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The capsaicin sensitivity of the preoptic region is preserved in adult rats pretreated as neonates, but lost in rats pretreated as adults.

Two days old rats were pretreated with subcutaneous injection of 50 mg/kg, and adult animals with either 20, 50 or 300 mg/kg capsaicin. The responsiveness of these and naive animals to microinjection into the preoptic region of capsaicin (10 micrograms) and to subcutaneously injected capsaicin (2 mg/kg) was studied at the age of 3--4 months by recording the tail skin vasodilatation and colon temperature, respectively. On preoptic injection of capsaicin, the reaction of neonatally-pretreated adult rats was similar to that of naive animals, while in all groups pretreated as adults the tail skin vasodilatation was abolished. In response to 2 mg/kg capsaicin administered subcutaneously, the group pretreated neonatally and the adults pretreated with 20 mg/kg capsaicin produced significantly less hypothermia than the naive animals. Rats pretreated as adults with 50 and 300 mg/kg capsaicin failed to show a hypothermic reaction. It is concluded that the sensitivity of the preoptic region to capsaicin is preserved when 2 days old rats are treated with the drug, but lost when adults are injected with capsaicin. These features of capsaicin sensitivity indicate a functioning preoptic and an impaired extrapreoptic thermoregulation in rats pretreated with capsaicin as neonates.

Age Factors↗

The role of the capsaicin-sensitive innervation of the rat urinary bladder in the activation of micturition reflex.

Capsaicin applied on the serosal surface of the urinary bladder in urethane-anaesthetized rats produces two distinct types of motor effects: a tetrodotoxin-, hexamethonium- and lidocaine-insensitive 'tonic' contraction and a series of tetrodotoxin-, hexamethonium- and lidocaine-sensitive rhythmic contractions. Both 'tonic' and rhythmic contractions are abolished by bladder denervation indicating their neurogenic origin. The rhythmic but not the 'tonic' component of the contractile effect of capsaicin is abolished by spinal cord transection indicating activation of a supraspinal micturition reflex. The motor effects of topical capsaicin are unaffected by pretreatment with indomethacin or diphenhydramine plus cimetidine. Pretreatment with a large dose of subcutaneous (SC) capsaicin increases both volume and pressure threshold for micturition while amplitude of micturition contraction is unaffected. Moreover the spinal somatovesical reflex elicited by pinching of the perineal skin is unaffected by capsaicin-desensitization. The intracerebroventricular (ICV) administration of capsaicin reproduces the effects of SC capsaicin on the bladder response to saline filling. Rats pretreated with ICV capsaicin are as sensitive as controls in reacting to noxious heat (hot plate test) while the wiping response to instillation of capsaicin into one eye was abolished. These findings provide functional evidence for the presence in the rat urinary bladder of a capsaicin-sensitive innervation which subserves a sensory function in relaying volume/pressure information from detrusor muscle to central nervous system. Information carried through these capsaicin-sensitive fibers appears to be relevant for initiation of a supraspinal vesico-vesical micturition reflex. Functional evidence indicates that these fibers may terminate at supraspinal level.

Acetylcholine↗

Dose-response relationships in the thermoregulatory effects of capsaicin.

The hypothermic effect of capsaicin, the reduced responsiveness towards the hypothermic effect of the drug as well as the impairment of thermoregulation in the warm environment subsequent to the administration of different doses of capsaicin have been studies in rats. The mortality after capsaicin treatment has also been established. 1. Capsaicin given subcutaneously in doses of 1-10 mg/kg induced a dose-dependent fall in body temperature lasting for 2-5 h. A single dose of 10 mg/kg caused the most pronounced hypothermic effect reaching its maximum (3,4 degrees C) after 107 min. After higher doses (20-50 mg/kg) the fall in body temperature was less, being similar to that observed after the administration of 1-2 mg/kg. 2. A decreased sensitivity towards the hypothermic effect of a test dose of 2 mg/kg capsaicin, as well as an impaired tolerance to high ambient temperature have been found in rats 2 weeks after the pretreatment either with a single dose of 20-50 mg/kg or fractionated administration of 50 mg/kg capsaicin. The fractionated administration of a dose of 50 mg/kg capsaicin proved to be beneficial in decreasing mortality without affecting the desensitizing effect of capsaicin pretreatment. 3. After single doses of capsaicin the hypothermic period was followed by a dose-dependent hyperthermia which lasted for at least 2 days. A close correlation between the prolonged hyperthermic action and the desensitizing effect of capsaicin administration has also been established. The possible relationship between the desensitizing and hyperthermia inducing effect of capsaicin is briefly discussed.

