and cholinergic neurons,³² and when administered exogenously, it acts prejunctionally to suppress the release of norepinephrine and acetylcholine from postganglionic nerve terminals.²¹ Although nitric oxide relaxes smooth muscle in the urethra, it is inactive in bladder smooth muscle.¹⁰ However, in the bladder, it may act on afferent nerves to modulate excitability.^10,31 VIP, which is released with acetylcholine, may function as an inhibitory transmitter in the bladder.¹⁰ Efferent control of the bladder and urethra is potentially complex and involves many transmitters and many synaptic gating mechanisms in ganglia and at postganglionic nerve terminals.

Lumbosacral Afferent Pathways

Afferent activity arising in the bladder is transmitted to the central nervous system by both sets of autonomic nerves.^2,33–37 The afferent nerves most important for initiating micturition are those passing in the pelvic nerves to the sacral spinal cord. These afferents consist of small, myelinated (A) and unmyelinated (C) fibers that convey impulses from tension receptors and nociceptors, respectively, in the bladder wall.^2,3,36 Electrophysiologic studies in the cat have shown that A bladder afferents respond in a graded manner to passive distention and to active contraction of the bladder.^35–37 The intravesical pressure threshold for activation of these afferents ranges from 5 to 15 mm Hg, which is consistent with pressures at which humans report the first sensation of bladder filling during cystometry. The A afferents in the cat show a linear increase in firing with increasing intravesical pressures that extend into the noxious range, suggesting that nociceptive stimuli in the bladder may be encoded in part by high rates of firing in polymodal afferents that also transmit non-noxious information.

High-threshold C-fiber afferents have also been detected in the cat bladder.³⁴ Under normal conditions, most of these afferents do not respond to bladder distention and therefore have been designated silent C fibers, but many can be activated by chemical irritation of the bladder mucosa^3,34 or cold temperatures (Fig. 3-2).³⁸ After chemical irritation, C-fiber afferents exhibit spontaneous firing with the bladder empty and increased firing during bladder distention.³⁴ Activation of C-fiber afferents by chemical irritation facilitates the micturition reflex and decreases bladder capacity.^2,3,39–41 Administration of capsaicin, a neurotoxin that desensitizes C-fiber afferents, blocks this facilitation but does not block micturition reflexes in normal animals, indicating that C-fiber afferent pathways are not essential for normal voiding.^2,42,43

Figure 3-2 The diagram shows the receptors in the urothelium and in sensory nerve endings in the bladder mucosa and the putative chemical mediators that are released by the urothelium, nerves, or smooth muscle that can modulate the excitability of sensory nerves. Urothelial cells and sensory nerves express common receptors (i.e., P2X, TRPV1, and TRPM8). Distention of the bladder activates stretch receptors and triggers the release of urothelial transmitters such as adenosine triphosphate (ATP), acetylcholine (ACh), and nitric oxide (NO) that may interact with adjacent nerves. Receptors in afferent nerves or the urothelium can respond to changes in pH, osmolality, high potassium ion (K⁺) concentration, chemicals in the urine, or inflammatory mediators released in the bladder wall. Neuropeptides (e.g., neurokinin A) released from sensory nerves in response to distention or chemical stimulation can act on NK-2 autoreceptors to sensitize the mechanosensitive nerve endings. The smooth muscle can generate a force that may influence some mucosal endings. Nerve growth factor released from muscle or urothelium can exert an acute and chronic influence on the excitability of sensory nerves though an action on tyrosine kinase A (Trk-A) receptors. MAChR, muscarinic acetylcholine receptor; TRPM8, menthol/cold receptor; TRPV1, transient receptor potential vanilloid receptor 1, sensitive to capsaicin.

In the rat, A-fiber and C-fiber bladder afferents are not distinguishable on the basis of stimulus modality; both types of afferents consist of mechanosensitive and chemosensitive populations.^44–47 C-fiber afferents that respond only to bladder filling have also been identified in the rat bladder and appear to be volume receptors possibly sensitive to stretch of the mucosa.^2,44 C-fiber afferents are sensitive to the neurotoxins capsaicin and resiniferatoxin and to other substances, such as tachykinins, nitric oxide, ATP, prostaglandins, and neurotrophic factors, released in the bladder by afferent nerves, urothelial cells, and inflammatory cells (see Fig. 3-2).^{2,3,41,45,48–54} These substances can sensitize the afferent nerves and change their response to mechanical stimuli.

