Sensory denervation with capsaicin reduces the liver collagen deposition induced by common bile duct obstruction in rats.
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Animals↗
Biomedical subjects
C A Maggi
Publications and source records attributed to C A Maggi.
2-Deoxy-D-glucose (2-DG)-induced increase in gastric acid secretion is impaired in capsaicin-pretreated rats.
This study investigated the increase in gastric acid secretion induced by intravenous administration of 2-deoxy-D-glucose (2-DG; 60 mg kg-1), insulin (5 U kg-1) or by electrical stimulation of the vagus nerve (1 mA, 1 ms, 3 Hz) in urethane-anesthetized rats pretreated when newborn with either capsaicin or the vehicle. The secretory response to 2-DG was substantially reduced in the capsaicin pretreated rats, while those induced by electrical vagal stimulation or insulin were unaffected. These findings suggest that capsaicin-sensitive fibers are involved in the afferent branch of the reflex response activated by 2-DG to stimulate gastric acid secretion.
Animals↗
Differential effect on neuropeptide release of different concentrations of hydrogen ions on afferent and intrinsic neurons of the rat stomach.
In the muscle layer of the glandular portion of the rat stomach, in vivo capsaicin pretreatment markedly reduced calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) but did not affect substance P-like immunoreactivity (SP-LI). Accordingly, in vitro superfusion of slices of this tissue with capsaicin (10 mumol/L) released CGRP-LI but not SP-LI, whereas both neuropeptides were released by 80 mmol/L K+. Exposure to relatively low-pH (pH 6) physiological salt solution induced an increase in the CGRP-LI outflow that was reduced by 70% in a Ca(2+)-free medium and was completely abolished by a previous exposure to capsaicin. However, superfusion with pH-6 medium did not produce any detectable SP-LI release. After exposure to pH-6 medium, both capsaicin and high-K+ medium were still able to release a consistent quantity of CGRP-LI and SP-LI, respectively. Increased mucosal blood flow induced by acid back-diffusion is considered a protective mechanism against mucosal gastric lesion. The present findings suggest that hydrogen ions diffusing into the gastric wall may promote protective vasodilatation by activating the "efferent" function of capsaicin-sensitive nerves without affecting the secretory process of other intrinsic peptidergic neurons.
Animals↗
Ruthenium red as a capsaicin antagonist.
Definition of the physiological and pharmacological properties of primary afferent neurons by the use of capsaicin and its analogues (e.g. resiniferatoxin) has represented one of the most active areas of research of the last decade (1-4 for reviews). In the past 3 years many important advancements have been made in this field, dealing with: a) discovery of the capsaicin (or 'vanilloid' receptor (5); b) discovery of capsazepine as a competitive receptor antagonist at the vanilloid receptor (6); c) definition of the cation channel coupled with the vanilloid receptor and the ionic basis for excitation and "desensitization" of primary afferents by capsaicin and related substances (7,8) and d) discovery of ruthenium red as a functional capsaicin antagonist. The aim of the present article is to briefly review the pharmacology of ruthenium red as a capsaicin antagonist and attempting to define the usefulness and the limits of this substance as a tool in sensory neuron research.
Animals↗
GABAA and GABAB receptors modulate the K(+)-evoked release of sensory CGRP from the guinea pig urinary bladder.
Superfusion of mucosa-free muscle slices of guinea-pig urinary bladder with 40 mM K+ produced a remarkable increase in calcitonin gene-related peptide-like immunoreactivity (CGRP-LI), that in this organ is entirely contained in capsaicin-sensitive nerves. GABA (1 mM) did neither affect the basal nor the 40 mM K+ evoked CGRP-LI release. Baclofen (0.1 mM) or muscimol (1 mM) did not affect the basal CGRP-LI outflow. However, baclofen (0.1 mM) significantly reduced by 32% and muscimol (0.1-1 mM) significantly increased by 60% and 70%, respectively the K(+)-evoked CGRP-LI release. These findings add neurochemical evidence to the functional data suggesting the existence of GABAA and GABAB receptors which modulate the efferent function of capsaicin-sensitive afferents.
Animals↗
In vivo pupillary constrictor effects of substance P in man.
The ocular effects of substance P (SP) were studied in 13 normal volunteers. Various concentrations of SP (0.135, 1.35 and 135 micrograms per 100 microliters) were instilled into the conjunctival sac and pupillary area changes were evaluated by means of an electronic pupillometer. The ability of SP to modify the mydriasis induced by pretreatment with 1% homatropine eyedrops was also studied. The instillation of SP produced miosis in a dose-dependent manner without provoking any ocular disturbances. Furthermore, the highest concentration tested was unable to reduce the homatropine-induced mydriasis. These findings indicate that SP exerts a pupillokinetic action in humans which probably occurs via a receptor mechanism. Since muscarinic blockade is not overcome by the peptide instillation, the results do not clarify whether SP causes miosis acting on iris muscles and/or cholinergic fibres.