Animals↗

Cytotoxicity and genotoxicity of capsaicin in human neuroblastoma cells SHSY-5Y.

Capsaicin, a natural product of Capsicum species, induces excitation of pain perception at nociceptive terminals. Our previous studies have shown that capsaicin inhibits protein synthesis in cultured monkey kidneys cells (Vero cells) and in primoculture of rat astrocytes. We have now investigated the effect of capsaicin on human neuroblastoma cells SHSY-5Y. The cytotoxicity has been assessed by incorporation of [(3)H]L-leucine into cellular protein in the presence of capsaicin and the genotoxicity has been evaluated using the comet assay and the fragmentation assay after incubation of neuroblastoma cells with 25-100 microM capsaicin. The concentration required to inhibit 50% of the protein synthesis (IC(50)) was found to be 60 microM after incubation with the toxin during one cellular cycle (5 days) of SHSY-5Y. The results of the comet test and DNA fragmentation assay clearly suggest that capsaicin is able to induce DNA strand breaks already with concentrations in the range of 50 microM, corresponding to 29.3 microM of capsaicin not bound to alpha-1 acid glycoprotein. Several daily topical applications of preparations containing 0.075% of capsaicin could lead to blood capsaicin concentration of this order of magnitude following transdermal passage (5% of the total quantity applied). Because DNA strand breaks or DNA lesions may affect cellular functions, lead to cell death and/or mutagenesis, our data in case of inappropriate DNA repair may have important implications for the possible health threats of capsaicin, specially in the case of misuse of capsaicin preparations in pathological situations.

Capsaicin↗

Protective effect of dietary capsaicin on induced oxidation of low-density lipoprotein in rats.

An animal study was carried out to examine the beneficial influence of the known hypocholesterolemic spice principle-capsaicin on the susceptibility of low-density lipoprotein to oxidation in normal and hypercholesterolemic condition. In rats rendered hypercholeterolemic by maintaining them on a cholesterol-enriched diet for eight weeks, inclusion of capsaicin (0.015%) in the diet, produced significant hypocholesterolemic effect. Oxidation of low-density lipoprotein was induced either by copper ion in vitro after its isolation, or by ferrous ion in vivo in experimental rats under either normal or hypercholesterolemic situation and the beneficial effect of dietary capsaicin on the same was evaluated. LDL oxidation was measured by the thiobarbituric acid reactive substances (TBARS) formed and relative electrophoretic mobility of oxidized LDL. Dietary capsaicin was found to be protective to the LDL oxidation in vitro in the case of normal rats as indicated by reduction in TBARS by more than 40%. In the case of LDL isolated from hypercholesterolemic rats the extent of copper induced LDL oxidation was significantly lower than that of LDL isolated from normal rats. Dietary capsaicin did not make any difference in the extent of LDL oxidation in vitro in hypercholesterolemic rats. Ferrous ion induced in vivo oxidation of LDL was 71% lower in capsaicin fed normal rats. In high cholesterol feeding, Fe-induced in vivo oxidation of LDL was 73% lower, while the same was still marginally lower in capsaicin fed hypercholesterolemic rats. Hepatic lipid peroxidation was significantly decreased by dietary capsaicin in normal rats. While a significantly decreased level of lipid peroxidation was observed in hypercholesterolemic rats compared to normal rats, the same was not significantly altered by dietary capsaicin. Results suggest that dietary spice principle capsaicin is protective to LDL oxidation both in vivo and in vitro under normal situation, while in hypercholesterolemic situation where the extent of LDL oxidation is already lowered, capsaicin does not offer any further reduction.

Animals↗

Quantitative electron-microscopic analyses of pulpal nerve fibres in the mouse lower incisor after neonatal capsaicin treatment.

