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PubMed1999

Rat offspring treated prenatally with capsaicin do not show some of the irreversible effects induced by neonatal treatment with neurotoxin.

The present study evaluates whether some of the irreversible effects induced by neonatally administered capsaicin are present in offspring prenatally treated with the neurotoxin as well, and investigated its foetal toxicity. Capsaicin was administered subcutaneously at doses of 50, 100 and 200 mg/kg in five injections every other day between gestational days 7-15, the period of major organogenesis, or in a single subcutaneous injection of 50 mg/kg only at day 15 of gestation. In one-month old rats prenatally capsaicin-treated the response to noxious stimulation (hot plate and wiping tests) and the urinary excretion in response to oral water load were evaluated. Parallel experiments were conducted in one-month old rats treated with capsaicin (50 mg/kg) on the 2nd day of life. Prenatal capsaicin induced no evident treatment-related signs of toxicity in dams and offspring, nor did it influence the body growth of the pups or induce cutaneous lesions. Unlike neonatal treatment, prenatal administration of neurotoxin did not raise the threshold to thermal and chemical pain, and did not modify diuresis induced by oral load. Since researchers have proposed the existence of more than one population of capsaicin-sensitive afferent neurones which differ in their age-dependent sensitivity to capsaicin, we hypothesized that failure of prenatal treatment might be due either to reduced foetal availability, not capable of selectively destroying capsaicin-sensitive neurones, or to incomplete rearrangement and maturation of developing primary sensory neurons, in fact, the existence is well known of more than one population of capsaicin-sensitive afferent neurons which differ in their age-dependent sensitivity to capsaicin. Future studies are needed to elucidate the effects of capsaicin at cellular and molecular levels.

Animals↗
PubMed1986

Functional evidence for the existence of a capsaicin-sensitive innervation in the rat urinary bladder.

Capsaicin (0.03-3 microM) induces contractions of the rat isolated bladder which are unaffected by either atropine (3 microM) or tetrodotoxin (0.5 microM). In the presence of capsaicin (0.1 microM) an enhancement of field stimulation-induced contractions was observed. Capsaicin-desensitization did not modify the height of these. The neurogenic nature of the capsaicin-induced contractions was proved by the observation that 'chronic' (48 h) denervation prevented, while 'acute' (2 h) denervation did not modify the effect of capsaicin. Denervated bladders maintained their responsiveness to acetylcholine but not to field stimulation. Isolated bladders from rat pups (1-2 days old) did not respond to capsaicin while strong contractile responses to acetylcholine or field stimulation were obtained in these preparations. In bladders from two week old animals, capsaicin produced similar contractions to those observed in preparations from adult animals. The bladders from rats receiving a high dose of capsaicin (50 mg kg-1 s.c.) at birth were heavier than those of their age-matched, vehicle-treated controls. Isolated bladders from 2 month old animals pretreated with capsaicin at birth were unresponsive to capsaicin while responsiveness to acetylcholine, substance P or field stimulation was unaffected compared with that of vehicle-treated controls. These experiments provide evidence that a capsaicin-sensitive innervation exists in the rat urinary bladder which undergoes a postnatal development at end organ level.

Animals↗
PubMed2003

Increased expression of vanilloid receptor 1 on myelinated primary afferent neurons contributes to the antihyperalgesic effect of capsaicin cream in diabetic neuropathic pain in mice.

Topical capsaicin is believed to alleviate pain by desensitizing the vanilloid receptor 1 (VR1) at the peripheral nerve endings. Here, we report that an up-regulation of VR1 expression on myelinated fibers contributes to the antihyperalgesic effect of capsaicin cream in streptozotocin (STZ)-induced diabetic neuropathic pain. Intravenous injection of STZ (200 mg/kg) in mice caused rapid onset of diabetes within 24 h. Thermal and mechanical hyperalgesia developed by 3 days after STZ injection and persisted at all time points tested until 28 days. There was also hyperalgesic response to intraplantar (i.pl.) prostaglandin I2 (PGI2) agonist-induced nociception in such mice. Application of capsaicin cream dose dependently reversed the thermal, mechanical, and PGI2 agonist-induced hyperalgesia observed in the diabetic mice. The i.pl. injection of capsaicin solution (0.4 microg/20 microl) produced nociceptive biting-licking responses in control mice, and these responses were significantly increased in STZ-induced diabetic mice. After neonatal capsaicin-treatment, which destroys most unmyelinated C-fibers, the i.pl. capsaicin-induced biting-licking responses were almost abolished. However, in neonatal capsaicin-treated diabetic mice, the i.pl. capsaicin-induced biting-licking responses reappeared. The i.pl. capsaicin-induced biting-licking responses were blocked by the competitive VR1 antagonist capsazepine. All these results suggest an increase in capsaicin receptor on myelinated fibers due to diabetes. Finally, we confirmed the up-regulation of VR1 expression on myelinated primary afferent neurons of diabetic mice by immunohistochemistry. Together, our results suggest that increased expression of VR1 on myelinated fibers might contribute to the antihyperalgesic effect of topical capsaicin in diabetic neuropathic pain.