Mechanosensitive afferents from the bladder and urethra have been identified in sympathetic nerves passing to the lumbar spinal cord.⁵⁵ These afferent pathways consist of myelinated and unmyelinated axons that respond to similar stimulus modalities as afferents in the pelvic nerve. The function of sympathetic nerve afferents in the control of micturition is uncertain; however, based on clinical observations, it is clear that in humans they carry nociceptive information from the lower urinary tract.

Afferent pathways from the urethra, which induce the sensations of temperature, pain, and passage of urine, travel in the pudendal nerve to the lumbosacral spinal cord.^2,3 Afferents from the female sex organs, including the clitoris, vagina, and part of the innervation of the uterine cervix, also travel in the pudendal nerve.^56,57 These afferents and pudendal nerve afferents from the striated sphincter muscles have a modulatory influence on micturition.^3,24

The properties of lumbosacral dorsal root ganglion cells innervating the bladder, urethra, and external urethral sphincter in the rat have been studied with patch-clamp recording techniques in combination with axonal tracing methods to identify the different populations of neurons.^58–65 Based on responsiveness to capsaicin, it is estimated that approximately 70% of bladder afferent neurons in the rat are the C-fiber type. These neurons exhibit high-threshold, tetrodotoxin-resistant sodium channels and action potentials and phasic firing (one to two spikes) in response to prolonged depolarizing current pulses.^58,60,61 Approximately 90% of the bladder C-fiber afferent neurons also are excited by ATP, which induces depolarization and firing of afferent neurons by activating P2X₃ or P2X_2/3 receptors.⁶⁵ These neurons express isolectin-B4 binding, which is commonly used as a marker for ATP-responsive sensory neurons.⁶⁰ A-fiber afferent neurons are resistant to capsaicin and ATP and exhibit low-threshold, tetrodotoxin-sensitive sodium channels and action potentials and tonic firing (multiple spikes) to depolarizing current pulses. C-fiber bladder afferent neurons also express a slowly decaying A-type K⁺ channel that controls spike threshold and firing frequency.^58,62 Suppression of this K⁺ channel induces hyperexcitability of bladder afferent nerves.⁵⁸ These properties of dorsal root ganglion cells are consistent with the different properties of A-fiber and C-fiber afferent receptors in the bladder.

Immunohistochemical studies have shown that a large percentage of bladder afferent neurons contain peptides: CGRP, VIP, substance P, pituitary adenylate cyclase-activating polypeptide (PACAP), corticotropin-releasing factor (CRF), and enkephalins.^66,67 In the bladder, these peptides are common in nerves in the submucosal and subepithelial layers and around blood vessels. The neurotoxin capsaicin, when applied locally to the bladder in experimental animals, releases peptides from peripheral afferent terminals and produces inflammatory responses, including plasma extravasation and vasodilatation.⁴¹ Afferent peptides can also modulate transmission in bladder ganglia.⁶ These findings suggest that the neuropeptides may be important neurotransmitters in afferent pathways in the lower urinary tract.

Efferent Neurons

Preganglionic neurons in the lumbosacral parasympathetic nucleus have been identified in the intermediolateral region of the spinal cord in several species.^3,97 In the cat, the sacral parasympathetic nucleus is divided into two groups of cells: a dorsal band and a lateral band. Neurons innervating the urinary bladder are located in the lateral band. These neurons have an extensive network of axon collaterals⁹⁸ that is involved in a recurrent inhibitory mechanism⁹⁹ that regulates reflex bladder activity. The neurons send dendrites to discrete regions of the spinal cord, including the lateral and dorsal lateral funiculus, lamina I on the lateral edge of the dorsal horn, the dorsal gray commissure, and the gray matter and lateral funiculus ventral to the autonomic nucleus (Fig. 3-3).⁹⁷ It has been suggested that the dendrites in the lateral funiculus receive inputs from descending pathways from the brain, whereas the other dendrites receive segmental inputs from interneurons or primary afferents. Lumbar sympathetic preganglionic neurons and motor neurons in Onuf’s nucleus that innervate the external urethral sphincter have similar dendritic distributions (see Fig. 3-3).^100–102

Figure 3-3 Neural connections between the brain and the sacral spinal cord that may be involved in the regulation of the lower urinary tract in the cat. Lower section of the spinal cord shows the location and morphology of a preganglionic neuron in the sacral parasympathetic nucleus (SPN), a sphincter motoneuron in Onuf’s nucleus (ON), and the sites of central termination of afferent projections from the urinary bladder. Upper section of the spinal cord shows the sites of termination of descending pathways arising in the pontine micturition center (medial), the pontine sphincter or urine storage center (lateral), and the paraventricular nuclei of the hypothalamus. Section through the pons shows the projection for anterior hypothalamic nuclei to the pontine micturition center.

