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PubMed1984

Capsaicin-induced stimulation of the guinea-pig atrium. Involvement of a novel sensory transmitter or a direct action on myocytes?

The mechanism underlying the positive inotropic and chronotropic effects of capsaicin were investigated using the spontaneously beating guinea-pig atrium in vitro. Capsaicin induced a long-lasting stimulatory effect (threshold dose 10(-9) M). Tetrodotoxin, phentolamine, 6-OHDA, mepyramine plus cimetidine, methysergide-, indomethacin-, somatostatin- or morphine pretreatment and local treatment with capsaicin on the vagal nerves did not reduce the capsaicin response, while it was abolished up to 1 month after systemic capsaicin pretreatment. The capsaicin response was subject to a rapid tachyphylaxis. During capsaicin tachyphylaxis, the positive inotropic and chronotropic effects of noradrenaline, serotonin and histamine were unchanged. Various neuropeptides were investigated with regard to cardiac activity. Physalaemin, eledoisin and somatostatin had negative inotropic and chronotropic effects. Substance P, bombesin, kassinin, CCK-8 or PHI (up to 10(-6)M of each) did not cause any detectable response on the guinea-pig auricle, while the substance P antagonist [D-Arg, D-Pro, D-Trp, Leu]SP induced a long-lasting stimulation of heart activity, VIP also stimulated the heart. Various adenyl compounds were also tested. Adenosine, AMP, ADP, ATP and beta-, gamma-methylene ATP had negative chronotropic and inotropic effects, while alpha-, beta-methylene ATP induced a stimulatory response. During alpha-, beta-methylene ATP tachyphylaxis, the auricles still responded to capsaicin. The inhibitory effects of adenosine and ATP analogues were antagonized by theophylline and 8-p-sulfophenyl theophylline. Capsaicin induced a small release of labelled nucleotides from 3(H)-adenine-prelabelled atria from control, but not from capsaicin-pretreated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1986

Bronchial, cardiovascular and secretory responses after central administration of capsaicin in the guinea-pig.

Capsaicin was injected intracisternally (i.c.), intrathecally (i.th.) or intravenously (i.v.) into guinea-pigs anaesthetized with urethane and ventilated artificially. The effects of 0.2-100 micrograms capsaicin on insufflation pressure, heart rate, arterial blood pressure and salivation were recorded. Low i.c. doses of 0.2 and 2 micrograms capsaicin induced bradycardia, hypertension and salivation but no change in insufflation pressure. An insufflation pressure increase, i.e. bronchoconstriction, was observed with 20 or 100 micrograms capsaicin i.c. and this was associated with tachycardia and hypertension. Bronchoconstriction after 20 micrograms capsaicin i.c. was augmented by propranolol (1 mg/kg i.v.). It was, however, unaffected by bilateral cervical vagotomy and could also be induced by i.th. capsaicin injections in the lumbar region. Capsaicin (3 micrograms/kg) injected i.v. induced bronchoconstriction and tachycardia. Propranolol enhanced bronchoconstriction but did not reduce the tachycardia indicating that capsaicin led to activation of sympathetic bronchial but not cardiac fibers. These results also indicate that i.c. capsaicin caused reflex responses consisting of salivation, bronchodilatation bradycardia and hypertension. High doses injected i.c. or i.th. also caused tachycardia and bronchoconstriction. This latter effect, however, was neither a vagal reflex nor did it seem to result from activation of central terminals of afferent fibers with subsequent release of mediators from the peripheral endings due to antidromic spread of nerve impulses. Instead, capsaicin seemed to be readily resorbed into the systemic circulation and thus acting at peripheral endings to cause bronchoconstriction and tachycardia.

Airway Resistance↗
PubMed1985

Calcitonin gene-related peptide (CGRP) and capsaicin-induced stimulation of heart contractile rate and force.