Afferent Pathways↗
PubMed2005

Capsaicin regulates voltage-dependent sodium channels by altering lipid bilayer elasticity.

At submicromolar concentrations, capsaicin specifically activates the TRPV1 receptor involved in nociception. At micro- to millimolar concentrations, commonly used in clinical and in vitro studies, capsaicin also modulates the function of a large number of seemingly unrelated membrane proteins, many of which are similarly modulated by the capsaicin antagonist capsazepine. The mechanism(s) underlying this widespread regulation of protein function are not understood. We investigated whether capsaicin could regulate membrane protein function by changing the elasticity of the host lipid bilayer. This was done by studying capsaicin's effects on lipid bilayer stiffness, measured using gramicidin A (gA) channels as molecular force-transducers, and on voltage-dependent sodium channels (VDSC) known to be regulated by bilayer elasticity. Capsaicin and capsazepine (10-100 microM) increase gA channel appearance rate and lifetime without measurably altering bilayer thickness or channel conductance, meaning that the changes in bilayer elasticity are sufficient to alter the conformation of an embedded protein. Capsaicin and capsazepine promote VDSC inactivation, similar to other amphiphiles that decrease bilayer stiffness, producing use-dependent current inhibition. For capsaicin, the quantitative relation between the decrease in bilayer stiffness and the hyperpolarizing shift in inactivation conforms to that previously found for other amphiphiles. Capsaicin's effects on gA channels and VDSC are similar to those of Triton X-100, although these amphiphiles promote opposite lipid monolayer curvature. We conclude that capsaicin can regulate VDSC function by altering bilayer elasticity. This mechanism may underlie the promiscuous regulation of membrane protein function by capsaicin and capsazepine-and by amphiphilic drugs generally.

Capsaicin↗
PubMed1996

Effect of capsaicin and cimetidine on the healing of acetic acid induced gastric ulceration in the rat.

BACKGROUND: Capsaicin protects the gastric mucosa against experimental injury while capsaicin desensitisation reduces the rate of gastric ulcer healing. The effect of exogenous capsaicin on gastric ulcer healing has not to date been reported. AIM/METHOD: To investigate the effect of capsaicin, cimetidine, and in combination, given intragastrically in the healing of acetic acid induced chronic gastric ulcer in the rat. Treatment started immediately after ulcer induction. RESULTS: At the end of one week, capsaicin, cimetidine, and in combination increased ulcer healing but the effect of combined treatment was less than that of capsaicin alone. In an in vivo gastric chamber preparation, capsaicin increased, while cimetidine decreased, gastric mucosal blood flow measured by laser Doppler flowmetry. A dose response effect in reduction of gastric mucosal blood flow could be demonstrated for cimetidine. The gastric hyperaemic effect of capsaicin was blunted by prior administration of cimetidine. In contrast, capsaicin had no effect on gastric acid secretion and its addition to cimetidine did not affect the acid suppressant effect of the latter. CONCLUSIONS: Capsaicin promotes the healing of acetic acid induced gastric ulcer, probably by its gastric hyperaemic effect. Although cimetidine also promotes ulcer healing due to its inhibitory effect on acid secretion it may have an antagonistic effect on the gastric ulcer healing effect of capsaicin by virtue of inhibition of gastric hyperaemia.

Acetic Acid↗
PubMed2000

Capsaicin responsiveness and cough in asthma and chronic obstructive pulmonary disease.

