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PubMed2001

Functional and biochemical evidence for capsaicin-induced neural endothelin release in isolated working rat heart.

In isolated working rat heart, capsaicin elicited a concentration-dependent constriction of coronary arteries accompanied by decline of all cardiac parameters recorded (heart rate, coronary and aortic flow, left ventricular developed pressure, and first derivative of left ventricular developed pressure). The following evidence suggests that capsaicin-induced changes are mediated by endothelin of neural origin: (1) the capsaicin (10 nM)-evoked decrease in coronary flow resulting in deterioration of cardiac functions was mimicked by endothelin (0.1 nM); (2) the selective endothelin ET(A) receptor antagonist, cyclo (D-alpha-aspartyl-L-propyl-D-valyl-L-leucyl-D-tryptophyl) (1 microM), abolished the cardiac effects provoked by capsaicin (10 nM); (3) reduction of extracellular Ca2+ concentration from 2.4 to 1.2 or 0.6 mM inhibited the cardiac effects of capsaicin (10 nM) but not those induced by endothelin (0.1 nM); (4) perfusion of the heart with 0.1% (v/v) Triton X-100 damaged the endothelium and reversed the enhancement of coronary flow evoked by bethanechol (1 microM), decreased the basal flow, but was without effect on capsaicin-induced coronary constriction; (5) in response to capsaicin challenge (10-100 nM), the endothelin concentration measured in coronary effluent by means of radioimmunoassay increased up to sevenfold but remained unchanged in the presence of 0.6 mM Ca2+; (6) no reduction of coronary flow was induced by capsaicin (100 nM) applied to the heart of rats which were desensitised by capsaicin (150 mg/kg). It is concluded that, in the rat heart, capsaicin acting on VR1 capsaicin receptors elicits a release of endothelin from the sensory nerve terminals.

Analysis of Variance↗
PubMed1998

Electromotive drug administration of lidocaine to anesthetize the bladder before intravesical capsaicin.

PURPOSE: The discomfort caused by intravesical capsaicin during instillation may restrict its use in some patients. We studied the effectiveness of using electromotive drug administration (EMDA) of lidocaine to anesthetize the bladder before capsaicin. MATERIALS AND METHODS: EMDA of lidocaine and epinephrine was performed in 8 patients with detrusor hyperreflexia using catheters, electrodes and an electrical current generator (20 mA., 15 minutes) followed immediately by intravesical capsaicin (2 mmol./l.) for 30 minutes under urodynamic monitoring. The patients scored suprapubic pain at 5 minutes and at the end of the capsaicin instillations on a scale of 0 to 10. Of the 8 patients 5 had had previous capsaicin treatments and the scores were compared to previous scores when intravesical lidocaine without EMDA had been used as local anesthesia before capsaicin. RESULTS: The pain scores during capsaicin instillations after EMDA of lidocaine were much lower than those during capsaicin instillations after lidocaine alone. EMDA virtually eliminated the hyperreflexic contractions of the bladder occurring during capsaicin instillations, thus reducing the risk of urethral leakage, and prevented autonomic dysreflexia that had previously occurred in 1 patient. CONCLUSIONS: EMDA of lidocaine is an effective means of reducing pain during subsequent intravesical capsaicin, which makes the use of capsaicin in the treatment of detrusor hyperreflexia more acceptable.

Administration, Intravesical↗
PubMed1997

Dose-dependent effects of capsaicin nasal challenge: in vivo evidence of human airway neurogenic inflammation.

