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Functional: Neural Control of Storage and Voiding: Difference between revisions

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* Nature Reviews Neuroscience article on the [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2897743/ neural control of micturition]
* Nature Reviews Neuroscience article on the [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2897743/ neural control of micturition]
** See [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2897743/figure/F1/ Figure 1] for efferent innervation of urogenital tract
** See [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2897743/figure/F1/ Figure 1] for efferent innervation of urogenital tract
* '''Micturition involves innervation from (3):'''
* '''<span style="color:#ff0000">Micturition involves innervation from (3):</span>'''
*# '''Parasympathetic nervous system via the pelvic (S2-S4) nerve'''  
*# '''<span style="color:#ff0000">Parasympathetic nervous system via the pelvic (S2-S4) nerve</span>'''  
*# '''Sympathetic nervous system via the hypogastric (T11-L2) nerve'''
*# '''<span style="color:#ff0000">Sympathetic nervous system via the hypogastric (T11-L2) nerve</span>'''
*# '''Somatic nervous system via the pudendal (S2-S4) nerve'''
*# '''<span style="color:#ff0000">Somatic nervous system via the pudendal (S2-S4) nerve</span>'''
** '''The pelvic, hypogastric, and pudendal nerve are mixed nerves and carry efferent and afferent innervation'''
** '''<span style="color:#ff0000">The pelvic, hypogastric, and pudendal nerve are mixed nerves and carry efferent and afferent innervation</span>'''


=== Efferent innervation ===
=== Efferent innervation ===


==== Autonomic nervous system ====
==== Autonomic nervous system ====
* '''Parasympathetic'''
* '''<span style="color:#ff0000">Parasympathetic</span>'''
** '''Parasympathetic preganglionic neurons''' innervating the LUT are located in the lateral part of the sacral '''intermediate gray matter of the S2-S4 spinal cord in a region called the sacral parasympathetic nucleus'''
** '''Parasympathetic preganglionic neurons''' innervating the LUT are located in the lateral part of the sacral '''intermediate gray matter of the S2-S4 spinal cord in a region called the sacral parasympathetic nucleus'''
** Parasympathetic preganglionic neurons send axons through the ventral roots to peripheral ganglia, where they release the excitatory transmitter Ach.
** Parasympathetic preganglionic neurons send axons through the ventral roots to peripheral ganglia, where they release the excitatory transmitter Ach.
** '''Parasympathetic postganglionic neurons are located in the detrusor wall layer as well as in the pelvic plexus'''
** '''Parasympathetic postganglionic neurons are located in the detrusor wall layer as well as in the pelvic plexus'''
** '''Patients with cauda equina or pelvic plexus injury are neurologically decentralized but may not be completely denervated'''. Cauda equina injury allows possible afferent and efferent neuron interconnection at the level of the intramural ganglia.
** '''Patients with cauda equina or pelvic plexus injury are neurologically decentralized but may not be completely denervated'''. Cauda equina injury allows possible afferent and efferent neuron interconnection at the level of the intramural ganglia.
** '''Activation contributes to voiding by (2):'''
** '''<span style="color:#ff0000">Activation contributes to voiding by (2):</span>'''
**# '''Excitation (contraction) of the bladder'''
**# '''<span style="color:#ff0000">Excitation (contraction) of the bladder</span>'''
**# '''Inhibition (relaxation) of the urethra''' [not the bladder base]
**# '''<span style="color:#ff0000">Inhibition (relaxation) of the urethra</span>''' [not the bladder base]
* '''Sympathetic'''
* '''<span style="color:#ff0000">Sympathetic</span>'''
** '''Arises from the T11-L2 level of the spinal cord'''
** '''<span style="color:#ff0000">Arises from the T11-L2 level of the spinal cord</span>'''
*** Sympathetic outflow from the rostral (anterior) lumbar spinal cord provides a noradrenergic excitatory and inhibitory input to the bladder and urethra
*** Sympathetic outflow from the rostral (anterior) lumbar spinal cord provides a noradrenergic excitatory and inhibitory input to the bladder and urethra
*** '''The peripheral sympathetic pathways follow a complex route''' that pass through the sympathetic chain ganglia to the inferior mesenteric ganglia and '''then through the hypogastric nerves to the pelvic ganglia'''
*** '''The peripheral sympathetic pathways follow a complex route''' that pass through the sympathetic chain ganglia to the inferior mesenteric ganglia and '''then through the hypogastric nerves to the pelvic ganglia'''
** '''Activation contributes to urine storage by (3):'''
** '''<span style="color:#ff0000">Activation contributes to urine storage by (3):</span>'''
**# '''Inhibition (relaxation) of the bladder'''
**# '''<span style="color:#ff0000">Inhibition (relaxation) of the bladder</span>'''
**# '''Excitation (contraction) of the bladder base'''
**# '''<span style="color:#ff0000">Excitation (contraction) of the bladder base</span>'''
**# '''Excitation (contraction) of the urethra'''
**# '''<span style="color:#ff0000">Excitation (contraction) of the urethra</span>'''
** '''Animal studies have shown that sympathetic postganglionic fibers release noradrenaline (NA) and contribute to bladder relaxation during storage (via stimulation of β-adrenergic receptors expressed in detrusor)'''
** '''Animal studies have shown that sympathetic postganglionic fibers release noradrenaline (NA) and contribute to bladder relaxation during storage (via stimulation of β-adrenergic receptors expressed in detrusor)'''