BACKGROUND: Chronic cough is associated with an increased sensitivity to inhaled capsaicin in a number of conditions but there are no data for patients with more severe asthma or chronic obstructive pulmonary disease (COPD). Moreover, the relationships between the capsaicin response (expressed as the concentration of capsaicin provoking five coughs, C5), self-reported cough, and routine medication is not known. METHODS: The cough response to capsaicin in 53 subjects with asthma, 56 subjects with COPD, and 96 healthy individuals was recorded and compared with a number of subjective measures of self-reported cough, measures of airway obstruction, and prescribed medication. In asthmatic subjects the relationships between the cough response to capsaicin and mean daily peak flow variability and non-specific bronchial hyperresponsiveness to histamine were also examined. RESULTS: Subjects with asthma (median C5 = 62 mM) and COPD (median C5 = 31 mM) were similarly sensitive to capsaicin and both were more reactive than normal subjects (median C5 >500 mM). Capsaicin sensitivity was related to symptomatic cough as measured by the diary card score in both asthma and COPD (r = -0.38 and r = -0.44, respectively), but only in asthma and not COPD when measured using a visual analogue score (r = -0.32 and r = -0.05, respectively). Capsaicin sensitivity was independent of the degree of airway obstruction and in asthmatics was not related to PEF variability or PC(20) for histamine. The response to capsaicin was not related to treatment with inhaled corticosteroids but was increased in those using anticholinergic agents in both conditions. CONCLUSIONS: These data suggest that an increased cough reflex, as measured by capsaicin responsiveness, is an important contributor to the presence of cough in asthma and COPD, rather than cough being simply secondary to excessive airway secretions. The lack of any relationship between capsaicin responsiveness and airflow limitation as measured by the FEV(1) suggests that the mechanisms producing cough are likely to be different from those causing airways obstruction, at least in patients with COPD.

Administration, Inhalation↗
PubMed1991

Neurogenic hyperalgesia: the search for the primary cutaneous afferent fibers that contribute to capsaicin-induced pain and hyperalgesia.

1. A local cutaneous injury can produce primary hyperalgesia within the injured area and secondary hyperalgesia in the normal surrounding skin. An intradermal injection of capsaicin in humans causes intense pain and hyperalgesia to heat and to mechanical stimuli in the surrounding skin. Psychophysical studies in humans supported the conclusions that the hyperalgesia was predominantly the secondary type and depended on one set of neurons sensitizing another ("neurogenic hyperalgesia") and that the latter set of neurons is located in the central and not the peripheral nervous system. To further test this hypothesis and to search for peripheral neural mechanisms contributing to the pain and neurogenic hyperalgesia from a local injury, we performed neurophysiological experiments in the monkey (Macaca fascicularis) and recorded the responses of cutaneous primary afferent fibers to an intradermal injection of capsaicin and to mechanical and heat stimuli delivered before and after the injection. 2. Most C- and A-fiber mechanoheat-sensitive nociceptive afferent fibers (CMHs and AMHs, respectively) responded too weakly or transiently to capsaicin to account quantitatively for the magnitude of capsaicin pain. Of the known primary afferents tested with capsaicin injections, only the responses of heat-selective nociceptors could potentially account for the pain measured psychophysically in the human. In addition, a novel type of primary afferent--tentatively termed "chemonociceptive"--may have contributed as well. 3. Nociceptive fibers did not become sensitized to either mechanical or heat stimulation after an injection of capsaicin either outside, adjacent to, or inside the receptive field (RF); any changes that occurred could not explain the hyperalgesia to mechanical or heat stimuli observed in humans. 4. The depressed responsiveness ("desensitization") of both myelinated and unmyelinated nociceptive fibers in the monkey to heat and/or mechanical stimulation of the injection site after capsaicin was injected inside their RFs correlated with the analgesia observed at the capsaicin injection site in the human. 5. Capsaicin, topically applied to the RF in a vehicle of dimethyl sulfoxide or alcohol, excited CMHs and AMHs and enhanced the responses of some of these fibers to heat and/or to stroking the skin. In some cases, similar results were produced by the vehicle alone. However, capsaicin and not the vehicle lowered the thresholds of some CMHs to heat. Thus the sensitization of CMHs contributes to the primary hyperalgesia known to occur within the area of skin directly exposed to topically applied capsaicin.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent Pathways↗
PubMed1996

Lactoseries carbohydrate antigen, Gal beta 1-4GlcNAc-R, is expressed by a subpopulation of capsaicin-sensitive rat sensory neurons.

