The effects of topical capsaicin on rat urinary bladder motility in vivo

doi:10.1016/0014-2999(84)90187-0

European Journal of Pharmacology

Volume 103, Issues 1–2, 3 August 1984, Pages 41-50

https://doi.org/10.1016/0014-2999(84)90187-0 Get rights and content

Abstract

The effects of topical capsaicin on urinary bladder motility were investigated following saline-induced distension of the bladder wall in urethane-anaesthetized rats and compared to the effects of topical substance P and acetylcholine. Capsaicin and substance P produced similar excitatory effects in both quiescent and rhythmically contracting bladders, i.e., a TTX resistant tonic contraction followed by a series of rhythmic, TTX sensitive, phasic contractions. Acetylcholine, in doses equieffective in producing TTX resistant contractions was less effective than capsaicin or substance P in triggering neurogenic rhythmic contractions of bladder muscle. Atropine pretreatment prevented the neurogenic component of the excitatory effect of both capsaicin and substance P. Repeated applications of capsaicin but not of substance P led to desensitization. Bladders of animals pretreated (4 days before) with a large dose of s.c. capsaicin developed insensitivity to topical capsaicin and a larger volume of saline was required to trigger neurogenic rhythmic contractions of the detrusor muscle. These results suggest that capsaicin acts by interfering with the mechanism(s) regulating the threshold for the micturition reflex to occur.