BACKGROUND: Nerve involvement has been implicated in the pathophysiology of chronic respiratory inflammatory diseases. Peptidergic nerve stimulation has been shown to induce leukocyte activation and plasma extravasation in the airways of various animal species. The occurrence of this phenomenon of neurogenic inflammation in the human airway, however, has not been established. OBJECTIVE: We conducted this study to determine whether neuronal stimulation can induce reproducible and dose-dependent inflammatory changes in the human upper airway. METHODS: Ten volunteers with active allergic rhinitis participated in the study. Capsaicin, the pungent component of hot pepper that specifically stimulates afferent nerve fibers, was administered by means of nasal spray in doses of 1 microg, 10 microg, and 100 microg in a double-blind, randomized, crossover manner with 1 week between doses. Symptom scores before and after capsaicin nasal challenge were recorded by using visual analog scales. Nasal lavage fluids collected before and at 30 minutes, 1 hour, and 4 hours after capsaicin challenge were analyzed for leukocyte counts; albumin and lysozyme levels were measured to evaluate effects on plasma leakage and gland secretion, respectively. RESULTS: Capsaicin nasal challenge produced symptoms of burning, congestion, and rhinorrhea. Leukocyte counts or albumin and lysozyme levels were not significantly increased after administration of 1 microg of capsaicin at any time point. On the other hand, there were significant increases in leukocyte counts 1 hour (p < 0.05) and 4 hours (p = 0.008) after 10 microg of capsaicin and 30 minutes (p = 0.009), 1 hour (p = 0.007), and 4 hours (p = 0.007) after 100 microg of capsaicin. Albumin and lysozyme levels were both significantly increased 30 minutes after 10 microg and 100 microg of capsaicin (p = 0.005 for both). Comparison of changes in symptom scores, leukocyte counts, and albumin and lysozyme levels among the three capsaicin challenges indicated generally increasing effects with higher capsaicin doses. CONCLUSION: Capsaicin-sensitive nerve stimulation in subjects with active allergic rhinitis produces reproducible and dose-dependent leukocyte influx, albumin leakage, and glandular secretion. These results provide in vivo evidence for the occurrence of neurogenic inflammation in the human upper airway with active allergic disease.

Adult↗
PubMed2001

Oxidative DNA damage by capsaicin and dihydrocapsaicin in the presence of Cu(II).

Capsaicin is the pungent phenolic principle of the Capsicum species, and has shown a wide range of pharmacological properties, including antigenotoxic, antimutagenic, and anticarcinogenic effects. Other studies have, however, shown it to be a tumor promoter and potential mutagen, and a carcinogen, resulting in capsaicin being termed a 'double edged sword'. In the present study, we show that capsaicin is capable of causing strand scission in calf thymus and plasmid DNA in the presence of Cu(II) and that this breakage is mediated by reactive oxygen species, especially the hydroxyl radical. Our results further show that capsaicin can directly generate hydroxyl radicals in the presence of Cu(II). To explore the chemical basis of the DNA breakage reaction by capsaicin, we have compared these properties of capsaicin with its saturated structural analog dihydrocapsaicin (DHC). The rate of DNA degradation, as well as hydroxyl radical formation, was found to be greater in the case of capsaicin. Both capsaicin and DHC are able to reduce Cu(II) to Cu(I), which was shown to be an essential intermediate in the DNA cleavage reaction. Stoichiometric analysis indicated that whereas 1 mol of capsaicin reduced 3 mol of Cu(II), 1 mol of DHC reduced only 2 mol of Cu(II). This explains the greater activity of capsaicin and also leads to a model for copper binding to the capsaicins.

Animals↗
PubMed2001

Influence of thermode size for detecting heat pain dysfunction in a capsaicin model of epidermal nerve fiber loss.

Quantitative sensory testing of heat pain sensation has become an important tool to evaluate small caliber afferent nerve function in peripheral neuropathy. In earlier studies, we found that topical application of capsaicin in humans results in the loss of epidermal nerve fibers (ENFs) with a corresponding decrease in detection of heat pain sensation. Capsaicin may therefore be a useful model for developing optimal psychophysical testing procedures for detection of neuropathy in its early stages. Here we determined the influence of thermal probe (thermode) size in detecting the diminished heat pain sensation following capsaicin application. Twelve healthy volunteers applied 0.075% capsaicin topically to the volar forearm four times daily for 7 days. Psychophysical measures of heat pain, mechanical (sharp) pain, and tactile threshold were obtained daily from untreated control skin and from capsaicin-treated skin during capsaicin application, and once weekly for 5 weeks following discontinuation of capsaicin. Heat pain sensation was assessed using a large (30 x 30 mm) and small (3 x 3 mm) thermode and different algorithms to assess pain threshold and suprathreshold heat pain. Skin biopsies were obtained and were processed for immunohistochemical localization of (ENFs) using the pan neuronal marker protein gene product 9.5. Capsaicin produced a rapid decrease in the number of ENFs, with nearly complete disappearance after 3 days of treatment. Heat pain evoked by the small, but not the large, thermode decreased dramatically after capsaicin treatment. The sensation of heat pain returned toward normal after 2--3 weeks following discontinuation of capsaicin treatment concordant with gradual reinnervation of the epidermis. Regression analysis indicated that the sensation of heat pain evoked by the small thermode correlated much better with the number of ENFs than heat pain evoked by the large thermode. The detection of sharp pain decreased moderately after capsaicin treatment. Assessment of heat pain sensation using small thermodes has potential for detecting sensory deficits in early stages of small fiber neuropathy.