1. The membrane properties of dorsal root ganglion (DRG) cells expressing the lactoseries carbohydrate antigen Gal beta 1-4GlcNAc-R were studied and compared with those of DRG cells lacking this antigen. Acutely dissociated rat DRG cells that expressed Gal beta 1-4GlcNAc-R on their outer cell membranes were detected with the use of a primary monoclonal mouse IgM antibody (A5), directed against Gal beta 1-4GlcNAc-R, and a fluorescent secondary antibody (fluorescein-conjugated goat anti-mouse IgM). We found 12.8 micrograms/ml of A5 to be a saturating concentration of primary antibody that labeled approximately 19% of the DRG cells. A battery of membrane properties including action potential (AP) duration; sensitivity to capsaicin; expression of H current (IH), A current (IA), and Ca2+ current subtypes (L, N, and T); and inhibition of high-threshold Ca2+ currents by serotonin (5HT) or 8-hydroxy-2-(di-N-propylamino)-tetralin (8-OH-DPAT) was measured in DRG cells labeled (A5+) and unlabeled (A5-) by a saturating concentration of A5. 2. There was a significant difference in the number of capsaicin-sensitive DRG cells and a significant difference in the magnitude of the capsaicin-induced inward current in A5+ versus A5- DRG cells. Of 35 A5+ cells tested, 33 were sensitive to 1 microM capsaicin, which produced an inward current averaging 4 +/- 0.46 (SE) nA (n = 33). In contrast, only 12 of 33 A5- cells were sensitive to 1 microM capsaicin, which produced an inward current averaging 1.2 +/- 0.52 nA (n = 12). 3. There were also significant differences between A5+ and A5- cells regarding average AP duration, N- and T-type Ca2+ current amplitude, and number of cells that expressed IH and IA. A5+ cells had significantly larger N-type Ca2+ currents and expressed IA more frequently than A5- cells. Conversely, A5- cells had significantly longer AP duration and larger T-type Ca2+ currents, and expressed IH more frequently compared with A5+ cells. 4. A5+ and A5- cells differed regarding the inhibition of high-threshold Ca2+ currents by maximal concentrations of 5HT1A agonists (10 microM 5HT or 1 microM 8-OH-DPAT). Inhibition of Ca2+ currents in A5+ cells by 1 microM 8-OH-DPAT (n = 15) or 10 microM 5HT (n = 18) averaged 4 +/- 0.9%. In contrast, inhibition of Ca2+ currents in A5- cells by 10 microM 5HT (n = 33) averaged 20 +/- 3.8%. 5. Cells for which sufficient data were collected were categorized as type 1, 2, 3, or 4 on the basis of sensitivity to capsaicin and expression of IH, IA, and T-type Ca2+ current amplitude, and the distribution of A5+ and A5- cells among the various groups was observed. The categories were defined as follows: type 1 (capsaicin sensitive, no IH or IA); type 2 (capsaicin sensitive, significant IA); type 3 (capsaicin insensitive, T-type Ca2+ currents < 1 nA, significant IH but no IA); and type 4 (capsaicin insensitive, T-type Ca2+ currents > 2.4 nA). On the basis of this criteria, 6 of 15 type 1 cells and all type 2 cells (n = 19) were A5+. All type 3 cells (n = 8) and all type 4 cells (n = 11) were A5-. 6. As indicated above, the expression of the Gal beta 1-4GlcNAc-R antigen differentiated two subgroups of DRG cells in the type 1 category (A5+, n = 6 and A5-, n = 9). These two groups varied regarding the sensitivity of Ca2+ currents to maximally effective concentrations of 5HTIA agonists. In type 1 A5+ DRG cells, high-threshold Ca2+ currents were not significantly inhibited by 1 microM 8-OH-DPAT (average inhibition = 1.2 +/- 0.8%, n = 6). However, in type 1 A5- cells, high-threshold Ca2+ currents were reduced 47 +/- 6.0% (n = 9) by 10 microM 5HT. 7. The several significant differences in membrane properties between A5+ and A5- DRG cells suggest that the Gal beta 1-4GlcNAc-R antigen is expressed by a distinct subset of DRG cells, consisting predominately of type 1 and type 2 cells. The observation that most A5+ DRG cells were capsaicin sensitive suggests that the Gal beta 1-4GlcNAc-R antigen is expressed primarily by n

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1997

Tachykinin-independent effects of capsaicin on smooth muscle in human isolated bronchi.