A single dose of capsaicin (50 mg/kg) was injected subcutaneously into four mice on day 2 of life; four untreated mice were used as controls. Six months later, a drop of 30 microM capsaicin was instilled on to the cornea of all the mice and the number of times the eyes were wiped was counted to assess the effect of capsaicin on trigeminal sensory neurones. Ultrathin cross-sections were made of the apical pulp of the incisors on both sides of control (n = 8) and capsaicin-treated animals (n = 8). Electron micrographs of pulp nerves were taken and enlarged to a final magnification of x34,000. The numbers of unmyelinated axons in the pulps of all 16 incisors and of unmyelinated axons per Schwann cell in the pulps of four incisors each from the control and capsaicin-treated groups were counted. The short diameters of unmyelinated axons were measured with a computer-operated image analyser. The number of eye wipings was eight-fold less in the capsaicin-treated than in the normal group. This finding clearly indicated that capsaicin irreversibly affected the chemogenic nociceptive trigeminal neurones. The mean number of unmyelinated axons was 345 in controls and 217 (37.1% reduction) in capsaicin-treated animals. The number of unmyelinated axons of less than 0.6 microns dia was 41.5% less in capsaicin-treated mice than in controls. Thus, fine unmyelinated axons in the mouse incisor pulp are capsaicin sensitive, and they are assumed to be nociceptive fibres conveying pain stimuli from the tooth. Capsaicin affected Schwann cells, even those with few unmyelinated axons.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Capsaicin pre-treatment prevents the development of antigen-induced airway hyperresponsiveness in neonatally immunised rabbits.

The effect of a 3-day pre-treatment regime of capsaicin (8-methyl-N-vanillyl-6-nonenamide) (80 mg/kg s.c.) on airway changes induced by Alternaria tenuis aerosol challenge 3 days later was assessed in adult rabbits immunised from birth to the age of 3 months. Pre-treatment with capsaicin did not alter basal lung function or basal responsiveness to inhaled histamine. While capsaicin had no significant effect on the acute bronchoconstriction induced by antigen, this dose was sufficient to significantly inhibit the increase in airway responsiveness to inhaled histamine achieved 24 h following antigen challenge. The pulmonary recruitment of neutrophils and eosinophils induced by antigen was unaltered by prior treatment with capsaicin. In vitro contractile responsiveness to methacholine was not significantly different in bronchial tissues removed from capsaicin- and vehicle-pre-treated rabbits. In addition, there were no significant differences in responses to methacholine in preparations denuded of epithelium. Contraction of bronchial tissue induced by exogenously applied capsaicin in vitro, although modest, was significantly inhibited in capsaicin-pre-treated animals. In vehicle-pre-treated rabbits, contraction induced by a second challenge with capsaicin 45 min later was significantly reduced to a level that made responses not significantly different from those obtained in capsaicin-pre-treated tissues. The results of the present study demonstrate that antigen-induced airway hyperresponsiveness to inhaled histamine in immunised rabbits is inhibited by prior treatment with capsaicin. These findings suggest the involvement of capsaicin-sensitive nerves in antigen-induced airway hyperresponsiveness but not acute bronchospasm or cell infiltration induced by antigen.

Alternaria↗

Gastric mucosal protection against ulcerogenic factors in the rat mediated by capsaicin-sensitive afferent neurons.

Treatment of newborn rats with capsaicin (0.16 mmol/kg) is known to cause a permanent degeneration of certain, primarily unmyelinated, afferent neurons. In this study, experimentally induced gastric ulceration was investigated in adult rats treated with capsaicin as neonates. It was found that in capsaicin-treated animals the formation of gastric mucosal lesions in response to indomethacin, ethanol, or cysteamine was significantly enhanced as compared with vehicle-treated controls. The duodenal ulceration caused by cysteamine was not altered after capsaicin treatment. In further experiments the possible pathways involved in the effect of capsaicin treatment on gastric mucosal protection were explored. It was found that the capacity of gastric tissue to release prostaglandins E2 and I2 was unchanged after capsaicin treatment. Atropine, hexamethonium, cimetidine, or terbutaline all reduced gastric ulceration in response to indomethacin in both solvent- and capsaicin-treated rats but did not counteract the enhancement of the ulcerogenic effect of indomethacin in capsaicin-treated rats. Guanethidine enhanced the ulcerogenic effect of indomethacin in solvent-treated but not in capsaicin-treated animals. Ethanol-induced formation of gastric lesions remained unaltered by guanethidine in both solvent- and capsaicin-treated rats. These results indicate that capsaicin-sensitive afferent neurons are involved in gastric mucosal protection against ulcerogenic factors. The data further suggest that this type of gastric defense is primarily due to a local mechanism initiated by sensory nerve endings in the gastric mucosa.