Adult↗
PubMed2002

Genetic diversity underlying capsaicin intake in the Mishima battery of mouse strains.

Capsaicin is the active substance responsible for the pungent sensation produced by red pepper. In order to approach the underlying genetic mechanism for preference of red pepper, we conducted a 12-h, 1-bottle intake test of capsaicin solution using both male and female animals from the Mishima battery of mouse strains: 10 wild-derived inbred strains (PGN2, BFM/2, HMI, CAST/Ei, NJL, BLG2, CHD, SWN, KJR, MSM), 1 strain derived from the so-called fancy mouse (JF1), and 3 widely used laboratory strains (C57BL/6J, DBA/1J and BALB/cAnN). The concentration of capsaicin was increased from 0.5 to 15 microM successively. Gender differences were not observed in this test, but we found striking strain differences in capsaicin intake. Relative to baseline water intake, C57BL/6J and DBA/1J consumed 10%, whereas two wild strains, KJR and MSM, ingested approximately 60% of the 15-microM capsaicin solution. In a 2-bottle fluid preference test, both C57BL/6J and MSM strains reject capsaicin fluid even at the 0.5-microM concentration, which indicates that the receptors for capsaicin in these strains recognize capsaicin at a similar level. Thus, the strain differences at higher capsaicin concentrations in the 1-bottle test may reflect differences in central nervous system response to the capsaicin solution. The genetic difference in intake of capsaicin observed in these strains may provide a useful tool for identifying genes underlying response to red pepper in mice and other mammalian species.

Animals↗
PubMedDate not supplied

Capsaicin and the stomach. A review of experimental and clinical data.

Capsaicin, the pungent principle of hot pepper, because of its ability to excite and later defunctionalize a subset of primary afferent neurons, has been extensively used as a probe to elucidate the function of these sensory neurons in a number of physiological processes. In the rat stomach, experimental data provided clear evidence that capsaicin-sensitive (CS) sensory nerves are involved in a local defense mechanism against gastric ulcer. Stimulation of CS sensory nerves with low intragastric concentrations of capsaicin protected the rat gastric mucosa against injury produced by different ulcerogenic agents. High local desensitizing concentrations of capsaicin or systemic neurotoxic doses of the agent markedly enhanced the susceptibility of the rat gastric mucosa to later noxious challenge. Resiniferatoxin, a potent analogue of capsaicin possesses an acute gastroprotective effect similar to that of capsaicin in the stomach. The gastroprotective effect of capsaicin-type agents involves an enhancement of the microcirculation effected through the release of mediator peptides from the sensory nerve terminals with calcitonin gene-related peptide being the most likely candidate implicated. They do not depend on vagal efferent or sympathetic neurons or involve prostanoids. The gastric mucosal protective effect of prostacyclin is retained after systemic or topical capsaicin desensitization. Capsaicin-sensitive fibers are involved in the repair mechanisms of the gastric mucosa. A protective role for CS sensory nerves has also been demonstrated in the colon. In most studies, capsaicin given into the stomach of rats or cats inhibited gastric acid secretion. In humans, although recent studies provide evidence in favor of a beneficial effect of capsaicin on the gastric mucosa, an exact concentration-related assessment of the effect of the agent is still lacking.

Animals↗
PubMed2001

Urodynamic effects induced by intravesical capsaicin in rats and hamsters.

This study compared the effect of acute intravesical capsaicin administration on transvesical cystometries in urethane-anesthetized rats and hamsters, and aimed to assess whether sensory neuropeptides (tachykinins; calcitonin gene-related peptide, CGRP) play a role in the urodynamic effects of capsaicin in these species. The following urodynamic parameters were evaluated: the mean micturition interval (MI), the pressure threshold for micturition (PT), and the mean amplitude of micturition contractions (MAC). Two concentrations of capsaicin (10 and 100 microM) were evaluated in both species. Here, we demonstrate that 10-microM capsaicin decreased the PT in both rats and hamsters, and 100-microM capsaicin decreased the PT in hamsters and decreased the MI in both species. In addition, 100-microM capsaicin increased the MAC in rats but decreased the MAC in hamsters. Administration of CGRP (10 nmol kg(-1) , i.v.) significantly decreased both MAC and PT in hamsters only, while capsaicin-induced desensitization of neuropeptide-containing afferents antagonized the urodynamic effects of intravesical capsaicin. In addition, administration of the tachykinin NK2 receptor antagonist, Nepadutant (100 nmol kg(-1), i.v.), reduced the effects of capsaicin (100 microM) only in rats. These results indicate that capsaicin induces bladder hyperactivity in both rats and hamsters, but the urodynamic characteristics of this hyperactivity markedly differ in these two species. The differences observed may be due to differential expression of sensory neuropeptides in capsaicin-sensitive bladder afferents or neuropeptide receptors in smooth muscle cells and in nerve fibers.