Adult↗
Calcitonin gene-related peptide increases the production of glycosaminoglycans but not of collagen type I and III in cultures of rat fat-storing cells.
We investigated whether calcitonin gene-related peptide (CGRP) was able to affect the production of collagen and glycosaminoglycans (GAG) in cultures of rat fat-storing cells (FSC). Rat CGRP (1 nM-1 microM) induced a dose-dependent increase of total GAG production in FSC cultures with an EC50 of 28 nM. One uM human CGRP (8-37) shifted the dose-response curve of rat CGRP to the right (EC50 = 257 nM) without depressing the maximal response. Salmon calcitonin (1 nM-1 microM) did not significantly modify total GAG accumulation in FSC cultures. Collagen type I and III production was not significantly affected by either CGRP or calcitonin in FSC cultures. These findings suggest that peripheral sensory neuropeptides may modulate liver fibrogenesis.
Adipose Tissue↗
Substance P induces migration of capillary endothelial cells: a novel NK-1 selective receptor mediated activity.
Substance P (SP) has been indicated as a main mediator of neurogenic inflammation, leading to vasodilation, increase in vascular permeability and modulation of immune cell function. Certain vascular effects produced by SP are endothelium mediated. We have studied the effect of SP and of selective NK-1, NK-2 and NK-3 receptor agonists on migration of cultured capillary endothelial cells of bovine origin. Our results indicate that SP (10(-14)-10(-6) M) induces a concentration-dependent migration of endothelial cells with maximal activity at 10(-10) M. This effect was mimicked by the selective NK-1 receptor agonist which showed a similar concentration-dependent curve, while selective NK-2 and NK-3 receptor agonists were ineffective. Our conclusions are that endothelial cells possess specific receptors for SP of the NK-1 type which affect mobilization of capillary endothelial cells.
Animals↗
Interactions between sialoadenectomy and capsaicin-sensitive afferent fibers on gastric acid secretion in rats.
In this study we have investigated the relative influence of capsaicin-sensitive afferents and sialoadenectomy on gastric acid secretion. Sialoadenectomized (SALX) rats showed a decrease in gastric acid secretion and an increase in gastric calcitonin gene-related peptide-like immunoreactivity (CGRP-li) as compared to sham-operated animals. Capsaicin pretreatment (50 + 100 mg kg-1 in two days) markedly decreased gastric CGRP-li in both sham and SALX-operated rats and increased acid concentration and output only in SALX animals. In this latter case the concomitant absence of two potent endogenous antisecretory agents (CGRP and epidermal growth factor; EGF) may contribute to the observed hypersecretion. Gastric content of vasoactive intestinal polypeptide (VIP)-li was unaffected in SALX and capsaicin-treated rats. Capsaicin-sensitive afferents and EGF contained in the salivary glands may interact in the regulation of the gastric acid secretion.
Analysis of Variance↗
Actinomycin D is a competitive and selective antagonist at NK2 tachykinin receptors.
The ability of actinomycin D, a known antineoplastic agent, to affect NK1 NK2 and NK3 tachykinin (TK) receptor types was assessed on several in vitro bioassays. Actinomycin D was completely ineffective as a TK antagonist in the guinea-pig ileum longitudinal muscle (GPI) and on the rat portal vein (RPV) (two issues containing NK1, and NK3 TK receptors, respectively) while it was a weak competitive antagonist in the endothelium-denuded rabbit pulmonary artery (RPA) and in the hamster trachea (HT) (tissues containing the NK2A and NK2B receptor subtypes, respectively). Furthermore actinomycin D was able to displace [125I]-His-NKA from NK2 receptor sites of the rat small intestine smooth muscle membranes. Although actinomycin D is about 3 orders of magnitude weaker as an NK2 antagonist as compared to the most effective ligands available, it could represent a starting point in the development of non-peptidic NK2 receptor antagonists.
Animals↗
Capsaicin-induced release of neurokinin A from muscle and mucosa of gastric corpus: correlation with capsaicin-evoked release of calcitonin gene-related peptide.