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The capsaicin receptor, transient receptor potential vanilloid receptor 1 (TRPV1), colocalizes with protease-activated receptors (PARs) in the urinary bladder, but functional interaction between TRPV1 and PARs remains to be clarified. In the present study, the role of capsaicin-sensitive sensory neurons in contraction induced by activation of PAR-2 was investigated in the rat urinary bladders. The contractile responses to trypsin and the PAR-2 agonist 2-furoyl-LIGRL-NH₂ were significantly attenuated by either desensitization of sensory neurons achieved by capsaicin (10 μM) or by the TRPV1 antagonist capsazepine (30 μM). These results suggest that stimulation of capsaicin-sensitive sensory fibers contributes, at least in part, to PAR-2-mediated bladder contractions in rats.
Differential effects of activation of peripheral and spinal tachykinin neurokinin<inf>3</inf> receptors on the micturition reflex in rats
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We clarified the roles of tachykinin neurokinin (NK)₃ receptors in the bladder or spinal cord for control of the micturition reflex in rats.
In female rats under urethane anesthesia repetitive bladder contractions were elicited by saline infusion into the bladder through intravesical bladder catheters. The effects of peripheral receptor activation were first examined by topical application of the tachykinin NK₃ receptor agonist [MePhe⁷]-NKB (Calbiochem, Darmstadt, Germany) in normal rats and rats pretreated with capsaicin (Sigma Chemical Co., St. Louis, Missouri) 4 days before the experiments. Subsequently the effects of spinal NK₃ receptor activation were examined by intrathecal administration of [MePhe⁷]-NKB via implanted intrathecal catheters. The effects of the tachykinin NK₃ receptor antagonist SB235375 and the opioid receptor antagonist naloxone on changes in bladder activity induced by [MePhe⁷]-NKB were also investigated.
Topical application of [MePhe⁷]-NKB onto the bladder surface decreased intercontraction intervals and bladder capacity, and increased baseline bladder pressure in dose dependent fashion. [MePhe⁷]-NKB induced bladder overactivity was inhibited by simultaneous topical administration of SB235375 or by capsaicin pretreatment. In contrast, intrathecal injection of [MePhe⁷]-NKB increased intercontraction intervals in dose dependent fashion and at a high dose it induced overflow incontinence or inefficient voiding. These inhibitory effects of [MePhe⁷]-NKB in the spinal cord were antagonized by the intrathecal injection of SB235375 or naloxone.
These results indicate that the tachykinin NK₃ receptor mediated neural control of the micturition reflex has dual actions depending on the location of receptor activation. Activation of tachykinin NK₃ receptors located in the bladder can induce bladder overactivity at least in part via the activation of capsaicin sensitive C-fiber afferents, while tachykinin NK₃ receptor activation in the spinal cord can inhibit the micturition reflex through an opioid mechanism.
The role of the vanilloid (capsaicin) receptor (TRPV1) in physiology and pathology
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The cloning of the vanilloid receptor 1 opened a floodgate for discoveries regarding the function of this complex molecule. It has been found that, in addition to heat, protons and vanilloids, this receptor also responds to various endogenous ligands. Furthermore, it has been also emerged that, through associations with other molecules, the vanilloid receptor 1 plays an important role in the integration of various stimuli and modulation of cellular excitability. Although, originally, the vanilloid receptor 1 was associated with nociceptive primary afferent fibres, it has been gradually revealed that it is broadly expressed in the brain, epidermis and visceral cells. The expression pattern of the vanilloid receptor 1 indicates that it could be involved in various physiological functions and in the pathomechanisms of diverse diseases. Here, we summarise the molecular, pharmacological and physiological characteristics, and putative functions, of the vanilloid receptor 1, and discuss the therapeutic potential of this molecule.
Spinal neurophysiologic correlates of the analgesic actions of intravesical dimethyl sulfoxide and capsaicin in the rat
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Citation Excerpt :
This effect was only marked at the spinal cord levels of L5-S1, which are those that receive pelvic nerve input.11 Desensitization of urinary bladder afferents by capsaicin has been extensively studied by Maggi and associates, who assessed the effect of the drug on the micturition reflex.2,23,26,36 The term desensitization is usually applied to the multiple capsaicin effects and is a generic label to describe a broad series of events ranging from tachyphylaxis associated with the vanilloid receptor to a neurotoxic effect and cell death.12
Peripheral analgesia produced by the intravesical instillation of dimethyl sulphoxide (DMSO) and capsaicin has been used to treat visceral pain originating in the urinary bladder. The present study sought to determine the neurophysiologic consequences of the intravesical instillation of these compounds by measuring spinal neuronal responses evoked by urinary bladder distension (UBD) in the rat. Subjects were spinally transected, decerebrate female Sprague-Dawley rats. The effect of 0.5 mL of solution of 10% or 50% DMSO, 100 μmol/L capsaicin, or the same volume of saline instilled into the bladder on excitatory neuronal responses to UBD was studied by using single-unit extracellular recordings of L6-S2 dorsal horn spinal cord neurons. Fifty-six dorsal horn neurons that were excited by UBD in a graded fashion were identified. All neurons were also excited by noxious or non-noxious cutaneous stimuli. Two hours after intravesical instillation, solutions of 50% DMSO or 100 μmol/L of capsaicin produced a reduction of the slope of stimulus-response functions for neuronal activity evoked by graded UBD. These data support a local effect of intravesical 50% DMSO or capsaicin and suggest the use of this model to study novel peripheral treatment strategies for bladder pain. © 2002 by the American Pain Society