Contractile and relaxant responses to capsaicin and resiniferatoxin were examined in human isolated bronchus (5-12 mm o.d.). Bronchi isolated from 10 of 16 lungs contracted in response to capsaicin. The contractions averaged 20% of maximal contraction at 1 microM and averaged > 40% maximal contraction at 300 microM (the highest concentration studied). The capsaicin-induced contractions were mimicked by resiniferatoxin (0.1-10 microM) and inhibited by the putative capsaicin receptor antagonist, capsazepine (10 microM). The contractile response to capsaicin was not affected by the potent NK-2 selective antagonist SR 48968 (0.3 microM), whereas responses to concentrations of neurokinin A (10 nM), neurokinin B (0.1 microM), substance P (1 microM), neuropeptide gamma (10 nM), and neuropeptide K (10 nM) which produced similar-size contractions were almost abolished by 0.1 microM SR 48968. The bronchi isolated from 8 of 16 lungs also exhibited relaxations in response to capsaicin. Capsaicin-induced relaxations were not inhibited by the nitric oxide synthase inhibitor L-nitro-n-arginine (10 microM). In whole-cell patch-clamp experiments on human cultured airway smooth muscle cells, capsaicin was found to enhance outward currents due to the activation of charybdotoxin-sensitive large conductance Ca2+-activated K+ channels. Neither the capsaicin-induced contractions nor the relaxations were mimicked by angiotensin II, bombesin, or calcitonin gene-related peptide at concentrations up to 1 microM. These results suggest that capsaicin and resiniferatoxin can alter smooth muscle tone, but this response does not appear to involve substance P or related neurokinins. Relaxations to capsaicin may, however, involve the activation of large conductance Ca2+-activated K+ channels.

Adult↗
PubMed2001

Capsaicin inhibits Jurkat T-cell activation by blocking calcium entry current I(CRAC).

Capacitative calcium entry (CCE) through stores-operated Ca2+ channels is an absolute requirement for normal activation of T lymphocytes. Organic blockers/inhibitors of the channel(s) that carry the inward Ca2+ current (I(CRAC)) responsible for CCE are few. Here we show that capsaicin, the pungent ingredient of hot chili pepper, blocks receptor-stimulated Ca2+ entry in Jurkat T cells. Indo-1 measurements of intracellular calcium show that capsaicin blocks CCE without affecting release of inositol-1,4,5-trisphosphate-sensitive internal Ca2+ stores with an IC50 of 32 microM. Block of Ca2+ entry by capsaicin is identical whether CCE is evoked by T-cell receptor (TCR) stimulation, heterologous muscarinic M1 receptor stimulation, or via thapsigargin depletion of internal Ca2+ stores. Patch-clamp experiments show that capsaicin rapidly and reversibly blocks I(CRAC) with an identical dose response as seen with indo-1 measurements. The major voltage-gated K+ channel in Jurkat cells, Kv1.3, is also blocked by capsaicin. Although Kv1.3 block may contribute to reducing CCE by changes in membrane potential, block of I(CRAC) is the primary mechanism by which capsaicin reduces CCE. Capsaicin analogs capsazepine and resiniferatoxin also produce inhibition of CCE via block of I(CRAC). Upon application of capsaicin to Jurkat cells in culture we observed an inhibition of interleukin-2 (IL-2) production in response to TCR stimulation. The dose dependence of capsaicin's reduction of IL-2 was comparable with its block of I(CRAC), thereby illustrating the functional relevance of capsaicin's block of lymphocyte CCE. Thus, capsaicin and its numerous analogs may have potential use as immunomodulatory drugs and should be further investigated in models of inflammation and T-cell activation.

Calcium Channel Blockers↗
PubMed2006

[Preparation and in vitro evaluations of topically applied capsaicin transfersomes].