It has been proposed that capsaicin-sensitive nerves might participate in a gastric defence mechanism, possibly via a local release of sensory neuropeptides. In this study, it was examined whether capsaicin might induce the release of neurokinin A (NKA), substance P (SP) and calcitonin gene-related peptide (CGRP) from different regions of rat stomach. Firstly, the tissue content of NKA-, SP- and CGRP-like immunoreactivity (LI) was measured in the fundus, in the corpus, in the muscle layer and in the mucosa of corpus of control rats and rats pre-treated with systemic capsaicin, s.c. (50 mg/kg as newborn). A large depletion (about 80%) of CGRP-LI following capsaicin treatment was observed in all regions examined, while no difference was observed for NKA-LI and SP-LI. NKA-LI, SP-LI and CGRP-LI release induced by capsaicin was measured in different regions of the rat stomach. Both in the gastric fundus and in the corpus, capsaicin (10 microM) produced a remarkable release of of CGRP-LI and NKA-LI, but not of SP-LI. A second administration of the drug had no longer effect, indicating desensitization. In the gastric corpus, the capsaicin-induced NKA-LI and CGRP-LI release was larger from the muscle layer than from the mucosa. The present findings provide neurochemical evidence that both NKA-LI and CGRP-LI are released from different regions of the rat stomach and both peptides should therefore be taken into account when considering the efferent function of capsaicin-sensitive primary afferents at gastric level.
Animals↗
Simultaneous recording of vesical and urethral pressure in urethane-anesthetized rats: effect of neuromuscular blocking agents on the activity of the external urethral sphincter.
In urethane-anesthetized rats we made a disconnection of the urinary bladder from the urethra and performed a simultaneous recording of the vesical and external urethral sphincter (EUS) pressures. Throughout the collecting phase, the EUS pressure was higher than that recorded into the bladder. Gallamine (10 mg/kg i.v.) or d-tubocurarine (100 micrograms/kg i.v.), did not alter the value of intraurethral pressure. When a reflex bladder contraction occurred in response to filling (expulsion phase) the intravesical pressure exceeded the urethral pressure and at the top of the vesical contraction a series of rapid intraluminal pressure high frequency oscillations (IPHFO) were recorded at the urethral recording site, which were abolished by neuromuscular blocking agents as well as after acute sectioning of pudendal nerves. IPHFO was still present in rats in which the periurethral muscles (pelvic floor), have been precedently dissected. To get further information about the physiological consequence of the EUS functional impairment induced by neuromuscular blocking agents, we used the non-stop transvesical cystometrogram. In these conditions, blockade of the EUS did not produce passive urine dripping during the filling phase, but absence of the rhythmic striated urethral activity during the vesical expulsion phase produced a significant increase of the residual volume from 35% (control) to 75%. We present an original pharmacological method in a species whose small dimensions create technical problems for recording pressure signals from the lower urinary tract. Moreover, we have gained information on the origin of the IPHFOs and about the role of the EUS during the collecting and the expulsion phase of the voiding cycle in urethane anesthetized rats.
Animals↗
Capsaicin and primary afferent neurons: from basic science to human therapy?
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Animals↗
The role of peptides in the regulation of the micturition reflex: an update.
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Animals↗
Neurochemical evidence of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) release from capsaicin-sensitive nerves in rat mesenteric arteries and veins.
1. The ability of capsaicin and antidromic stimulation of perivascular nerve fibers to release sensory neuropeptides (SP-LI and CGRP-LI) have been investigated in rat mesenteric arteries and veins. 2. Both in mesenteric arteries and veins substantial SP-LI and CGRP-LI tissue levels were measured. A significant reduction in sensory neuropeptides levels was observed in tissues obtained from capsaicin-pretreated animals. 3. Superfusion of isolated vessels with capsaicin (1 microM) produced a prompt and remarkable release of both SP-LI and CGRP-LI, which can be evoked only once in each preparation. 4. Electrical field stimulation (EFS, 20 Hz, 50 V, 0.5 msec, trains of 10 sec every 20 sec for 15 min) of isolated vessels resulted in a significant release of CGRP-LI. This release was significantly greater in veins as compared to arteries. EFS-induced CGRP-LI release was unaffected by atropine or guanethidine and absent in preparations obtained from capsaicin-pretreated rats. 5. These neurochemical findings further suggest that the local release of sensory neuropeptides from capsaicin-sensitive nerve endings might be important in the regulation of mesenteric circulation.
Animals↗
On the role of NK-2 tachykinin receptors in the mediation of spinal reflex excitability in the rat.
The effects of intrathecal administration of neurokinin A, substance P and [Tyr5, D-Trp6,8,9 Arg10]neurokinin A-(4-10) (Men 10207), a specific NK-2 receptor antagonist, on the spinal nociceptive flexor reflex were studied in decerebrate, spinalized, unanesthetized rats. Intrathecal neurokinin A and substance P facilitate the flexor reflex in a similar manner. The reflex facilitation to intrathecal neurokinin A, but not substance P, is dose-dependently blocked by pretreatment with Men 10207. The NK-2 receptor antagonist by itself facilitates the flexor reflex with a potency about 10 times less than that of neurokinin A, indicating a partial agonistic property. Reversible depression of the flexor reflex, which is not due to nonspecific spinal blockade, is observed after 700 pmol Men 10207. Further increasing the dose of Men 10207 to 7 nmol for 20 s at an intensity that activates unmyelinated (C) fibers stimulation of peripheral nerves at 1 Hz for 20 s at an intensity that activates unmyelinated (C) fibers facilitates the ipsilateral flexor reflex. The duration of the facilitation after conditioning stimulation of the cutaneous sural nerve is several minutes and about 1 h after conditioning stimulation of the gastrocnemius muscle nerves. Pretreatment with Men 10207 (70-700 pmol) has no effect on facilitation by the sural nerve conditioning stimulation, but effectively blocks the long-term reflex facilitation to the gastrocnemius nerve stimulation. The present results indicate a distinct role for NK-2 tachykinin receptors in mediation of spinal reflex excitability in the rat. Neurokinin A may be involved in the long-term increase of spinal reflex excitability after activation of unmyelinated fibers innervating muscle.