The capsaicin analogue SDZ249-665 attenuates the hyper-reflexia and referred hyperalgesia associated with inflammation of the rat urinary bladder
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This study assessed the effects of the systemically administered capsaicin analogue SDZ249-665 in an animal model of visceral pain and hyper-reflexia. The effects of prophylactic administration of SDZ249-665 (in the dose range 0.05–1 mg/kg) on the viscero-visceral hyper-reflexia (VVH) and the referred viscero-somatic hyperalgesia to mechanical stimuli (VSH) associated with turpentine inflammation of the rat urinary bladder were evaluated. SDZ249-665 attenuated both the VVH and the VSH in a dose related fashion. In the VVH model, following solvent control administration, intra-vesical turpentine administration was associated with a significant reduction in micturition threshold to 43.7% (SEM 6.3) of baseline, indicating the presence of a VVH. This effect was not observed when animals were prophylactically treated with SDZ249-665 alone. At a dose of 0.1 mg/kg the micturition threshold was 90.7% (SEM 10.2) of baseline at 1 h after intra-vesical instillation of turpentine. In the VSH model, curves were plotted of the difference in fore and hind limb withdrawal latencies from a mechanical stimulus and the area under these curves (AUCs) were compared between different treatment protocols. Intra-vesical turpentine was associated with a negative deflection of the curve (AUC −5.2×10³ SEM 1.7) in comparison with naı̈ve animals (AUC −0.02×10³ SEM 0.6), indicative of a referred hyperalgesia. This was prevented, in a dose-related manner, by prophylactic administration of SDZ249-665. For example, at a dose of 0.5 mg/kg the AUC was +0.4×10³ (SEM 0.8). These findings support previous work indicating that capsaicin sensitive neurones participate in patho-physiological events occurring following inflammation of the bladder, and provides evidence that systemically active capsaicin based compounds may be developed for use in the clinical setting.
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At that time, in collaboration with Paolo Santicioli, we were interested in defining possible new treatments for micturition disturbances and started using capsaicin as a tool to address the neurotransmitter mechanisms regulating primary afferent input from the rat urinary bladder to the spinal cord. The connection to substance P (SP) was a quite obvious step and we obtained evidence [1,2] suggesting that TKs could have a role in excitatory nonadrenergic noncholinergic (NANC) neurotransmission to the rat detrusor muscle, although formal proof supporting this conclusion (blockade of electrically induced nerve-mediated responses by appropriate antagonists) was obtained 12 years later [3]. In 1984, following the advice of Prof. Domenico Regoli from the University of Sherbrooke, Canada, we started studying the effect of the ‘novel’ TKs, neurokinin A and neurokinin B (NKA and NKB, respectively), and were soon involved in heavy work on the characterization of TK receptors.
The tachykinins substance P (SP) and neurokinin A (NKA) are synthesized and released from nerves in the peripheral and enteric nervous system (PNS and ENS). They act as nonadrenergic noncholinergic (NANC) excitatory transmitters in mammalian airways, and the genitourinary and gastrointestinal tract. At the postjunctional level, both NK₁ (SP-preferring) and NK₂ (NKA-preferring) receptors are often co-expressed by target cells innervated by TKergic nerves. Thus an issue of duplication seems to exists with regard to peripheral tachykininergic co-transmission, the duplication involving both messengers (the peptides) and effectors (the receptors). By using receptor selective antagonists it has been possible to dissect the relative contribution of different receptors to TKergic co-transmission: the available results indicate that multiple arrangements exist involving both summation, cooperation and specialization of different messengers/effectors in producing the overall response.

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The effects of topical capsaicin on rat urinary bladder motility in vivo

Abstract

Neuroscience

Brain Res.

J. Autonom. Nerv. Syst.

Neuroscience

T.I.P.S.

Life Sci.

J. Pharmacol. Meth.

J. Pharmacol. Meth.

Gen. Pharmacol.

Brain Res.

J. Autonom. Nerv. Syst.

Neuroscience

Neuroscience

Evidence that the contractile response of the guinea pig ileum to capsaicin is due to release of substance P

J. Physiol. (London)

Pulmonary afferent fibers of small diameter stimulated by capsaicin and hyperinflation of the lung

J. Physiol. (London)

Afferent C fibers and cardiorespiratory reflexes

Am. Rev. Respir. Dir.

Inhibition and facilitation in parasympathetic ganglia of the urinary bladder

Reflexes to sacral parasympathetic neurons concerned with micturition in the cat

J. Physiol. (London)

Reflex activation of sympathetic pathways to vesical smooth muscle and parasympathetic ganglia by electrical stimulation of vesical afferents

J. Physiol. (London)

The action of sodium dicromoglycate on “C” fibers endings in the dog lung

Br. J. Pharmacol.