OBJECTIVE: Capsaicin transfersomes were prepared and its quality specifications were evaluated. METHOD: Capsaicin transfersomes were prepared by high shear dispersing machine and evaluated on the entrapment efficiency, drugs release rate and in vitro skin permeation. RESULT: Capsaicin transfersomes is composed of single unilamellar vesicles, with average size of 150.6 nm. Capsaicin entrapment efficiency achieved 96.7% while concentration of lecithin used was 8%. cumulative release amount of capsaicin was in direct proportion to the ethanol concentration in the medium. The in vitro rate cumulative penetration rate of capsaicin was higher in transfersomes than in cream and suspension in rats. Adomen skin cumulative penetration rate in vitro of capsaicin transfersomes in mouse was significantly higher than that from rat and men. In the same way,cumulative penetration rate in vitro of capsaicin transfersomes through abdomen skin epidermal membrance was significantly higher than that with derma and full skin in men. CONCLUSION: Entrapment efficiency of capsaicin transfersomes reached 96.7%, meeting the criterion of China pharmacopia( > 80%), skin penetration of capsaicin was enhanced by a capsaicin transfersomes preparation and was affected by diverse characters and levels of skin.

Administration, Cutaneous↗
PubMed1990

Resiniferatoxin: an ultrapotent selective modulator of capsaicin-sensitive primary afferent neurons.

Resiniferatoxin (RTX) has been shown to function as an ultrapotent analog of capsaicin. It is reported here that RTX, like capsaicin, acts selectively on primary sensory neurons in rats to produce ultrastructural alterations and calcitonin gene-related peptide depletion. To evaluate RTX actions on capsaicin-sensitive nociceptors of vagal origin in the lung, the activation and desensitization of the pulmonary chemoreflex in both rats and cats were examined. In rats, RTX (2 ng-5 micrograms/kg i.v.) failed to elicit the full reflex triad (apnea, systemic hypotension and bradycardia); RTX did, however, desensitize the pulmonary chemosensitive receptors to capsaicin and phenyldiguanide. This effect is not achievable upon acute capsaicin treatment. RTX pretreatment (300 micrograms/kg s.c.) of rats also abolished the neurogenic edema formation, another response mediated via capsaicin-sensitive vagal fibers, in rat trachea to challenge either by capsaicin or ether. The effect of electrical stimulation of vagal nerve was not impaired after RTX injection, indicating that RTX desensitized only the capsaicin-sensitive pathway whereas the parasympathetic pathway remained unaltered. In cats, unlike in the rat, the full pulmonary chemoreflex occurred in response to 0.1 micrograms/kg RTX. It is concluded that RTX is a selective probe for capsaicin-sensitive neural pathways but the spectrum of action of the two compounds is not identical. The failure of RTX to provoke the pulmonary chemoreflex in the rat, which is the main limiting factor in the use of capsaicin, suggests a further advantage to the use of RTX for probing capsaicin-sensitive neural pathways.

Animals↗
PubMed1986

Tachykinins and calcitonin gene-related peptide in relation to peripheral functions of capsaicin-sensitive sensory neurons.

Antidromic stimulation of sensory nerves or administration of capsaicin and SP in the guinea-pig induced vascular protein leakage with a similar pattern of distribution in different peripheral organs, characterized by a wide-spread but highly selective occurrence. The protein-extravasation responses in the tissues, following nerve stimulation or i.v. capsaicin, were highly correlated with the concentration of SP-LI. Systemic capsaicin treatment caused an almost total loss of SP-LI in visceral organs, in which the extravasation responses to capsaicin or nerve stimulation were also abolished. The ureter of the guinea-pig was most densely innervated by capsaicin-sensitive sensory nerves, which arrive at the rostral part of the ureter via the inferior mesenteric ganglion. The caudal ureter was mainly innervated from the pelvic nerves. The vascular permeability increase induced by SP or capsaicin was more pronounced in the ureter than in any other organ investigated. SP-LI, TK-LI and CGRP-LI coexist in sensory neurons of the guinea-pig and man, as shown by immunohistochemistry. These three kinds of immunoreactivity were found in sensory cell bodies with similar regional and terminal distribution patterns in both the central and peripheral areas. Systemic capsaicin treatment induced marked reduction of SP- and TK-LI in peripheral organs except for the ileum. CGRP-LI in the ureter was also sensitive to the capsaicin treatment. Characterization of the TK-LI (K12) of the guinea-pig ureter and lung, using ion-exchange chromatography and HPLC, demonstrated that at least three immunoreactive components corresponding to NKA, NPK and ELE were present. The major form of SP-LI eluted in the same position as synthetic SP. The NKA- and ELE-like components were also identified by HPLC in water extracts of human ureter. NKB was not detectable in the sensory neurons of the guinea-pig. Capsaicin caused an acute release of SP-, NKA- and ELE-like components from superfused slices of both the spinal cord and ureter of the guinea-pig in vitro. The release of tachykinins by capsaicin was calcium-dependent but tetrodotoxin-resistant. No detectable release of NKB- or NPK-LI was induced by capsaicin. Tachykinins share a common spectrum of biological activities with regard to hypotension, bronchoconstriction and protein extravasation when given systemically to guinea-pigs. The potency of the hypotensive action of tachykinins was similar. NKA and NPK evoked much stronger bronchoconstrictor effects than SP, while SP was more active than NKA in inducing vascular permeability changes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Neurotoxic effect of capsaicin in mammals.