==== Somatic nervous system ====
==== Somatic nervous system ====
* '''The pudendal nerve arises from the S2-S4 level of the spinal cord'''
* '''<span style="color:#ff0000">The pudendal nerve arises from the S2-S4 level of the spinal cord</span>'''
** '''The motorneurons of the EUS are located along the lateral border of the ventral horn, commonly referred to as the Onuf nucleus'''
** '''<span style="color:#ff0000">The motorneurons of the EUS are located along the lateral border of the ventral horn, commonly referred to as the Onuf nucleus</span>'''
* '''Activation contributes to urine storage by (1):'''
* '''<span style="color:#ff0000">Activation contributes to urine storage by (1):</span>'''
*# '''Excitation (contraction) of the EUS'''
*# '''<span style="color:#ff0000">Excitation (contraction) of the EUS</span>'''


=== Afferent innervation ===
=== Afferent innervation ===
* '''The most important afferents for initiating and maintaining normal micturition are those in the pelvic nerve.'''
* '''<span style="color:#ff0000">Afferent input reaches the spinal cord from (3):</span>'''
** '''Most of the afferent input from the bladder and urethra reaches the spinal cord through the pelvic nerve and dorsal root ganglia, and some reaches the spinal cord through the hypogastric nerve.'''
*#'''<span style="color:#ff0000">Pelvic nerve (S2-S4)</span>'''
** '''Afferent input from the striated muscle of the sphincter and pelvic floor travels in the pudendal nerve.'''
*#'''<span style="color:#ff0000">Hypogastric nerve (T11-L2)</span>'''
*#'''<span style="color:#ff0000">Pudendal nerve (S2-S4)</span>'''
* '''The primary afferent neurons of the pelvic and pudendal nerves are contained in sacral dorsal root ganglia, whereas afferent innervation in the hypogastric nerves arises in the''' rostral '''lumbar dorsal root ganglia.'''
** The central axons of the dorsal root ganglia neurons carry the sensory information from the LUT to second-order neurons in the spinal cord. These second-order neurons provide the basis for spinal reflexes and ascending pathways to higher brain regions involved in micturition, continence, and mediation of sensation.
* '''<span style="color:#ff0000">Pelvic nerve afferents</span>'''
** '''<span style="color:#ff0000">Most important afferent for initiating and maintaining normal micturition</span>'''
**'''Consist of myelinated (Aδ) and unmyelinated (C) axons'''
** '''Monitor the volume of the bladder and the amplitude of the bladder contraction'''
**'''<span style="color:#ff0000">Provides most of the afferent input from the bladder and urethra</span>'''
*'''<span style="color:#ff0000">Hypogastric nerve afferents</span>'''
**'''<span style="color:#ff0000">Provides some of afferent input from the bladder and urethra</span>'''
*'''<span style="color:#ff0000">Pudendal nerve afferents</span>'''
**'''<span style="color:#ff0000">Provides afferent input from the striated muscle of the sphincter and pelvic floor</span>'''
* '''<span style="color:#ff0000">Bladder Afferent Properties</span>'''
 