Animals↗
PubMed2003

Metabolism of capsaicin by cytochrome P450 produces novel dehydrogenated metabolites and decreases cytotoxicity to lung and liver cells.

Capsaicin is a common dietary constituent and a popular homeopathic treatment for chronic pain. Exposure to capsaicin has been shown to cause various dose-dependent acute physiological responses including the sensation of burning and pain, respiratory depression, and death. In this study, the P450-dependent metabolism of capsaicin by recombinant P450 enzymes and hepatic and lung microsomes from various species, including humans, was determined. A combination of LC/MS, LC/MS/MS, and LC/NMR was used to identify several metabolites of capsaicin that were generated by aromatic (M5 and M7) and alkyl hydroxylation (M2 and M3), O-demethylation (M6), N- (M9) and alkyl dehydrogenation (M1 and M4), and an additional ring oxygenation of M9 (M8). Dehydrogenation of capsaicin was a novel metabolic pathway and produced unique macrocyclic, diene, and imide metabolites. Metabolism of capsaicin by microsomes was inhibited by the nonselective P450 inhibitor 1-aminobenzotriazole (1-ABT). Metabolism was catalyzed by CYP1A1, 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4. Addition of GSH (2 mM) to microsomal incubations stimulated the metabolism of capsaicin and trapped several reactive electrophilic intermediates as their GSH adducts. These results suggested that reactive intermediates, which inactivated certain P450 enzymes, were produced during catalytic turnover. Comparison of the rate and types of metabolites produced from capsaicin and its analogue, nonivamide, demonstrated similar pathways in the P450-dependent metabolism of these two capsaicinoids. However, production of the dehydrogenated (M4), macrocyclic (M1), and omega-1-hydroxylated (M3) metabolites was not observed for nonivamide. These differences may be reflective of the mechanism of formation of these metabolites of capsaicin. The role of metabolism in the cytotoxicity of capsaicin and nonivamide was also assessed in cultured lung and liver cells. Lung cells were markedly more sensitive to cytotoxicity by capsaicin and nonivamide. Cytotoxicity was enhanced 5 and 40% for both compounds by 1-ABT in BEAS-2B and HepG2, respectively. These data suggested that metabolism of capsaicinoids by P450 in cells represented a detoxification mechanism (in contrast to bioactivation).

Animals↗
PubMed2000

Low-threshold heat response antagonized by capsazepine in chick sensory neurons, which are capsaicin-insensitive.

The heat-transducing receptor VR1 cloned from rat sensory neurons can be activated by both noxious heat and capsaicin. As the response of sensory neurons to capsaicin is species dependent, it is conceivable that the responses to noxious heat and to capsaicin are transduced by distinct receptors across different species. Therefore, we investigated responses to noxious heat from a capsaicin-insensitive (chick) and a capsaicin-sensitive (rat) species. In chick, whole-cell patch-clamp experiments in isolated dorsal root ganglion neurons revealed two populations of neurons with different thresholds to noxious heat, activated at approximately 43 degrees C and approximately 53 degrees C. In cobalt uptake experiments, the proportion of neurons showing a heat-induced response increased with increasing heat stimuli. Application of capsaicin (1-10 microM) did not result in inward currents or cobalt uptake. Rat neurons yielded comparable results in heat experiments, but were capsaicin-sensitive. Although chick neurons are insensitive to capsaicin, the competitive capsaicin antagonist capsazepine (1-10 microM) was effective in blocking heat-induced responses, verified by patch-clamp and cobalt uptake methods. The noncompetitive capsaicin antagonist ruthenium red (10 microM) reduced to almost nil the proportion of heat-responsive neurons identified with the cobalt uptake method. These findings suggest that chick DRG neurons express a low-threshold heat-transducing receptor with a pharmacological profile distinct from the low-threshold heat receptor VR1 cloned from rat DRG neurons. The data support the idea that there might be heat receptor subtypes with differences in the capsaicin binding site.

Animals↗
PubMed1996

Urodynamic changes during therapeutic intravesical instillations of capsaicin.