(From de Groat WC: Neural control of urinary bladder and sexual organs. In Bannister R, Mathias, CJ [eds]: Autonomic Failure, 3rd ed. Oxford, Oxford University Press, 1992, p 129.)

Afferent Projections

Afferent pathways from the lower urinary tract project to discrete regions of the dorsal horn that contain the soma or dendrites of efferent neurons innervating the lower urinary tract. Pelvic nerve afferent pathways from the urinary bladder of the cat^103,104 and the rat¹⁰⁵ project into Lissauer’s tract at the apex of the dorsal horn and then pass rostrocaudally, giving off collaterals that extend laterally and medially through the superficial layer of the dorsal horn (lamina I) into the deeper layers (laminae V to VII and X) at the base of the dorsal horn (Fig. 3-4A and see Fig. 3-3). The lateral pathway, which is the most prominent projection, terminates in the region of the sacral parasympathetic nucleus and also sends some axons to the dorsal commissure (see Figs. 3-3 and 3-4A).

Figure 3-4 The distribution of bladder afferent projections to the L6 spinal cord of the rat (A) is shown, with the distribution of Fos-positive cells in the L6 spinal segment after chemical irritation of the lower urinary tract of the rat (B) and the distribution of interneurons in the L6 spinal cord labeled by transneuronal transport of pseudorabies virus injected into the urinary bladder (C). Afferents labeled by lectin wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) injected into the urinary bladder. Fos immunoreactivity is present in the nuclei of cells. CC central canal; DH, dorsal horn; SPN, sacral parasympathetic nucleus. D, Laminar organization of the cat spinal cord.

Pudendal nerve afferent pathways from the external urethral sphincter of the cat have central terminations that overlap in part with those of bladder afferents in lateral laminae, I, V to VII, and X.^100,101 Afferents from the female sexual organs also terminate in these areas.^56,57 The overlap of the central projections of bladder afferents and the afferents in the pudendal nerve to the sex organs and urethra is of interest, because activation of the latter afferents can markedly influence bladder function.^106–109

Spinal Interneurons

The spinal neurons involved in processing afferent input from the lower urinary tract and the sex organs have been identified by physiologic and anatomic tracing techniques.^110–115 Interneurons that fire in response to bladder distention or mechanical stimulation of the vagina or uterine cervix have been detected in lateral intermediate gray matter near the sacral parasympathetic nucleus and in the region of the dorsal commissure (lamina X).^2,108 Commonly, stimulation of sex organ afferents inhibits neurons activated by bladder distention, which is consistent with the inhibitory effect of these afferents on bladder reflexes.^108,109

Spinal interneurons have also been identified by the expression of the immediate-early gene FOS (see Fig. 3-4B)^110–112 and by transneuronal transport of pseudorabies virus from the bladder (see Fig. 3-4C).^40,113–115 The protein product of the FOS gene can be detected immunocytochemically in the nuclei of neurons within 30 to 60 minutes after synaptic activation. In the rat, noxious or non-noxious stimulation of the bladder and urethra and electrical stimulation of the pelvic or pudendal nerves increased the levels of FOS protein, primarily in the dorsal commissure and in the area of the sacral parasympathetic nucleus (see Fig. 3-4B), the major sites of termination of afferents from the lower urinary tract. Neurons in these same regions are labeled by the pseudorabies virus (see Fig. 3-4C), which passes transsynaptically in a sequential manner from postganglionic to pregang-lionic efferent neurons and then to segmental interneurons and eventually to neurons in the brain (Fig. 3-5) (discussed later).^113–115 Interneurons in the dorsal commissure region also project to the sphincter motor nucleus.^116,117 These results indicate that interneurons in restricted regions of the intermediate gray matter and dorsal commissure play a major role in coordinating the different aspects of lower urinary tract function.