Animals↗

The behavioral response induced by intravesical instillation of capsaicin rats is mediated by pudendal urethral sensory fibers.

The behavioral response induced by the intravesical instillation of capsaicin has been investigated in catheter-implanted, freely moving, conscious male and female rats. Intravesical instillation of capsaicin (25 nmol/rat in 0.5 ml) evoked an intense licking directed toward the lower abdominal and perineal skin which lasted for 15 min. Capsaicin-induced licking was reduced by systemic capsaicin pretreatment at a dose of 150 mg/kg but not at 50 mg/kg, administered 4 days before the intravesical instillation. Both doses of capsaicin effectively abolished the eye-wiping response to local capsaicin application. The capsaicin-induced licking was preserved (and prolonged) in both male and female animals subjected to bilateral ablation of the pelvic ganglia, 48 h before the intravesical instillation of the irritant. The capsaicin-induced licking was almost abolished by placing a ligature around the proximal urethra (24 h before), in order to avoid the contact of the irritant with the urethra or by previous section of the pudendal nerves (48 h before). One hour intravesical infusion with tetrodotoxin (1 and 10 microM) reduced the amplitude of micturition contractions but did not prevent the licking response evoked by capsaicin. On the contrary, the intravesical infusion of lidocaine (100 mM) abolished both micturition contractions and the capsaicin-induced licking. We conclude that the behavioral response induced by the intravesical instillation of capsaicin is mainly due to the stimulation of urethral afferents travelling within pudendal nerves.

Animals↗

Detection of capsaicin-evoked release of glutamate from spinal dorsal horn slices of rat with on-line monitoring system.

We examined whether capsaicin evokes the release of glutamate from unmyelinated primary afferent fibers, using a fluorometric on-line monitoring system, in which immobilized glutamate dehydrogenase column was connected to an in vitro superfusion system. In this system, an application of capsaicin (1 microM) resulted in an increased outflow of glutamate from dorsal horn slices in a tetrodotoxin-resistant manner, while capsaicin (3 microM) was without effect on ventral horn slices. This effect of capsaicin on the dorsal horn slices was in a concentration-dependent manner at 0.1-3 microM and the effect at 10 microM was not larger than that at 3 microM. The competitive capsaicin antagonist capsazepine significantly reduced the release of glutamate evoked by 1 microM capsaicin. Twice exposures of dorsal horn slices to capsaicin led a significant decrease in the release of glutamate evoked by the second capsaicin stimulation, indicating desensitization to capsaicin. Thus, using on-line monitoring system, we actually demonstrated that capsaicin induced the release of glutamate from the dorsal horn, probably from capsaicin-sensitive primary afferent terminals.

Animals↗

Early and late effects of prolonged topical capsaicin on cutaneous sensibility and neurogenic vasodilatation in humans.

Cutaneous sensibility and neurogenic vasodilatation (flare) were measured before, during and after long-term topical application of capsaicin in humans. Each subject applied a vehicle cream containing 0.075% capsaicin (Axsain, GalenPharma Inc.) to a 4 cm2 area of skin on one volar forearm and vehicle alone to an identical treatment area on the other forearm, according to a double-blind procedure. Each substance was applied 4 times/day for 6 weeks. Psychophysical measurements of sensory detection thresholds, magnitude of suprathreshold heat pain, magnitude and duration of histamine-induced itch and flare area were obtained before, at 1, 3 and 7 days after the first application, and once a week thereafter for a total of 8 weeks. Capsaicin produced mild burning in all subjects which diminished in magnitude and duration over several weeks. Capsaicin significantly altered detection thresholds for heat pain and the magnitude of pain produced by suprathreshold painful stimuli. Mean detection threshold for heat pain was lowered 1.6 degrees C following 1 day of capsaicin application but subsequently increased to become elevated 3.5 degrees C after 6 weeks of application. In addition, mean magnitude of suprathreshold heat pain diminished progressively after 1 week. Heat pain thresholds returned to or near pretreatment values within 2 weeks after discontinuing application. Detection thresholds for touch, cold sensation and pain induced by low temperature and by mechanical stimulation were not altered by capsaicin. Similarly, capsaicin did not alter the magnitude or duration of itch produced by intradermal injection of 1 microgram histamine. However, the area of flare produced by histamine was significantly reduced in capsaicin-treated skin. These studies demonstrate that prolonged application of capsaicin at low concentration selectively diminishes sensations of heat pain and neurogenic vasodilatation, presumably via desensitization of heat-sensitive nociceptors. It is also shown that the decrease in heat pain is temporary and is maintained with repeated capsaicin application. There appears to be a therapeutic role for capsaicin in cutaneous painful syndromes mediated, at least in part, by activity of heat-sensitive nociceptors.