The effects of calcitonin gene-related peptide (CGRP) on guinea-pig heart contractility were investigated in vitro in relation to the response of capsaicin and noradrenaline (NA). Synthetic rat CGRP (greater than 10(-8) M) caused a long-lasting, positive inotropic and chronotropic effect on the spontaneously beating right atrium. The response to CGRP mimicked the effects of capsaicin and was resistant to beta-adrenoceptor blockade using metoprolol. Furthermore, CGRP did not change basal efflux or the release of 3H-NA induced by transmural nerve stimulation, suggesting an action independent of sympathetic mechanisms. Mepyramine and cimetidine did not reduce the response to CGRP. After tachyphylaxis to the effects of CGRP (5 X 10(-7) M) which developed within 15-20 min, the positive inotropic and chronotropic atrial response to capsaicin was abolished. The effects of NA, however, were not influenced by CGRP tachyphylaxis. In the isolated perfused whole heart, CGRP had more pronounced stimulatory effects on ventricular contractile rate than on force compared to NA. The CGRP response was resistant to metoprolol and still present in capsaicin-pretreated animals. Capsaicin caused a slight initial inhibition of ventricular contractility, which was followed by a marked stimulatory action. As for CGRP, the cardioexcitatory response to capsaicin was more pronounced on rate than on force. The stimulatory responses to capsaicin were absent 2 weeks after systemic capsaicin pretreatment. In conclusion, CGRP mimics the non-adrenergic, cardioexcitatory effects of capsaicin, and the capsaicin response is absent after CGRP tachyphylaxis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Effect of capsaicin inhalation on methacholine responsiveness in normal subjects.

It has been reported that capsaicin stimulates bronchial C-fibers to release neuropeptides and enhances bronchial responsiveness in animal studies. This study was conducted to examine the effect of inhaled capsaicin on bronchial responsiveness in humans. A provocative concentration of methacholine producing a 20% fall in forced expiratory volume in one second (PC20-FEV1) was measured before and one hour after, one minute inhalation of 15.6 microM capsaicin solution (capsaicin day) or saline (saline day) in seven normal subjects whose PC20-FEV1 values were 40 mg/ml or less. Geometric mean value of PC20-FEV1 measured one hour after saline inhalation following pretreatment methacholine challenge was 89.3 (GSEM, 1.69) mg/ml which was significantly (p = 0.018) greater than that of the pre-treatment methacholine challenge [19.1 (GSEM, 1.37) mg/ml] on a saline day. However, PC20-FEV1 was not different before and one hour after inhalation of capsaicin [18.1 (GSEM, 1.40) and 23.1 (GSEM, 1.80) mg/ml] on a capsaicin day. The PC20-FEV1 value of the post-treatment methacholine test was significantly (p = 0.0277) lower after capsaicin inhalation than after saline inhalation while the value of pre-treatment methacholine provocation was not different between capsaicin and saline days. Change of the post-treatment PC20-FEV1 from the pre-treatment value shown as doubling concentrations was 0.35 +/- 0.60 on a capsaicin day which was significantly lower than that (2.23 +/- 0.47) on a saline day. These results confirm the decreased responses to repeated inhalation of methacholine (methacholine tachyphylaxis) in normal subjects and indicate that capsaicin inhalation reduces the methacholine tachyphylaxis.

Administration, Inhalation↗
PubMed1996

Comparison of the inhibitory action of synthetic capsaicin analogues with various NADH-ubiquinone oxidoreductases.

Capsaicin is a new naturally occurring inhibitor of proton-pumping NADH-ubiquinone oxidoreductase (NDH-1), that competitively acts against ubiquinone. A series of capsaicin analogues was synthesized to examine the structural factors required for the inhibitory action and to probe the structural property of the ubiquinone catalytic site of various NADH-ubiquinone reductases, including non-proton-pumping enzyme (NDH-2), from bovine heart mitochondria, potato tuber (Solanum tuberosum, L) mitochondria and Escherichia coli (GR 19N) plasma membranes. Some synthetic capsaicins were fairly potent inhibitors of each of the three NDH-1 compared with the potent rotenone and piericidin A. Synthetic capsaicin analogues inhibited all three NDH-1 activities in a competitive manner against an exogenous quinone. The modification both of the substitution pattern and of the number of methoxy groups on the benzene ring, which may be superimposable on the quinone ring of ubiquinone, did not drastically affect the inhibitory potency. In addition, alteration of the position of dipolar amide bond unit in the molecule and chemical modifications of this unit did not change the inhibitory potency, particularly with bovine heart and potato tuber NDH-1. These results might be explained assuming that the ubiquinone catalytic site of NDH-1 is spacious enough to accommodate a variety of structurally different capsaicin analogues in a dissimilar manner. Regarding the moiety corresponding to the alkyl side chain, a rigid diphenyl ether structure was more inhibitory than a flexible alkyl chain. Structure-activity studies and molecular orbital calculations suggested that a bent form is the active conformation of capsaicin analogues. On the other hand, poor correlations between the inhibitory potencies determined with the three NDH-1 suggested that the structural similarity of the ubiquinone catalytic sites of these enzymes is rather poor. The sensitivity to the inhibition by synthetic capsaicins remarkably differed between NDH-1 and NDH-2, supporting the notion that the sensitivity against capsaicin inhibition correlates well with the presence of an energy coupling site in the enzyme (Yagi, T. (1990) Arch. Biochem. Biophys. 281, 305-311). It is noteworthy that several synthetic capsaicins discriminated between NDH-1 and NDH-2 much better than natural capsaicin.

