The contribution of capsaicin-sensitive innervation to activation of the spinal vesico-vesical reflex in rats: relationship between substance P levels in the urinary bladder and the sensory-efferent function of capsaicin-sensitive sensory neurons

doi:10.1016/0006-8993(87)90263-0

Brain Research

Volume 415, Issue 1, 7 July 1987, Pages 1-13

https://doi.org/10.1016/0006-8993(87)90263-0 Get rights and content

Abstract

In acute spinal rats (C₂–C₃) the transvesical infusion of saline activates a vesico-vesical excitatory reflex (Brain Res., 380 (1986) 83–93). In bladders containing a subthreshold amount of fluid the topical application of capsaicin on the outer surface of the bladder dome activated this spinal reflex and also produced a transient rise in blood pressure and heart rate. The effects of systemic capsaicin desensitization (50 mg/kg s.c. 5 min, 60 days before) on the sensory (activation of the spinal vesico-vesical reflex) and ‘efferent’ (tetrodotoxin-insensitive capsaicin-induced contraction) functions mediated by the capsaicin-sensitive sensory fibers were correlated to changes in substance P-like immunoreactivity (SP-LI) content of the urinary bladder in adult rats. Blockade of both sensory and efferent functions was observed at a time (60 min from capsaicin administration) when the SP-LI content of the urinary bladder was unaffected. Four days after capsaicin desensitization the SP-LI levels of the bladder are almost depleted indicating that the neuropeptide(s) are entirely stored in sensory structures. At this time the sensory-efferent functions mediated by these fibers are still blocked. At 15–60 days from systemic capsaicin desensitization there was a progressive, time-related recovery of SP-LI levels in the bladder as well as of the sensory-efferent functions. These findings indicate a role of the capsaicin-sensitive innervation of the urinary bladder in activating the spinal vesico-vesical reflex. The present findings suggest that measurement of SP-LI levels in the rat bladder may be a useful biochemical index for monitoring the function(s) of the capsaicin-sensitive, peptidergic sensory neurons.