OBJECTIVE: To describe the technique for and urodynamic changes during therapeutic instillations of intravesical capsaicin in patients with detrusor hyper-reflexia. PATIENTS AND METHODS: Ninety intravesical instillations of capsaicin were performed as a therapeutic procedure in 30 patients; 21 patients had various causes of non-traumatic spinal cord disease, five patients were very severely neurologically impaired and were bed-bound with an indwelling catheter, and four were neurologically normal. Simultaneous cystometry was performed in 25 patients during the instillation of capsaicin; 100 mL of 1 or 2 mmol/L capsaicin in 30% ethanol/saline was instilled into the bladder for 30 min and two patients received 30% ethanol/saline only. The last 56 capsaicin treatments were preceded by the instillation of 40 mL of 2% lignocaine for 20 min. Detrusor hyper-reflexia was decreased and urinary continence improved for 3-6 months after a single instillation; the instillation was then repeated. Two patients who received only ethanol/saline showed no clinical or urodynamic improvement. RESULTS: The treatment was not abandoned in any patient due to discomfort and there were no short- or medium-term complications. All patients with spinal cord disease and phasic detrusor hyper-reflexia had similar, frequent and repetitive detrusor contractions during the instillation of capsaicin. These acute reactive contractions did not occur in the neurologically normal patients. Similarly, the instillation of intravesical lignocaine only caused no phasic detrusor contractions. Intravesical lignocaine instillation before capsaicin markedly reduced and sometimes abolished the detrusor overactivity and lessened the discomfort for the patients. The instillation of lignocaine before capsaicin did not alter the benefit from each instillation of intravesical capsaicin. CONCLUSION: A method has been developed for administering capsaicin intravesically which diminishes discomfort for the patient and in the short- and medium-term is free of complications. The study also provides functional evidence of the role of capsaicin-sensitive afferents in phasic detrusor hyper-reflexia due to spinal cord disease.

Administration, Intravesical↗
PubMed2003

The role of capsaicin-sensitive afferents in autonomic dysreflexia in patients with spinal cord injury.

OBJECTIVES: To determine whether capsaicin-sensitive nerves in the bladder form the afferent limb involved in autonomic dysreflexia (AD) in patients with spinal cord injury (SCI). PATIENTS AND METHODS: Seven men with SCI (five cervical cord, two thoracic cord) with AD and detrusor hyper-reflexia (DH) were enrolled. Under general anaesthesia, capsaicin solution (100 mL of 2 mmol/L in 10% ethanol) was instilled in the bladder and retained for 30 min. The patients were assessed by medium-fill cystometry (CMG) just before and 50 min after the capsaicin treatment. Intra-arterial blood pressure (BP) and heart rate were monitored continuously throughout the procedure; 10% ethanol was instilled before capsaicin treatment in four patients as a control. Serum catecholamines were measured during bladder filling and capsaicin treatment, and the blood ethanol concentration also measured after instillation in all patients. The CMG with concomitant monitoring of BP and heart rate was repeated 1 week, 1, 3, 6, 12 and 24 months after instillation. In two patients the instillations were repeated 5 and 12 months after the first because of recurrence of DH. Urodynamic variables assessed were maximum cystometric capacity (MCC), maximum amplitude of uninhibited detrusor contraction (UICmax), the bladder capacity at 40 cmH2O detrusor pressure (Cdp40) and a systolic BP of> 140 mmHg or diastolic BP of> 90 mmHg (C(HT)). RESULTS: There was an increase in BP and a decrease in heart rate in all patients during bladder filling before capsaicin treatment. Instillation of capsaicin produced a significant increase in both systolic and diastolic BP and a significant decrease in heart rate. The maximum cardiovascular effects were at 5-10 min after instillation and gradually returned to baseline within 40 min. The vehicle had negligible effects on either BP or heart rate. After capsaicin treatment, the responses of BP and heart rate to bladder distension were significantly reduced. Both serum catecholamine values and the blood ethanol concentration remained within normal limits. The mean (range) follow-up after the first treatment was 15 (6-30) months. One month after treatment all seven patients became continent and their episodes of AD became negligible and well tolerable between catheterizations (for 3-4 h); the effects lasted for >or= 3 months in all. MCC was significantly increased at 4 weeks and 3 months, and UICmax significantly decreased at 4 weeks after treatment. Both mean Cdp40 and C(HT) increased 1 week, 1 and 3 months after treatment. Two patients received a second instillation, and have been continent with no symptomatic AD for 6 and 24 months. The remaining five patients have been continent with no symptomatic AD for 6-12 months. CONCLUSION: These results indicate that intravesical capsaicin, but not the vehicle, acutely triggers AD in patients with SCI, suggesting involvement of bladder capsaicin- sensitive afferents in AD in these patients. The results also suggest that intravesical capsaicin may be a promising therapy for both AD and DH in such patients. Further long-term follow-up studies are needed to evaluate the duration of its effect.