Animals↗
PubMed1983

Capsaicin treatment in adult Wistar-Kyoto and spontaneously hypertensive rats: neurochemical effects in the spinal cord.

The effects of s.c. capsaicin treatment on the thoracic spinal cord contents of immunoreactive substance P (ISP), norepinephrine (NE) and serotonin (5-HT) were investigated in adult male Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Capsaicin administered s.c. significantly reduced the concentration of ISP in the thoracic spinal cords from rats of both the WKY and SHR strains. The s.c. administration of capsaicin significantly increased the NE contents of the thoracic spinal cords in rats of both the WKY and SHR strains, and both vehicle- and capsaicin-treated SHR animals exhibited significantly greater thoracic spinal cord NE concentrations than did rats from the corresponding WKY treatment groups. In contrast, s.c. capsaicin treatment significantly increased the concentration of 5-HT only in the thoracic spinal cords of SHR subjects. These results strongly suggest that the neurochemical effects of s.c. capsaicin administration on the spinal cord were not specific to ISP-containing neurons since significant changes in the concentrations of NE and 5-HT were also produced by capsaicin treatment. These capsaicin induced changes in the concentrations of putative neurotransmitter substances in the spinal cord are related to previously reported alterations in nociception and cardiovascular regulation produced by s.c. capsaicin administration. Physiological and pharmacological mechanisms possibly relating the neurochemical changes produced by capsaicin to the behavioral and cardiovascular effects of the drug previously reported are advanced and discussed.

Animals↗
PubMed1988

Vascular effects of capsaicin in isolated perfused rat mesenteric bed.

The effects of intra- and extraluminal capsaicin administration were evaluated in isolated perfused rat mesenteric bed. Capsaicin (10 nM-1 microM) produced a potent concentration-dependent relaxation of the tonic vasoconstriction induced by norepinephrine (1 microM) but not by high-K+ (60 mM). The capsaicin-induced relaxation was nearly abolished in preparations pretreated in vitro with a high concentration of capsaicin (1 microM, for 10 min, 1 h before). Capsaicin-induced relaxation was reduced but not abolished in preparations obtained from rats pretreated neonatally with capsaicin. The capsaicin effects were unaffected by atropine, guanethidine, propranolol, hexamethonium or tetrodotoxin. The observation that capsaicin (0.1 microM)-induced relaxation was virtually abolished in presence of the proteolytic enzyme alpha-chymotrypsin (1 U/ml) supports the involvement of neuropeptide(s) in this response. Bolus injections of calcitonin gene-related peptide (CGRP) elicited a potent and rapidly ensuing relaxation which underwent tachyphylaxis. However, no cross-desensitization with capsaicin was observed. It is concluded that activation of capsaicin-sensitive sensory fibers could release neuropeptides locally with a potent effect on intestinal blood flow.

Animals↗
PubMed1995

In vitro effects of capsaicin: antiarrhythmic and antiischemic activity.