Administration, Cutaneous↗

The effect of calcium free medium and nifedipine on the release of substance P-like immunoreactivity and contractions induced by capsaicin in the isolated guinea-pig and rat bladder.

1. Capsaicin produced a prompt release of substance P-like immunoreactivity (SP-LI) from superfused mucosa-free muscle strips excised from the guinea-pig urinary bladder. A second application of capsaicin had no further effect, indicating desensitization. 2. Neither tetrodotoxin (1 microM) or nifedipine (10 microM) had any inhibitory effect on SP-LI release by capsaicin nor influenced the establishment of the desensitized state. Nifedipine produced per se some SP-LI release. 3. SP-LI release by capsaicin was abolished by incubation in a Calcium(Ca)-free medium containing EDTA (1.0 mM) which also afforded a partial protection toward desensitization. A lower EDTA concentration (0.1 mM) did not suppress SP-LI release by capsaicin but still inhibited desensitization. 4. When the concentration of CaCl2 in the medium was lowered to 1/10-1/100 of that present in normal Krebs solution, capsaicin still evoked a marked SP-LI release and desensitization occurred. In a nominally Ca free medium (maximal Ca concentration due to impurities was 6.7 microM) SP-LI release was still observed and desensitization was incomplete. 5. In a nominally Ca free medium, removal of Mg ions enhanced the SP-LI release induced by capsaicin and enhanced desensitization. 6. In functional studies, nifedipine greatly reduced or abolished the capsaicin- or SP-induced contraction of the rat or guinea-pig isolated bladder but did not prevent desensitization. Likewise, SP-LI depletion in the rat bladder following systemic capsaicin desensitization was not prevented by nifedipine pretreatment. On the other hand, the protective action of Ca free media (containing EDTA) was confirmed in organ bath studies (guinea-pig bladder). 7. These findings indicate that: (a) the requirements of extracellular calcium for activation of neuropeptide release from sensory nerves by capsaicin are very low; (b) both excitation of sensory fibers (SP-LI release) and desensitization are dependent upon the presence of extracellular calcium and (c) L-type voltage-sensitive Ca channels are not likely to be involved in the actions of capsaicin on sensory nerve terminals.

Animals↗

Multiple capsaicin-evoked currents in isolated rat sensory neurons.

The response to capsaicin in functional assays suggests multiple sites of capsaicin action. This hypothesis is supported by the results of the present patch-clamp study of isolated dorsal root ganglion cells of the rat. The response to a prolonged application of capsaicin of different concentrations in an external solution with different ion compositions was investigated. Capsaicin evoked up to three distinct current components. The first and second current components could be activated independently. The third component occurred only in the presence of sodium and only in cells in which the second component was also elicited. In an extracellular solution with a physiological composition of ions and 300 nM capsaicin, the peaks of the three components, when evoked, occurred at 10.1 +/- 1.35 s (mean +/- S.E.M., n = 9), 44.0 +/- 2.64 s (n = 16) and 79.0 +/- 8.10 s (n = 5). The activation of the first and/or second current component depended on the concentration of capsaicin. A low concentration predominantly elicited the second component, while a high concentration activated the first and suppressed the second one. The third component seems to be a secondary response of the cell and was not investigated in detail. The activation and decay phases of the first two current components could be fitted by single exponential functions, whereas those of the third component could not. The first and second current components were carried by sodium and calcium. After tachyphylaxis, if the extracellular medium was then acidified to a pH of 6.3, the second component alone could then be elicited by capsaicin. The results demonstrate that capsaicin can elicit different current components that are distinguishable by their time-course, by the effects of acidification of the extracellular solution and by the concentration of capsaicin required to activate these currents. We postulate two distinct binding sites of capsaicin causing two distinct current components. This may account for the variety of physiological responses evoked by capsaicin and the variations in these responses between species.