Administration, Intravesical↗
PubMed2004

Involvement of NADPH oxidase-mediated generation of reactive oxygen species in the apototic cell death by capsaicin in HepG2 human hepatoma cells.

Although capsaicin (8-methyl-N-vanillyl-6-nonenamide), a pungent ingredient in a variety of red peppers of the genus Capsicum, has been shown to induce apoptotic cell death in many cancer cells, the exact mechanism of this action of capsaicin is not completely understood. In this study, we investigated the possible mediation of the NADPH oxidase-modulated production of reactive oxygen species (ROS) in the apoptotic mechanism of capsaicin in HepG2 human hepatoblastoma cells. Capsaicin induced apoptotic cell death in a time- and dose-dependent manner. Capsaicin at the concentration of inducing apoptosis also markedly increased the level of ROS. The capsaicin-induced generation of ROS and apoptosis was significantly suppressed by treatment with antioxidants, DPPD and tocopherol. In addition, inhibitors of NADPH oxidase, diphenylene iodonium, apocynin and neopterine, profoundly blocked the capsaicin-induced ROS generation and apoptosis. The expression of Rac1N17, a dominant negative mutant of Rac1, also significantly inhibited the capsaicin-induced apoptosis. Activation of nuclear factor-kappaB, a transcription factor essentially involved in ROS-induced apoptosis, was also observed by treatment with capsaicin. Collectively, these results suggest that the NADPH oxidase-mediated generation of ROS may be essentially involved in the mechanism of capsaicin-induced apoptosis in HepG2 cells. These results further suggest that capsaicin may be a valuable agent for the therapeutic intervention of human hepatomas.

Antioxidants↗
PubMed2006

Effect of repeated capsaicin ingestion on intestinal chemosensation and mechanosensation.

BACKGROUND: Ingestion of capsaicin reduces symptoms in functional dyspepsia but induces upper abdominal symptoms initially. AIMS: To evaluate the effects of one week of oral dosing with capsaicin on mechanonociception and chemonociception. METHODS: Healthy subjects ingested capsules containing 0.5 mg capsaicin t.d.s (n = 8) or placebo (n = 5) for 7 days. Before (day 0) and after (day 8) capsule ingestion the jejunum was distended with a balloon and perfused with a capsaicin solution. A graded questionnaire evaluated distension- and capsaicin-induced sensation, aggregate perception scores were calculated. RESULTS: Infusion of capsaicin induced sensations similar to distension. In subjects receiving capsaicin capsules, mean +/- S.E.M. perception scores at 24 mL distension volumes were 4.7 +/- 1.2 (day 0) and 3.2 +/- 1.3 (day 8, N.S.). Distension with 40 mL induced perception scores of 10.3 +/- 1.0 vs. 8.2 +/- 1.0 (P < 0.05). During capsaicin perfusion, first sensation was reported after 13.2 +/- 1.9 min (day 0) and 8.1 +/- 0.8 min (day 8, N.S.), discomfort thresholds after 44.1 +/- 6.0 and 31.2 +/- 5.7 min (P < 0.05). In the placebo group, mechano- and chemonociception remained unaltered on days 0 and 8. CONCLUSIONS: One week of ingestion of capsaicin sensitized chemonociceptors, while sensitivity of mechanonociceptors for distension decreased. Painful sensations during the first week of treatment with capsaicin can be attributed to a sensitizing effect of capsaicin on vanilloid receptors.

Administration, Oral↗
PubMed1989

Effects of capsaicin desensitization on the stimulatory effect of kinins, prostaglandins, biogenic amines and various drugs in guinea-pig isolated atria.