The antiarrhythmic effects of vehicle (0.1% dimethyl sulfoxide: DMSO) or capsaicin were evaluated in isolated perfused rat and guinea pig heart preparations. In the rat, capsaicin reduced ischemic ventricular tachycardia from 100% in control to 0%, and ischemic ventricular fibrillation from 60% in control to 0% at 30 microM, and diltiazem reduced the incidence of ischemic ventricular tachycardia and ventricular fibrillation to 55% and 0%, respectively. Reperfusion ventricular fibrillation was reduced from 90% to 20% and 33% for capsaicin and diltiazem, respectively, at these concentrations. In isolated perfused globally ischemic rat hearts, antiischemic efficacy was assessed as a significant extension (36% and 50%) in time to contracture with 30 microM capsaicin and 1 microM diltiazem, respectively. Capsaicin reduced left ventricular developed pressure by 35% in non-ischemic rat hearts, and increased coronary flow by 40%. The increased time to contracture for either compound was not blocked by glyburide (0.1 microM) suggesting a lack of any involvement of ATP-sensitive K+ channels. In isolated guinea pig hearts subjected to global ischemia, capsaicin and diltiazem reduced reperfusion ventricular fibrillation from 100% to 10% and 0% at 30 and 3 microM, respectively. Electrophysiologic evaluation in guinea pig papillary muscles using standard microelectrode techniques demonstrated significant (P < 0.05) action potential durations at 90% repolarization shortening at 1 Hz by 9%, 28% and 39%, and 23%, 37% and 51% at 10, 30, and 100 microM of capsaicin or diltiazem, respectively. Unlike diltiazem, no changes in action potential duration were observed with capsaicin (up to 100 microM) at faster stimulation rates (5 Hz). In conclusion, capsaicin displays both antiarrhythmic and antiischemic efficacy. These data suggest that the effects of capsaicin are mediated primarily through block of Ca2+ channels in these preparations.

Action Potentials↗
PubMed1996

Sensitization and desensitization to capsaicin and menthol in the oral cavity: interactions and individual differences.

It was reported in a recent study that, like capsaicin, menthol is capable of producing a desensitization to sensory irritation in the oral cavity. Whereas capsaicin is known to be able to cross-desensitize with other chemical irritants, no such information exists for menthol. To address this question, the first experiment was designed to reveal whether cross-desensitization would occur between menthol and capsaicin. After a pretest on the tongue tip in which subjects rated the intensity of irritation and cold produced by 3.5 ppm capsaicin or 0.3% l-menthol, five samples of the same stimuli were sipped and swished at 1-min intervals for 5 min. Fifteen minutes later subjects were tested on the tongue tip with either capsaicin or menthol. The results 1) confirmed self-desensitization for both chemicals, 2) demonstrated cross-desensitization of menthol by capsaicin, and 3) revealed cross-sensitization of capsaicin by menthol. This series of outcomes suggests that menthol produces much of its sensory irritation via capsaicin-sensitive pathways, but that it excites and/or desensitizes those pathways via different mechanisms than does capsaicin. Analysis of the individual data revealed large differences in sensitization, and desensitization that were significantly correlated across chemicals, which suggests the possibility that the perceptual response to repeated exposures to irritants may be idiosyncratic. Contrary to earlier findings, the first experiment also revealed apparent self- and cross-desensitization of the menthol sensation of coolness. The latter outcome was investigated in a second experiment in which the effect of capsaicin desensitization on the perception of physical as well as chemical (menthol) cooling was measured when the stimuli were presented as oral rinses. No desensitization was found for either form of stimulation, which implied the apparent desensitization of coolness in Experiment I may have been due to the difficulty of discriminating sensations of cold from sensations of chemical irritation. The overall findings are discussed in terms of the complex sensory and perceptual interactions that take place within the chemesthetic modality.

Adult↗
PubMed1991

Effect of capsaicin neonatal treatment on the salt intake of the adult rat.

The present study investigated the involvement of capsaicin-sensitive sensory neurons on salt intake control in the rat, following capsaicin neonatal treatment. Capsaicin did not affect salt appetite induced by intramuscular injection of deoxycorticosterone enantate, or by intracranial injection of renin. Moreover, it did not alter salt preference of rats given access to a variety of NaCl concentrations, or the need-free salt intake of multidepleted male rats. On the other hand, in response to furosemide-induced sodium depletion, the salt intake of capsaicin-treated rats was lower than that of controls. However, furosemide-induced Na+ excretion of capsaicin-treated rats proved to be lower than that of controls, thus suggesting that difference in salt intake might be secondary to lower sensitivity of capsaicin-treated rats to the natriuretic action of furosemide. Salt intake is known to be influenced by sensory information from the oral cavity, from the liver and from the intravascular compartment. The absence of effect of capsaicin neonatal treatment suggests that sensory fibers relevant to salt intake control may not be capsaicin sensitive. On the other hand, our findings indicate that capsaicin treatment alters the renal response to furosemide and stimulate further studies on the effects of capsaicin on renal function.