Animals↗

Capsaicin inhibits the production of tumor necrosis factor alpha by LPS-stimulated murine macrophages, RAW 264.7: a PPARgamma ligand-like action as a novel mechanism.

Capsaicin, a major ingredient of hot pepper, is considered to exhibit anti-inflammatory properties. Our previous study demonstrated that capsaicin inhibited the production of pro-inflammatory mediators through NF-kappaB inactivation in LPS-stimulated macrophages. In order to further clarify the mechanism underlying the anti-inflammatory action of capsaicin, we investigated whether capsaicin alters PPARgamma activity, which regulates the production of the pro-inflammatory cytokine TNFalpha. Capsaicin significantly inhibited the production of TNFalpha by macrophages in a dose-dependent manner. Simultaneous exposure of the cells to capsaicin and PPARgamma agonist troglitazone or RXR agonist LG100268 resulted in stronger inhibition of TNFalpha production compared to the cells treated with either capsaicin, troglitazone, or LG100268 alone. Luciferase reporter assay revealed that capsaicin induced GAL4/PPARgamma chimera and full length PPARgamma (PPRE) transactivations in a dose-dependent manner. Furthermore, a specific PPARgamma antagonist T0070907 abrogated the inhibitory action of capsaicin on LPS-induced TNFalpha production by RAW 264.7 cells, indicating that capsaicin acts like a ligand for PPARgamma. Our data demonstrate for the first time that the anti-inflammatory action of capsaicin may be mediated by PPARgamma activation in LPS-stimulated RAW 264.7 cells.

Animals↗

Pain behaviors produced by capsaicin: influence of inflammatory mediators and nerve injury.

UNLABELLED: The present study was undertaken to characterize spontaneous (ie, nonevoked) pain behaviors (flinching, biting/licking) produced by local injections of capsaicin into the rat hindpaw as a model of chemogenic pain, and to determine effects of inflammatory mediators and nerve injury on such behaviors. Capsaicin antagonists are a potential class of novel topical analgesics, and this model may be of value for preclinical screening of novel compounds. Local injections of capsaicin (0.1-30 microg) into the hindpaw produced flinching and biting/licking behaviors over 5 min, and these were reduced by capsazepine, a competitive antagonist for capsaicin at the TRPV1 receptor. Coadministration of noradrenaline (NA), prostaglandin E(2) (PGE(2)), and 5-hydroxytryptamine (5-HT) augmented capsaicin-evoked responses primarily by extending the duration of behaviors. Partial sciatic nerve ligation decreased flinching produced by capsaicin alone, by capsaicin in combination with each of NA, PGE(2), and 5-HT, and by formalin. Tibial nerve injury also reduced capsaicin-evoked flinching, and responses to formalin, but spinal nerve ligation did not affect either. These results indicate that (1) spontaneous pain behaviors occur as a result of TRPV1 receptor activation with a different time course than evoked responses, (2) inflammatory mediators augment capsaicin-evoked pain behaviors, and (3) various forms of nerve injury produce different effects on capsaicin-evoked pain behaviors. PERSPECTIVE: The VR1 receptor is a potential target for development of novel topical analgesics. This study characterized pain behaviors produced by local injections of capsaicin in the presence of inflammatory mediators and following various forms of nerve injury. Results are of interest for the preclinical screening of novel VR1 receptor antagonists.

Animals↗

Genotoxicity studies with pure trans-capsaicin.

Both positive and negative effects have been found in classical genetic toxicology assays with capsaicin. However, the capsaicin tested in most studies has been derived from pepper plant extracts, which is likely to display varying degrees of purity and possibly diverse impurity profiles. Therefore, the objective of the series of studies reported here was to test the genotoxic potential of pure, synthetic trans-capsaicin (the only naturally occurring geometric isomer of capsaicin), using four genotoxicity assays widely used to evaluate drug substances. These included the Ames, mouse lymphoma cell mutation, mouse in vivo bone marrow micronucleus and chromosomal aberration in human peripheral blood lymphocytes (HPBL) assays. In the Ames assay, pure trans-capsaicin was not mutagenic to Salmonella typhimurium or Escherichia coli when dissolved in dimethylsulfoxide and tested at concentrations extending into the toxic range. trans-Capsaicin was weakly mutagenic in mouse lymphoma L5178Y cells, in the presence of S9 mix, when dissolved in dimethylsulfoxide and tested at concentrations extending into the toxic range. Limited evidence for very weak activity was also obtained in the absence of S9 mix. trans-Capsaicin did not induce micronuclei in bone marrow cells when tested to the maximum tolerated dose of 800 mg/kg per day in male and 200 mg/kg per day in female CD-1 mice using a 0 h plus 24 h oral dosing and 48 h sampling regimen. Finally, trans-capsaicin did not induce structural or numerical chromosomal aberrations when evaluated for its ability to induce clastogenicity in blood lymphocytes. Taken together, these data suggest that the genotoxic potential of pure trans-capsaicin is very low, especially as the clinical significance of weak mutagenicity in the mouse lymphoma assay for catechol-moiety containing compounds is unclear. Moreover, the different genotoxicity profiles of pure trans-capsaicin and purified chili pepper extracts suggest that the purity and source of capsaicin should always be an important consideration for toxicological evaluations.