1. A simple desensitization protocol was set up using capsaicin and isolated, spontaneously beating atria of guinea-pigs to assess the possible participation of cardiac, capsaicin-sensitive, substance P (SP)- and calcitonin gene-related peptide (CGRP)-containing sensory nerve fibres, in the cardiac stimulatory effects of bradykinin (Bk), kallidin (Kd), 5-hydroxytryptamine (5-HT), histamine, prostaglandin E2 (PGE2), prostaglandin E1 (PGE1), prostaglandin F2 alpha, (PGF2 alpha), adrenaline (Ad), glucagon, nicotine and angiotensin II (AII). 2. The positive chronotropic and inotropic effects of Bk, Kd and 5-HT were markedly reduced in capsaicin-desensitized atria compared to control. The percentage inhibition of the chronotropic and inotropic responses to the three agonists seemed to be inversely related to the concentration of agonist used and to vary also with the type of cardiac effect produced by the drug (for Bk the percentage inhibition was: 36-81% (chronotropic effect) and 62-86% (inotropic effect); for Kd: 61-78% (chronotropic effect) and 53-77% (inotropic effect); for 5-HT: 25-66% (chronotropic effect) and 40-64% (inotropic effect]. 3. The positive chronotropic and inotropic effects of histamine, PGE1, PGE2, PGF2 alpha, glucagon and AII had similar amplitudes in capsaicin-desensitized and control atria. 4. The positive chronotropic and inotropic effects of Ad and nicotine were differentially affected by capsaicin desensitization. The inotropic effects of 7.5 x 10(-7) and 7.5 x 10(-6) M Ad were reduced by 41 and 27% respectively, in capsaicin-desensitized atria compared to control. The chronotropic effects of 1.54 x 10(-5) and 6.17 x 10(-5) M nicotine were inhibited by 57 and 26% respectively, by capsaicin desensitization. On the other hand, the chronotropic effect of Ad and the inotropic action of nicotine were of similar amplitude in capsaicin-desensitized and control atria. 5. These results were taken as an indication that a substantial part of the chronotropic and inotropic effects of Bk, Kd or 5-HT in guinea-pig atria, unlike those of histamine, PGE1, PGE2 PGF2 alpha, glucagon and AII, might be the result of stimulation of capsaicin-sensitive, SP- and CGRP- containing sensory nerve fibres. The slight, differential inhibition of the chronotropic and inotropic effects of Ad and nicotine by capsaicin desensitization suggests a minor contribution by cardiac, capsaicin-sensitive sensory nerve fibres to the effects of nicotine and Ad in guinea-pig atria.

Animals↗
PubMed1990

The effect of capsaicin on voltage-gated calcium currents and calcium signals in cultured dorsal root ganglion cells.

1. The effects of capsaicin on voltage-gated Ca2+ currents (ICa), and intracellular Ca2+ concentrations [( Ca2+]i) in cultured dorsal root ganglion (DRG) neurones of the rat were examined in vitro by use of combined patch clamp-microfluorometric recordings. 2. Under voltage-clamp conditions, capsaicin (0.1-10 microM) caused a concentration-dependent decrease in the magnitude of the ICa, an elevation in the holding current (Ih) and a concomitant rise in the [Ca2+]i in most cells examined. Repeated application of capsaicin produced marked desensitization. 3. Some decrease in the ICa produced by capsaicin was also observed when the rise in [Ca2+]i was buffered with EGTA or BAPTA and when Ba2+ was used as the charge carrier; under these conditions the desensitization previously observed was smaller. 4. The decrement in voltage-gated current was smaller in Ba2+ containing solutions than in Ca2+ containing solutions suggesting that the capsaicin-induced influx of Ca2+ partially mediated the observed decrease in the voltage-gated current. In cells which showed a marked response to capsaicin an outward (positive) current was sometimes observed upon depolarization from -80 to 0 mV. This effect was consistent with an outward movement of cations through the capsaicin conductance pathway which may also account, in part, for the apparent reduction in ICa by capsaicin. 5. The effects of capsaicin under voltage-clamp conditions were prevented by ruthenium red (1 microM). 6. Under current clamp conditions, capsaicin depolarized and caused a rise in [Ca2+]i in the majority of DRG cells examined. Both of these effects could be prevented by ruthenium red (500 nM). 7. It is concluded that capsaicin reduces the Ic. of rat DRG neurones primarily by indirect mechanisms.

Animals↗
PubMed1993

Capsaicin-induced relaxation in the rat isolated external urethral sphincter: characterization of the vanilloid receptor and mediation by CGRP.