Animals↗
Low pH-induced release of calcitonin gene-related peptide from capsaicin-sensitive sensory nerves: mechanism of action and biological response.
Protons can release in a Ca(2+)-dependent manner, calcitonin gene-related peptide (CGRP)-like immunoreactivity from peripheral endings of capsaicin-sensitive afferents. Here we have studied the mechanism by which proton promotes CGRP-like immunoreactivity release and whether the neuropeptide released might exert a biological action. In muscle slices of guinea-pig urinary bladder high pH (pH 8 or 9) media neither enhanced CGRP-like immunoreactivity outflow nor affected the capsaicin-evoked CGRP-like immunoreactivity release. The CGRP-like immunoreactivity release evoked by superfusion with pH 5 medium was not affected by tetrodotoxin (0.3 microM) indomethacin (10 microM) or the protein kinase C inhibitor H-7 (30 microM). However, it was reduced by 35% in the presence of the voltage-sensitive Ca(2+)-channel antagonists nifedipine (1 microM) and omega-conotoxin (0.1 microM) and by 80% in presence of the capsaicin "antagonist" Ruthenium Red (10 microM). The CGRP-like immunoreactivity release by capsaicin (10 microM) was reduced by 80% in the presence of Ruthenium Red, and not affected by voltage-sensitive Ca(2+)-channel blockers, while that evoked by 80 mM K+ was decreased by 82% in the presence of nifedipine and omega-conotoxin. The Ca(2+)-channel agonist Bay K 8644 enhanced the high K(+)-evoked CGRP-like immunoreactivity release but not that induced by capsaicin or pH 5 medium. Exposure to pH 6 solution of one half of the neck of guinea-pig urinary bladder induced a slowly developing inhibition of electrically evoked contractions, that was absent in the half pre-exposed in vitro to a desensitizing dose of capsaicin.(ABSTRACT TRUNCATED AT 250 WORDS)
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Acrylamide-induced visceral neuropathy: evidence for the involvement of capsaicin-sensitive nerves of the rat urinary bladder.
The mechanisms underlying the severe urinary retention induced by acrylamide intoxication were studied in detail in the rat. Subcutaneous treatment with acrylamide monomer (50 mg/kg daily for 10 days) almost completely impaired the micturition reflex, resulting in urinary retention. In fact, the ability to eliminate an oral water load was virtually abolished, while bladder filling with saline (transvesical cystometrogram) failed to activate reflex micturition. Instead, a picture of overflow incontinence resulted in urethane-anaesthetized rats, which was not reversed by intravenous administration of 4-aminopyridine. The nerve-mediated contractile response to field stimulation (0.1-20 Hz, 0.5 ms, 60 V) of the isolated bladder was unaffected, thus suggesting the integrity of bladder efferent innervation, and no evidence was found from in vitro experiments that the myogenic contractility of the bladder was depressed by acrylamide treatment. Conversely, the sensory nerve-mediated response to capsaicin was abolished and sensory nerve fibres of the bladder were selectively depleted of their content of substance P- and calcitonin gene-related peptide immunoreactivity following acrylamide treatment. In fact, concentrations of the same neuropeptides in other organs, including the adjoining ureters, were unaffected. As to the urethral segment, including the striated sphincter, the D-tubocurarine (0.2 mM)-sensitive urethral response to electrical stimulation (0.1 Hz, 0.1 ms, 20 V) was significantly reduced in acrylamide-treated animals. At the same level, neurofilament protein immunostaining revealed striking accumulations of neurofilament protein-like material in motor end-plates, thus indicating that neuromuscular junctions of the urethral striated sphincter were severely affected. Thus, the afferent arm of the micturition reflex was shown to be severely deranged by acrylamide intoxication, especially in its capsaicin-sensitive component. Since twitch-like contractions of the urethral striated sphincter are probably involved in promoting bladder voiding, a decreased efficiency of this mechanism could participate in the picture of urinary retention induced by acrylamide.
Acrylamide↗