Animals↗

Capsaicin and nitric oxide synthase inhibitor interact to evoke a hypothermic synergy.

The present study investigated the effect of a drug combination of capsaicin and L-NAME on hypothermia in rats. Capsaicin administration (0.1, 0.25, 0.5, 1 and 2mg/kg, i.m.) caused a significant hypothermia. L-NAME (50mg/kg, i.p.), a nonspecific nitric oxide synthase (NOS) inhibitor, was ineffective. For combined administration, progressively increasing doses of capsaicin (0.1, 0.25, 0.5, 1 and 2mg/kg, i.p.) were given with a non-hypothermic dose of L-NAME (50mg/kg, i.p.). Experiments revealed that L-NAME (50mg/kg, i.p.) enhanced the hypothermic response to capsaicin (0.25, 0.5, 1, and 2mg/kg, i.m.). Comparison of the graded dose-effect curves for capsaicin alone and capsaicin plus L-NAME revealed a significant difference (P<0.05), thus indicating synergy for the drug interaction. To determine if L-NAME acted centrally, a fixed dose of L-NAME (1mg/rat, i.c.v.) was given with graded doses of capsaicin (0.25, 0.5, 1, and 2mg/kg, i.m.). L-NAME (1mg/rat, i.c.v.) only enhanced the hypothermia at a single dose of capsaicin (0.5mg/kg, i.m.). The super-additive hypothermia produced by the concurrent administration of capsaicin and L-NAME (50mg/kg, i.p.) is the first evidence of synergy for a drug combination of capsaicin and a NOS inhibitor. The synergy is apparent only when L-NAME is given systemically, thus indicating that the inhibition of peripheral NO production enhances the hypothermic response to capsaicin.

Animals↗

Neonatal primary neuronal death induced by capsaicin and axotomy involves an apoptotic mechanism.

To clarify the mechanism of capsaicin-induced primary neuronal cell death, newborn and adult rats were given a subcutaneous injection of capsaicin (50 mg/kg). Neonatal capsaicin injection induced neuronal apoptosis in the trigeminal ganglion. Apoptotic neurons had peripheral stacks of long parallel endoplasmic reticulum that are characteristic to primary neurons of the B-type, and exhibited nucleoplasmic condensation, nuclear shrinkage and cytoplasmic fragmentation. Light microscopically, apoptotic neurons exhibited a sign of DNA fragmentation as revealed by a nick end labelling method. The proportion of apoptotic cells was quite low during the first 12 h after capsaicin injection (<1%), rapidly increase to 10.44% by 24 h, and decreased to 0.29% by 48 h. Normal and vehicle control levels of apoptosis were <1%. Nerve growth factor (NGF, 0.5 mg/kg) simultaneously administered with capsaicin reduced the incidence of apoptosis by about 35% at 24 h post-injection. Neonatal transection of the infraorbital nerve induced neuronal apoptosis similar to that produced by the neonatal capsaicin in the maxillary division of the trigeminal ganglion. Unlike capsaicin, however, the neurotomy-induced apoptosis was seen in neurons of both the A- and B-types. Neither the capsaicin injection nor the neurotomy induced apoptosis in adult rats, though mitochondrial swelling similar to that seen at 0.5 h after neonatal capsaicin was observed after capsaicin injection in adults. The results indicate that the capsaicin-induced and nerve injury-induced primary neuronal damages in newborn rats share a common final pathway, apoptosis.

Animals↗