{| class="wikitable"
!Fiber type
!Location
!Normal function
!Inflammation effect
|-
!Aδ (finely myelinated axons)
|Smooth muscle
|'''Sense bladder fullness''' (wall tension)
|Increase discharge at lower pressure threshold
|-
!C fiber (unmyelinated axons)
|Mucosa
|Respond to stretch (bladder volume sensors)
|Increase discharge at lower threshold
|-
!<span style="color:#ff0000">C fiber (unmyelinated axons)</span>
|Mucosa muscle
|'''<span style="color:#ff0000">Nociception</span>''' to overdistention; silent afferent
|Sensitive to irritants; become mechanosensitive and unmask new afferent pathway during inflammation
|}
 
* '''Decreased afferent sensitivity or excitability due to a number of conditions in addition to normal aging may be an important factor leading to impaired voiding;''' '''diabetes mellitus has been linked with impaired sensory function''' and increased residual urine
 
* '''Modulators of afferent sensitivity'''
** '''Nitric oxide (NO)'''
*** '''Major transmitter mediating relaxation/inhibition of the urethral smooth muscle during micturition'''
*** PDE5 terminates the action of NO, and PDE inhibitors can be used therapeutically to prolong the action of NO at a number of sites including the bladder, prostate, and blood vessels
*** '''Influences bladder afferent nerve activity'''
**** '''Data suggest that these agents may represent a target for treatment of hypersensitivity disorders of the bladder such as BPS/IC and OAB.'''
** '''Urothelium releases ATP in response to stretch''' and this acts in a paracrine fashion to influence the function of myofibroblasts and bladder afferent nerves.
** A number of different members of the transient receptor potential channel family are expressed in the bladder, mostly in association with sensory nerve fibers involved in mechanotransduction and in nociception.
** '''Unmyelinated C fibers signal inflammatory or noxious events in the bladder; during inflammation and possibly other pathologic conditions, there is recruitment of mechanosensitive C fibers that form a new functional afferent pathway. This is the rationale for intravesical C-fiber neurotoxin capsaicin and RTX therapy'''
** Cannabinoid receptors in the bladder may have a modulatory role in sensory afferent signaling.


== Supraspinal pathways ==
== Supraspinal pathways ==


* Midbrain–pontine–spinal cord circuits and reflexes control filling, storing and emptying of the bladder
* Midbrain–pontine–spinal cord circuits and reflexes control filling, storing and emptying of the bladder
* '''Pontine micturition center (PMC)'''
* '''<span style="color:#ff0000">Pontine micturition center (PMC)</span>'''
** '''Also known as Barrington nucleus''', Dorsal pontine tegmentum, M region
** '''Also known as Barrington nucleus''', Dorsal pontine tegmentum, M region
** '''Located in the pons'''
** '''Located in the pons'''
** '''The essential control center for micturition''' under normal conditions, '''integrating afferent input and ultimately responsible for initiating and coordinating the act of bladder emptying (inhibition of the urethral sphincter coordinated with detrusor contraction)'''
** '''The essential control center for micturition''' under normal conditions, '''<span style="color:#ff0000">integrating afferent input and ultimately responsible for initiating and coordinating the act of bladder emptying (inhibition of the urethral sphincter coordinated with detrusor contraction)</span>'''
** '''Within the PMC, glutamate is thought to be the primary neurotransmitter involved in stimulating preganglionic parasympathetic neurons responsible for detrusor contraction in the micturition pathway.'''
** '''Within the PMC, glutamate is thought to be the primary neurotransmitter involved in stimulating preganglionic parasympathetic neurons responsible for detrusor contraction in the micturition pathway.'''
** PMC neurons express corticotropin-releasing factor, which has an inhibitory influence micturition pathway.
** PMC neurons express corticotropin-releasing factor, which has an inhibitory influence micturition pathway.
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* See [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2897743/figure/F5/ Figure 5a] for storage reflex
* See [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2897743/figure/F5/ Figure 5a] for storage reflex
* '''Also known as “guarding reflex”, “spinal reflex”, “spinal reflex pathway”, “bladder sympathetic reflex”'''
* '''Also known as “guarding reflex”, “spinal reflex”, “spinal reflex pathway”, “bladder sympathetic reflex”'''
* '''Promotes continence'''
* '''<span style="color:#ff0000">Promotes continence</span>'''
** '''During the storage of urine, distention of the bladder produces low-level bladder afferent firing via Aδ-myelinated nerves'''
** '''During the storage of urine, distention of the bladder produces low-level bladder afferent firing via Aδ-myelinated nerves'''
** '''There is a gradual increase in proximal urethral pressure during bladder filling''', contributed to at least by the striated sphincteric element and perhaps by the smooth sphincteric element as well.
** '''There is a gradual increase in proximal urethral pressure during bladder filling''', contributed to at least by the striated sphincteric element and perhaps by the smooth sphincteric element as well.
** '''Afferent stimulation, in turn, results in efferent(2):'''
** '''<span style="color:#ff0000">Afferent stimulation, in turn, results in efferent(2):</span>'''
**# '''Sympathetic outflow resulting in'''
**# '''<span style="color:#ff0000">Sympathetic outflow resulting in</span>'''
**## '''Excitation (contraction) of bladder base and urethra'''
**## '''<span style="color:#ff0000">Excitation (contraction) of bladder base and urethra</span>'''
**## '''Inhibition (relaxation) of bladder'''
**## '''<span style="color:#ff0000">Inhibition (relaxation) of bladder</span>'''
**# '''Pudendal outflow to the EUS'''
**# '''<span style="color:#ff0000">Pudendal outflow to the EUS</span>'''
**#* The increase in urethral pressure seen during the filling/storage phase of micturition can be correlated with an increase in efferent pudendal nerve impulse frequency and gradual increase in striated sphincter activity.
**#* The increase in urethral pressure seen during the filling/storage phase of micturition can be correlated with an increase in efferent pudendal nerve impulse frequency and gradual increase in striated sphincter activity.
**# '''Note that the parasympathetic outflow is inactive'''
**# '''<span style="color:#ff0000">Note that the parasympathetic outflow is inactive'''