Animals↗
PubMed1994

Evidence that glutamate is released from capsaicin-sensitive primary afferent fibers in rats: study with on-line continuous monitoring of glutamate.

The aim of this study is to elucidate whether the excitatory amino acid glutamate is released from capsaicin-sensitive primary afferent fibers, and to compare the releasing effect of capsaicin on glutamate with that on substance P. The release of glutamate was measured using a fluorometric on-line continuous monitoring system, in which the immobilized glutamate dehydrogenase column was connected to an in vitro superfusion system. In the presence of 0.3 microM tetrodotoxin, 2-min application of capsaicin produced an increased outflow of glutamate, as well as an increase in the release of immunoreactive substance P from dorsal horn slices of the rat. The release of glutamate was concentration-dependently increased by capsaicin at concentrations in the range of 0.1-3 microM, and the release evoked by 10 microM capsaicin was not higher than that evoked by 3 microM. On the other hand, capsaicin at concentrations of 1-10 microM produced a concentration-dependent increase in the release of immunoreactive substance P, without effect at 0.1 microM. The amount of glutamate release evoked by 3 microM capsaicin was about 42.8 pmol.mg-1 protein, and 290 times that of immunoreactive substance P. The release of glutamate by 3 microM capsaicin was suppressed by the depletion of calcium from the superfusate. Capsaicin at 3 microM failed to increase the release of glutamate from the dorsal horn slices of the rats made an L4-L6 dorsal rhizotomy. These results suggest that capsaicin evoked the release of glutamate from primary afferent fibers in the dorsal horn and that glutamate may play an important role in pain transmission between primary afferent fibers and dorsal horn neurons.

Animals↗
PubMed1989

Capsaicin desensitization of peripheral nociceptive fibres does not impair sensitivity to other noxious stimuli.

Capsaicin was tested on peripheral fibres in vitro to determine whether evoked depolarization or desensitization were likely to explain the antinociception observed after acute systemic capsaicin in vivo. The activation of peripheral fibres by noxious (capsaicin, bradykinin, heat) and innocuous (light brush) stimuli was recorded as a depolarization of a spinal ventral root (L3-L5) in the neonatal rat spinal cord with attached tail. Prolonged superfusion of the tail with low doses (0.2-2 microM) of capsaicin produced a short lasting depolarization followed by a complete loss of sensitivity to capsaicin without changes in sensitivity to other noxious or innocuous stimuli. Partial recovery from this selective desensitization could be observed 3-5 h later. In most preparations superfusion of the tail with 20 microM capsaicin produced a prolonged and non-selective impairment of sensitivity to all noxious stimuli. These data suggest that neither depolarization by capsaicin nor the selective desensitization of peripheral fibres to capsaicin are likely to account for the acute antinociceptive effect of systemic capsaicin. On the other hand the non-selective reduction in sensitivity to noxious stimuli induced by capsaicin may contribute to its antinociceptive action.

Animals↗
PubMed1990

Motor response of the human isolated colon to capsaicin and its relationship to release of vasoactive intestinal polypeptide.

The aim of this study was to obtain indirect evidence of the presence of capsaicin-sensitive afferents in the human colon by studying the motor response to capsaicin of longitudinal strips from the human isolated taenia coli in parallel to the ability of capsaicin or KCl to induce peptide release from the human superfused colon. Capsaicin (1 microM) evoked a relaxation of the taenia, approaching 60-80% of the response to isoprenaline. Tachykinins evoked contractions of the taenia, while calcitonin gene-related peptide induced a relaxation. Neither tachyphylaxis to calcitonin gene-related peptide nor preincubation with an anti-calcitonin gene-related peptide serum did block the response to capsaicin which was also unaffected by tetrodotoxin, apamin, naloxone or an anti-galanin serum. Vasoactive intestinal polypeptide produced a concentration-dependent tetrodotoxin-resistant relaxation which was shifted rightward in the presence of anti-vasoactive intestinal polypeptide serum. The anti-vasoactive intestinal polypeptide serum reduced the response to capsaicin and application of capsaicin prevented the ability of anti-vasoactive intestinal polypeptide serum to block exogenous vasoactive intestinal polypeptide. Capsaicin (1 microM) evoked a significant release of vasoactive intestinal polypeptide-like immunoreactivity from the superfused muscle but not mucosa of the human colon. A significant vasoactive intestinal polypeptide-like immunoreactivity release was also observed in response to KCl (80 mM). KCl but not capsaicin evoked a significant release of neurokinin A-like immunoreactivity from colonic muscle and mucosa. No significant release of either substance P-, neuropeptide Y-, galanin- or calcitonin gene-related peptide-like immunoreactivity was detected in response to capsaicin or KCl although detectable levels of each peptide were evident in tissue extracts.(ABSTRACT TRUNCATED AT 250 WORDS)