1. The potential role of capsaicin-sensitive nerves in the relaxation of the rat external urethral sphincter (REUS) was evaluated by demonstrating the existence of specific vanilloid (capsaicin) receptors and by investigating the sensory neurotransmitter(s) putatively involved in this relaxation. 2. Capsaicin (1 microM) relaxed REUS strips precontracted with noradrenaline (NA) (0.1 mM). This effect underwent desensitization and it was absent in preparations taken from adult capsaicin-pretreated rats. 3. Capsaicin-induced relaxation of NA-precontracted REUS was mimicked by calcitonin gene-related peptide (CGRP, 0.3-10 microM), but not by substance P (1 microM), vasoactive intestinal polypeptide (VIP, 1 microM), alpha-beta methylene ATP (10 microM), gamma-aminobutyric acid (GABA, 3 mM) or galanin (1 microM). A cross-tachyphylaxis between capsaicin (1 microM) and CGRP (1 microM) was observed. Both capsaicin and CGRP-induced relaxation were partially antagonized by the proposed CGRP antagonist, CGRP (8-37) (10 microM). 4. Electrical field stimulation (EFS, 2.5 Hz, 60 V, 1 ms, trains of 5 s every 5 min) of REUS evoked a contraction characterized by a largely adrenergic slowly developing tonic contraction with superimposed fast twitches due to the striated component of the strips. Both capsaicin (1 microM) and CGRP (0.01-1 microM) produced an almost complete inhibition of EFS-induced tonic contraction. A cross-tachyphylaxis between capsaicin and CGRP was observed. Furthermore, these inhibitory actions were unaffected by CGRP (8-37) (10 microM). 5. [3H]-resiniferatoxin displayed specific, saturable binding to rat urethral membranes. Data were consistent with a single site with a Kd of 105 pM and a Bmax of 40 fmol mg-1 protein. This binding was inhibited by capsaicin with a Ki of 0.6 microM and it was reduced by approximately 80% in preparations taken from rats that had undergone surgical ablation of the major pelvic ganglion 4 days earlier.6. In conclusion we have demonstrated the existence of vanilloid receptors on capsaicin-sensitive nerves innervating the rat urethra mainly through the major pelvic ganglion. The activation of this set of nerves could lead to a local release of CGRP that in turn elicits a remarkable urethral relaxation. Such a mechanism could be of relevance in physiological conditions to facilitate urine expulsion during micturition and in pathological conditions to help removal of noxious stimuli following mechanical/chemical irritation of the lower urinary tract.

Animals↗
PubMed1993

Profile of capsaicin-induced mouse ear oedema as neurogenic inflammatory model: comparison with arachidonic acid-induced ear oedema.

1. We have investigated the mechanism of capsaicin-induced mouse ear oedema compared with that of arachidonic acid (AA)-induced ear oedema, and evaluated the possible involvement of neuropeptides in the development of capsaicin-induced oedema. 2. Topical application of capsaicin (0.1-1.0 mg per ear) to the ear of mice produced immediate vasodilatation and erythema followed by the development of oedema which was maximal at 30 min after the treatment. This oedema was of shorter duration with less swelling than AA-induced oedema (2.0 mg per ear). 3. Capsaicin-induced ear oedema was unaffected when inhibitors of arachidonate metabolites including platelet activating factor (PAF) were administered before capsaicin (250 micrograms per ear) application, while these agents significantly prevented AA-induced oedema. Dexamethasone, histamine H1 and/or 5-hydroxytryptamine (5-HT) antagonists, and substance P (SP) antagonists were effective in inhibiting both models. Furthermore, a Ca(2+)-channel blocker and the capsaicin inhibitor, ruthenium red, were effective inhibitors of capsaicin oedema but had no effect on AA-induced oedema. 4. Phosphoramidon (50 micrograms kg-1, i.v.), an endopeptidase inhibitor, markedly (P < 0.001) enhanced only capsaicin-induced ear oedema, but bestatin (0.5 mg kg-1, i.v.), an aminopeptidase, failed to enhance oedema formation. 5. Neuropeptides (1-100 pmol per site) such as rat calcitonin gene-related peptide (CGRP), SP, neurokinin A (NKA), and vasoactive intestinal peptide (VIP), which are released from capsaicin-sensitive neurones, caused ear oedema by intradermal injection. Furthermore, a synergistic effect of CGRP (10 fmol per site) and SP (10 pmol per site) on oedema formation was observed. 6. The oedema induced by neuropeptides was significantly (P<0.05 or P<0.001) inhibited when cyproheptadine (20 mg kg-1, p.o.), a histamine H, and 5-HT antagonist, was administered before injection. In contrast, nifedipine (50 mg kg-1, p.o.), a Ca2+-channel blocker, and indomethacin(10 mg kg-1, p.o., except for NKA), a cyclo-oxygenase inhibitor, had little effect on neuropeptide induced oedema.7. These results suggest that the mechanism of capsaicin-induced ear oedema is different from that of AA-induced oedema and suggest that the development of capsaicin-induced ear oedema is primarily mediated by neuropeptides. The neuropeptides released after activation of sensory nerves cause an increase of vascular permeability by interactions with endothelial cells and by histamine (and 5-HT)release from mast cells.

Administration, Cutaneous↗