=== Voiding reflexes ===
=== Voiding reflexes ===
* See [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2897743/figure/F5/ Figure 5b] for voiding reflex
* See [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2897743/figure/F5/ Figure 5b] for voiding reflex
* '''Also known as “micturition reflex”, “spinobulbospinal reflex”'''
* '''Also known as “micturition reflex”, “spinobulbospinal reflex”'''
* '''Upon initiation of micturition, there is high-level afferent activity signaling wall tension, which activates the PMC'''
* '''<span style="color:#ff0000">Upon initiation of micturition, there is high-level afferent activity signaling wall tension, which activates the PMC</span>'''
* '''In response, the PMC:'''
* '''<span style="color:#ff0000">In response, the PMC:</span>'''
*# '''Inhibits the guarding reflex, thereby reducing sympathetic''' (resulting in inhibition (relaxation) of bladder base and urethra and excitation (contraction) of the detrusor muscle) '''and pudendal''' (resulting in inhibition (relaxation) of EUS) '''nerve outflow'''
*# '''<span style="color:#ff0000">Inhibits the guarding reflex, thereby reducing sympathetic</span>''' (resulting in inhibition (relaxation) of bladder base and urethra and excitation (contraction) of the detrusor muscle) '''<span style="color:#ff0000">and pudendal</span>''' (resulting in inhibition (relaxation) of EUS) '''<span style="color:#ff0000">nerve outflow</span>'''
*# '''Stimulates parasympathetic outflow resulting in (2):'''
*# '''<span style="color:#ff0000">Stimulates parasympathetic outflow resulting in (2):</span>'''
*## '''Excitation (contraction) of bladder'''
*## '''<span style="color:#ff0000">Excitation (contraction) of bladder</span>'''
*## '''Inhibition (relaxation) of [urethra]/'''internal sphincter smooth muscle
*## '''<span style="color:#ff0000">Inhibition (relaxation) of [urethra]/</span>'''internal sphincter smooth muscle
* '''Maintenance of the voiding reflex is through ascending afferent input from the spinal cord, which may pass through the periaqueductal gray matter (PAG) before reaching the PMC'''
* '''Maintenance of the voiding reflex is through ascending afferent input from the spinal cord, which may pass through the periaqueductal gray matter (PAG) before reaching the PMC'''
* Described as a spinobulbospinal reflex because of the ascending signal from afferent pelvic nerve stimulation, which passes through the periaqueductal gray matter in the bulbar region of the brain before reaching the pontine micturition center and descending to elicit parasympathetic contraction of the detrusor, and somatic relaxation via the pudendal nerve
* Described as a spinobulbospinal reflex because of the ascending signal from afferent pelvic nerve stimulation, which passes through the periaqueductal gray matter in the bulbar region of the brain before reaching the pontine micturition center and descending to elicit parasympathetic contraction of the detrusor, and somatic relaxation via the pudendal nerve
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* '''Relaxation of the urethral smooth muscle during micturition is mediated by activation of a parasympathetic pathway to the urethra that triggers the release of NO, an inhibitory transmitter, and by removal of excitatory [sympathetic] inputs to the urethra.'''
* '''Relaxation of the urethral smooth muscle during micturition is mediated by activation of a parasympathetic pathway to the urethra that triggers the release of NO, an inhibitory transmitter, and by removal of excitatory [sympathetic] inputs to the urethra.'''
* '''Secondary reflexes elicited by flow of urine through the urethra facilitate bladder emptying'''
* '''Secondary reflexes elicited by flow of urine through the urethra facilitate bladder emptying'''