Apamin↗
PubMed1992

Participation of capsaicin-sensitive afferent neurons in gastric motor inhibition caused by laparotomy and intraperitoneal acid.

Stimulation of somatic or visceral nociceptors causes changes in gastrointestinal motor activity and blood pressure. The present study examined the possible participation of capsaicin-sensitive afferent and noradrenergic efferent neurons in the blood pressure and gastric motor responses to laparotomy and intraperitoneal injection of capsaicin or hydrochloric acid in the rat. Gastric motor activity was measured by recording the intragastric pressure of phenobarbital-anaesthetized rats via an oesophageal catheter. Laparotomy as well as intraperitoneal injection of capsaicin (33 and 330 microM) or hydrochloric acid (30 mM) caused a transient reduction of gastric motor activity stimulated by intravenous infusion of bombesin (200 pmol/min) and a brief fall of blood pressure (depressor effect). The depressor effect of laparotomy was followed by prolonged hypertension. Defunctionalization of capsaicin-sensitive afferent neurons by systemic pretreatment of rats with capsaicin (0.4 mmol/kg) prevented the depressor effect and gastric motor inhibition elicited by laparotomy, intraperitoneal capsaicin (33 microM) or intraperitoneal hydrochloric acid (30 mM). However, the effects of 330 microM capsaicin on blood pressure and gastric motility were only partially reduced by capsaicin pretreatment. Blockade of noradrenergic sympathetic neurons by pretreating rats with guanethidine (0.225 mmol/kg) prevented the gastric motor inhibition and depressor effects of laparotomy and intraperitoneal injection of hydrochloric acid (30 mM). The inhibition of gastric motility caused by capsaicin (33 and 330 microM) was only partially reduced by guanethidine pretreatment. The secondary hypertension following the depressor effect of intraperitoneal capsaicin or hydrochloric acid was enhanced in guanethidine-pretreated rats whereas the prolonged hypertension induced by laparotomy was left unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

The role of calcium in capsaicin-induced desensitization in rat cultured dorsal root ganglion neurons.

The effects of capsaicin cytosolic Ca2+ concentration ([Ca2+]i) were measured in individual dorsal root ganglion neurons of the rat in culture. Capsaicin produced a rapid concentration-dependent (EC50 value of 72 nM) increase in [Ca2+]i which was entirely dependent on Ca2+ entry. Exposure of the neurons to a high concentration of capsaicin resulted in desensitization, but only in the presence of external Ca2+. Raising [Ca2+]i with a depolarizing concentration of potassium or the Ca2+ ionophore ionomycin did not reduce the response to a subsequent application of capsaicin. Capsaicin did not induce desensitization in Ca(2+)-free medium even if [Ca2+]i was simultaneously raised with a combination of ionomycin plus carbonyl cyanide m-chlorophenyl-hydrazone. Okadaic acid, a known inhibitor of protein phosphatases 1 and 2A, caused a transient dose-dependent (EC50 value, 100nM) rise in [Ca2+]i, but had no effect on either the responsiveness to capsaicin or capsaicin induced desensitization. The capsaicin antagonist capsazepine blocked the increase in [Ca2+]i evoked by capsaicin and prevented desensitization. These results suggest that desensitization requires the presence of extracellular Ca2+, cannot be mimicked by raising the concentration of [Ca2+]i and may involve Ca2+ entry through activated capsaicin-operated ion channels.

Animals↗
PubMed1995

Capsaicin-induced neurotoxicity in cultured dorsal root ganglion neurons: involvement of calcium-activated proteases.