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In the normal urinary bladder, tachykinins (TKs) are expressed in a population of bladder nociceptors that is sensitive to the excitatory and desensitizing effects of capsaicin (i.e., capsaicin-sensitive primary afferent neurons (CSPANs)). Several endobiotics or xenobiotics excite CSPANs and release TKs and other mediators at both the peripheral and spinal cord level. The peripheral release of TKs determines a set of responses (known as neurogenic inflammation) that includes vasodilatation, plasma protein extravasation, smooth muscle contraction and stimulation of afferent nerves. Following chronic inflammation, both immune cells and capsaicin-resistant sensory neurons can de novo express TKs: whether these pools of TKs are releasable and contribute to inflammatory processes is presently unsettled. At the spinal cord level, the release of TKs contributes in determining an altered pattern of vesicourethral reflexes in response to nociceptive stimulation of the bladder by conveying: (a) the afferent transmission to supraspinal sites, and (b) descending or sensory inputs to the sacral parasympathetic nucleus (SPN). Recent evidence also attribute a synergetic role of TKs in the supraspinal modulation of the sensory arm of the micturition reflex.
The overall available information suggests that TK receptor antagonists may affect bladder motility/reflexes which occur during different pathological states, while having little influence on the normal motor bladder function.
Peptide immunoreactivity and ultrastructure of rat urinary bladder nerve fibers after topical desensitization by capsaicin or resiniferatoxin
2000, Autonomic Neuroscience: Basic and Clinical
In the present study the decrease of neuropeptide containing nerve fibers and the increase in the volume threshold to reflex micturition occurring in the rat bladder after intravesical application of capsaicin or resiniferatoxin were compared. The ultrastructure of bladder terminal axons was evaluated at the moment of maximal peptide depletion and compared to that of nerve fibers after systemic capsaicin application. Adult Wistar rats were treated intravesically for 30 min with 0.5 ml of 100 nM RTX, 1 mM capsaicin or 30% ethanol in saline, the vehicle solution. Twenty-four hours and 1, 2, 3, 4 and 8 weeks later the bladders were immunostained for CGRP, SP, VIP and NPY. Cystomanometric studies were performed 24 h and 1, 8, and 12 weeks after vanilloid instillation. Twenty-four hours after systemic capsaicin or intravesical capsaicin or RTX, bladders were prepared for electron microscopic (EM) observation. Intravesical capsaicin or RTX decreased, in a similar way, the number of CGRP and SP-IR (immunoreactive) fibers coursing in the muscular layer and the mucosa. IR fibers amounted to less than 20% of controls at 24 h and returned to normal levels in the eighth week. At the EM level, bladders treated with topical vanilloids did not show morphological changes in terminal axons coursing in the mucosa. In contrast, bladders from animals treated systemically with capsaicin contained numerous grossly degenerated nerve fibers. VIP and NPY-IR fibers were not affected by the treatment. Cystometrograms showed an increase of the volume threshold to reflex micturition that started at 24 h and disappeared at 12 weeks. We conclude that intravesical capsaicin or RTX were equally effective in terms of reducing the number of SP and CGRP-IR fibers and increasing the volume threshold for reflex micturition. Both changes were transient and were not associated with ultrastructural changes of the bladder nerve fibers, excluding terminal axon degeneration as the main mechanism of action of intravesical vanilloids.
Nicotinic acetylcholine receptors in the autonomic control of bladder function
2000, European Journal of Pharmacology
Micturition is achieved through complex neurological mechanisms involving somatic, autonomic and central components. This article briefly reviews recent findings on the autonomic control of urinary bladder function. Neuronal nicotinic acetylcholine receptors mediate fast synaptic transmission in autonomic ganglia, and activation of nicotinic receptors in parasympathetic bladder neurons produces contraction of the destrusor muscle. Autonomic ganglia contain transcripts for the α₃, α₄, α₅, α₇, β₂ and β₄ nicotinic subunits, which can assemble to form multiple nicotinic receptor subtypes, but the exact nicotinic receptor subunit composition in bladder ganglia is unknown. Mutant mice lacking the α₃ or the β₂ and the β₄ nicotinic subunits have enlarged bladders with dribbling urination and develop urinary infection and bladder stones. Bladder strips from α₃ null mice do not respond to nicotine but contract when stimulated with a muscarinic agonist or electric field stimulation. Mice lacking the β₂ subunit have no overt bladder phenotype, and their bladders contract in response to nicotine. Surprisingly, bladder strips from β₄ mutant mice do not respond to nicotine despite the absence of major bladder dysfunction in vivo. These findings suggest that nicotinic receptors containing the α₃ and the β₄ subunits are necessary for normal bladder function.
Effects of systemic resiniferatoxin treatment on substance P mRNA in rat dorsal root ganglia and substance P receptor mRNA in the spinal dorsal horn
1999, Brain Research
Capsaicin depletes the sensory neuropeptide substance P (SP) in the rat due to a combination of neuron loss and decreased synthesis in the surviving cells. Resiniferatoxin (RTX) mimics most, but not all, capsaicin actions. In the present study, the effects of RTX (300 μg/kg, s.c.) were examined on mRNA levels for SP and its receptor in the adult rat. The percentage of dorsal root ganglia (DRG) neuronal profiles showing an in situ hybridization signal for preprotachykinin mRNAs encoding SP was not altered following RTX treatment (up to 8 weeks), though the signal became perceptibly weaker. In accord, 2 weeks after RTX administration a 60% decrease was observed in the steady-state levels of SP-encoding mRNAs using Northern blot analysis, leaving the ratio of β- and γ-preprotachykinin mRNAs unchanged. No change was, however, observed in mRNA levels encoding tachykinins NK-1 receptors in the dorsal horn, the spinal targets for SP. The present findings suggest that RTX does not kill SP-positive DRG neurons, though it suppresses the synthesis of SP. Since RTX treatment does not alter NK-1 receptor expression, this reduced SP synthesis is likely to play a central role in the analgesic actions of RTX.
Effect of capsaicin on micturition and associated reflexes in chronic spinal rats
1995, Brain Research
The role of capsaicin-sensitive bladder afferents in micturition was studied in unanesthetized chronic spinal rats. Reflex voiding in response to tactile stimulation of the perigenital region appeared 5–9 days after spinal cord injury (SCI) whereas voiding induced by bladder distension occurred 2–3 weeks after SCI. The frequency and amplitude of reflex bladder contractions recorded under isovolumetric conditions were similar in chronic spinal and urethane-anesthetized CNS-intact rats. However, cystometrograms (CMGs) performed 6–8 weeks after SCI revealed that the chronic spinal rats had larger bladder capacities (1.86 ml) than CNS-intact rats (0.48 ml) and also exhibited multiple, small-amplitude, nonvoiding bladder contractions that were not detected in CNS-intact rats. Administration of capsaicin (50 mg/kg s.c.) acutely (onset 14–40 min) suppressed reflex bladder activity induced by bladder distension or by perigenital stimulation in chronic spinal animals. However, pretreatment of chronic spinal rats with capsaicin (125 mg/kg s.c.) 4 days before the experiment did not depress voiding reflexes or change bladder capacity but did eliminate the nonvoiding contractions. Inhibition of reflex bladder contractions by mechanical stimulation of rectoanal canal or the uterine cervix-vagina was not altered by pretreatment with capsaicin. These data indicate that capsaicin-sensitive bladder afferents are not essential for the initiation of reflex micturition in chronic spinal rats. However, these afferents do contribute to hyperactivity of the bladder during the filling phase of the CMG. Thus, capsaicin-sensitive bladder afferents should be evaluated as possible targets for the pharmacological treatment of bladder hyperreflexia in patients with SCI.
Tachykinins and calcitonin gene-related peptide (CGRP) as co-transmitters released from peripheral endings of sensory nerves
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The contribution of capsaicin-sensitive innervation to activation of the spinal vesico-vesical reflex in rats: relationship between substance P levels in the urinary bladder and the sensory-efferent function of capsaicin-sensitive sensory neurons

Abstract

Brain Research

Brain Research

J. Auton. Nerv. Syst.

Pharmacol. Res. Commun.

Brain Research

Regul. Peptides

Brain Research

Neurosci. Lett.

Eur. J. Pharmacol.

Neurosci. Lett.

J. Pharmacol. Methods

Eur. J. Pharmacol.

J. Urol.

Eur. J. Pharmacol.

J. Pharmacol. Methods

Brain Research

Neuroscience

Neuroscience

Mechanisms of depletion of substance P by capsaicin

Neural control of the urinary bladder and large intestine

Decrease of substance P in primary afferent neurons and impairment of neurogenic plasma extravasation by capsaicin

Br. J. Pharmacol.