== Afferent innervation ==
* '''The primary afferent neurons of the pelvic and pudendal nerves are contained in sacral dorsal root ganglia, whereas afferent innervation in the hypogastric nerves arises in the''' rostral '''lumbar dorsal root ganglia.'''
** The central axons of the dorsal root ganglia neurons carry the sensory information from the LUT to second-order neurons in the spinal cord. These second-order neurons provide the basis for spinal reflexes and ascending pathways to higher brain regions involved in micturition, continence, and mediation of sensation.
* '''Pelvic nerve afferents'''
** '''Consist of myelinated (Aδ) and unmyelinated (C) axons'''
** '''Monitor the volume of the bladder and the amplitude of the bladder contraction'''
** '''Bladder Afferent Properties'''
{| class="wikitable"
!Fiber type
!Location
!Normal function
!Inflammation effect
|-
!Aδ (finely myelinated axons)
|Smooth muscle
|'''Sense bladder fullness''' (wall tension)
|Increase discharge at lower pressure threshold
|-
!C fiber (unmyelinated axons)
|Mucosa
|Respond to stretch (bladder volume sensors)
|Increase discharge at lower threshold
|-
!C fiber (unmyelinated axons)
|Mucosa muscle
|'''Nociception''' to overdistention; silent afferent
|Sensitive to irritants; become mechanosensitive and unmask new afferent pathway during inflammation
|}
* '''Decreased afferent sensitivity or excitability due to a number of conditions in addition to normal aging may be an important factor leading to impaired voiding;''' '''diabetes mellitus has been linked with impaired sensory function''' and increased residual urine
* '''Modulators of afferent sensitivity'''
** '''Nitric oxide (NO)'''
*** '''Major transmitter mediating relaxation/inhibition of the urethral smooth muscle during micturition'''
*** PDE5 terminates the action of NO, and PDE inhibitors can be used therapeutically to prolong the action of NO at a number of sites including the bladder, prostate, and blood vessels
*** '''Influences bladder afferent nerve activity'''
**** '''Data suggest that these agents may represent a target for treatment of hypersensitivity disorders of the bladder such as BPS/IC and OAB.'''
** '''Urothelium releases ATP in response to stretch''' and this acts in a paracrine fashion to influence the function of myofibroblasts and bladder afferent nerves.
** A number of different members of the transient receptor potential channel family are expressed in the bladder, mostly in association with sensory nerve fibers involved in mechanotransduction and in nociception.
** '''Unmyelinated C fibers signal inflammatory or noxious events in the bladder; during inflammation and possibly other pathologic conditions, there is recruitment of mechanosensitive C fibers that form a new functional afferent pathway. This is the rationale for intravesical C-fiber neurotoxin capsaicin and RTX therapy'''
** Cannabinoid receptors in the bladder may have a modulatory role in sensory afferent signaling.


== Spinal ascending and descending influences ==
== Spinal ascending and descending influences ==
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** In a healthy individual, ice-water in the bladder would elicit no response.
** In a healthy individual, ice-water in the bladder would elicit no response.
** In a bladder responsive to C fiber-mediated spinal reflexes, patients cannot retain the ice-water.
** In a bladder responsive to C fiber-mediated spinal reflexes, patients cannot retain the ice-water.
== Aging-related changes to micturition ==
# '''Decreased afferent activity (bladder sensation''')
# '''Decreased efferent activity'''
# '''Decreased detrusor contractility'''
# '''Decreased urethral pressure'''


== Questions ==
== Questions ==
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