We examined the mechanism by which capsaicin produces its toxic effects on cultures of rat sensory neurons. Capsaicin caused a robust increase in [Ca2+]i in a subpopulation of cultured rat dorsal root ganglion neurons. Similarly, a brief exposure to capsaicin resulted in delayed degeneration of a subpopulation of the cells. This subpopulation (about 35% of the cells present) was characterized by a capsaicin-induced uptake of Co2+, which could be detected cytochemically. Both capsaicin-induced Co2+ uptake and capsaicin-induced cell death were blocked by the capsaicin antagonist Ruthenium Red. Cell death was also prevented by removal of external calcium or by inhibiting calcium-activated proteases such as calpain. Evidence that calpain activity was increased was provided by examining the amount of degradation of the preferred calpain substrate alpha-spectrin. Capsaicin treatment produced a significant increase in the levels of the 150,000 molecular weight spectrin breakdown product. Furthermore, applying the protease inhibitors E64 or MDL 28,170 reduced capsaicin-mediated cell death. It is concluded that capsaicin kills a subpopulation of sensory neurons by activating a receptor-operated channel. The consequent Ca2+ ion influx causes large increases in [Ca2+]i and subsequent activation of Ca(2+)-sensitive proteases. This model provides support for the role of [Ca2+]i as the orchestrator of delayed neuronal degeneration.

Animals↗
PubMed1987

Neuroendocrine and behavioral effects of intrathecal capsaicin in adult female rats.

Neural feedback from the gonads and the reproductive tract has an integral role in normal reproductive function in female rats. To further assess the role of sensory feedback in neuroendocrine control, the effects of an intrathecal injection of the neurotoxin, capsaicin (100-125 micrograms) into the lumbosacral region of the spinal cord on reproductive function was tested in female rats. In addition, the effects of capsaicin on the response to noxious heat and pressure were tested. Intrathecal capsaicin had no effect on estrous cycles, ovarian compensatory hypertrophy or female sexual behavior. However, capsaicin treated animals showed a dramatic reduction in fertility, relative to vehicle treated control rats and this was shown to be due to the reduced capacity of vaginal/cervical stimulation to produce pseudopregnancy. Consistent with a selective loss in the effectiveness of cervical stimulation, immobilization produced by vaginal probing was reduced in capsaicin treated rats, but this response slowly recovered across time in some animals. Similarly, the ability of vaginal probing to induce a lordotic response during estrogen treatment was reduced in the capsaicin treated animals. The capsaicin treated animals showed analgesia to noxious heat, as measured by the tail flick test, but showed a normal foot withdrawal in response to pressure. The analgesic effect of vaginal stimulation on noxious pressure was unaltered in the capsaicin treated rats. Finally, the neurotoxic effect of capsaicin was verified in terms of a quantitative reduction in substance P immunoreactivity in the dorsal horns of the lumbosacral region of the spinal cord of capsaicin treated rats, relative to control animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Nitric oxide mediates capsaicin-induced increase in cochlear blood flow.

Capsaicin has been previously shown to increase cochlear blood flow (CBF) in a dose-dependent manner. The aim of this study was to define the role of nitric oxide (NO) in capsaicin-induced changes in CBF. This was investigated in the anesthetized guinea pig, utilizing laser Doppler flowmetry. Application of capsaicin (64.8 and 6.48 nmol in 2 microliters of saline) to the round window membrane (RWM) caused increases in CBF (34 +/- 2.8% of baseline (BL) and 28 +/- 2.3% BL, respectively (P < 0.001)). Application of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) (10 mg/kg intravenously or topically to the RWM) reduced blood flow in the cochlea, as previously reported. After pretreatment with i.v. L-NAME, the effect of capsaicin on CBF was significantly decreased. With the dose of capsaicin at 64.8 nmol, the increase in CBF fell from 34 +/- 2.8% BL to 6.9 +/- 1.5% BL (P < 0.001), and at 6.48 nmol it fell from 28 +/- 2.3% BL to 4.8 +/- 1.6% BL (P < 0.001). RWM L-NAME application also decreased the capsaicin vasodilatation effect. A capsaicin dose of 64.8 nmol resulted in only a 10 +/- 2.5% BL increase in CBF, and with 6.48 nmol capsaicin the increase was 7.8 +/- 2.2% of BL (P < 0.001). Capsaicin-sensitive sensory neurons in other systems are generally known to release substance P (SP), which in turn elicits release of endothelium derived relaxing factor (NO). The results of this study indicate that NO is a mediator of capsaicin-sensitive sensory neuronal function in CBF regulation.

Animals↗