Figure 3-5 Structures in the brain and spinal cord of the adult and neonatal rat were labeled after injection of pseudorabies virus into the urinary bladder or the urethra. Virus is transported transneuronally in a retrograde direction (dashed arrows). Normal synaptic connections are indicated by solid arrows. At long survival times, the virus can be detected in neurons at specific sites in the spinal cord and brain, extending to the pontine micturition center in the pons (i.e., Barrington’s nucleus) and to the cerebral cortex. Other sites in the brain labeled by the virus are the paraventricular nucleus (PVN), medial preoptic area (MPOA), and periventricular nucleus (Peri.V.N.) of the hypothalamus; periaqueductal gray (PAG); locus ceruleus (LC) and subceruleus; red nucleus (Red N.); medullary raphe nuclei; and the noradrenergic cell group (A5).

Patch-clamp recordings from parasympathetic preganglionic neurons in the rat spinal slice preparations have revealed that interneurons located immediately dorsal and medial to the parasympathetic nucleus make direct monosynaptic connections with the preganglionic neurons (PGNs).^118–120 Microstimulation of interneurons in both locations elicits glutamatergic, N-methyl-D-aspartic acid (NMDA), and non-NMDA excitatory postsynaptic currents in PGNs. Stimulation of a subpopulation of medial interneurons elicits GABAergic and glycinergic inhibitory postsynaptic currents.¹¹⁸ In this way, local interneurons likely play an important role in excitatory and inhibitory reflex pathways controlling the preganglionic outflow to the lower urinary tract. Glutamatergic excitatory inputs have also been elicited by stimulation of the projections from lamina X and the lateral funiculus.^121,122

Pathways in the Brain

The neurons in the brain that control the lower urinary tract have been studied with a variety of anatomic tracing techniques in several species. In the rat, transneuronal virus tracing methods^113–115 have identified many populations of central neurons that are involved in the control of the bladder, urethra, and urethral sphincter, including the Barrington nucleus, the pontine micturition center (PMC); the medullary raphe nucleus, which contains serotonergic neurons; the locus ceruleus, which contains noradrenergic neurons; the periaqueductal gray (PAG); and the A5 noradrenergic cell group (see Fig. 3-5). Several regions in the hypothalamus and the cerebral cortex also exhibited virus-infected cells. Neurons in the cortex were located primarily in the medial frontal cortex.

Other anatomic studies in which anterograde tracer substances were injected into brain areas and then identified in terminals in the spinal cord are consistent with the virus-tracing data. Tracer injected into the paraventricular nucleus of the hypothalamus labeled terminals in the sacral parasympathetic nucleus and the sphincter motor nucleus (see Fig. 3-3).^123–125 Neurons in the anterior hypothalamus project to the PMC, and neurons in the PMC project primarily to the sacral parasympathetic nucleus and the lateral edge of the dorsal horn and the dorsal commissure, areas containing dendritic projections from the preganglionic neurons, sphincter motoneurons, and afferent inputs from the bladder. Conversely, projections from neurons in the lateral pons terminate rather selectively in the sphincter motor nucleus (i.e., Onuf’s nucleus) (see Fig. 3-3).¹²⁵ The sites of termination of descending projections from the PMC are optimally located to regulate reflex mechanisms at the spinal level.

Storage Reflexes

Somatic Efferent Pathways to the Urethral Sphincter

Reflex control of the striated urethral sphincter is similar to control of sympathetic pathways to the lower urinary tract (see Fig. 3-6A). During bladder filling, pudendal motor neurons are activated by vesical afferent input, whereas during micturition, motor neurons are reciprocally inhibited. Inhibition depends in part on supraspinal mechanisms, because in animals with chronic spinal lesions and in paraplegic patients, it is weak or absent. In paraplegics, the uninhibited spinal vesicosphincter excitatory reflex pathway commonly initiates a striated sphincter contraction in concert with a contraction of the bladder (i.e., bladder-sphincter dyssynergia) (see Fig. 3-7C). This reflex interferes with bladder emptying.

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related posts:

DEVELOPMENTAL ANATOMY AND UROGENITAL ABNORMALITIES USE OF CADAVERIC FASCIA FOR PUBOVAGINAL SLINGS ANTERIOR COLPORRHAPHY FOR CYSTOCELE REPAIR TRANSVAGINAL CLOSURE OF THE BLADDER NECK IN THE TREATMENT OF URINARY INCONTINENCE FEMALE SEXUAL FUNCTION AND DYSFUNCTION FUNCTIONAL ANATOMY AND PATHOPHYSIOLOGY OF PELVIC ORGAN PROLAPSE

Stay updated, free articles. Join our Telegram channel

Join