Capsaicin is now widely used to explore and/or prove the role of peptide-containing primary afferent neurones in different somato- and viscerosensory functions. The present paper deals with the morphological effects of capsaicin administered according to currently used experimental paradigms. As it has been repeatedly confirmed in the recent literature, administration of capsaicin to newborn mammals results in a highly selective degeneration of a particular population of small sized, B-type primary afferent neurones located in spinal and cranial sensory ganglia. Chemosensitive i.e. capsaicin sensitive primary sensory neurones (CPSNs) correspond to primary sensory ganglion cells which contain neuropeptides. The permanent functional impairments and the decrease in the peptide contents of the sensory neurones observed after neonatal capsaicin treatment may be accounted for an irreversible loss of CPSNs. Direct application of capsaicin to peripheral nerves results in an apparently irreversible functional impairment of unmyelinated afferent fibres implicated in nociceptive, viscerosensory and neurogenic inflammatory mechanisms. Morphological observations indicate that perineural treatment with capsaicin initiates a selective but delayed degeneration process of unmyelinated afferent nerve fibres presumably due to an inhibition of intraneuronal transport mechanisms. In contrast with perineural capsaicin treatment affecting the chemistry and function of the whole sensory neurone, injection of capsaicin into the subarachnoid space results in an irreversible abolition of the "afferent" but not the "efferent" function of CPSNs. Accordingly, noxious thermal or chemical stimuli applied to the peripheral innervation areas of the trigeminal nucleus caudalis or the affected segments of the spinal cord fail to induce nociceptive reflexes because of the degeneration of the central terminals of CPSNs. However, in these same skin areas, application of chemical irritants invariably evoked the neurogenic inflammatory response, indicating that CPSNs deprived of their central terminals maintain their capacity to synthesize and release the peptide(s) responsible for the initiation of that response. In contrast with previous findings, our recent studies furnished evidence for a selective neurodegenerative action of systemically injected capsaicin in adult mammals, as well. Therefore, some of the irreversible functional impairments produced by capsaicin in adult animals may result from the degeneration of a particular subpopulation of CPSNs.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent Pathways↗
PubMed1993

Regulation of neuropeptide release from pulmonary capsaicin-sensitive afferents in relation to bronchoconstriction.

An isolated perfused lung model was developed in which the mechanisms of regulation of sensory neuropeptide overflow and bronchoconstrictor responses evoked by antidromic vagal nerve stimulation or various irritants could be studied. For further comparison, non-adrenergic non-cholinergic (NANC) bronchoconstriction was also studied in guinea-pig isolated bronchus and in vivo. In the isolated guinea-pig lung, spontaneous strong postmortem bronchoconstriction occurred; this had to be overcome by the beta 2-adrenoceptor agonist terbutaline. Vagal stimulation, capsaicin, resiniferatoxin (RTX), nicotine, and pH 5 buffer all caused sensory peptide release and bronchoconstriction via a capsaicin-sensitive mechanism. Bradykinin and histamine also stimulated sensory peptide release but evoked bronchoconstriction mainly via capsaicin-resistant mechanisms. Stimulation at low frequency (1 Hz) caused similar degree of sensory nerve activation (peptide release in perfused lung and NANC bronchial contraction in bronchus) as stimulation at 10 Hz. Dactinomycin and the non-peptide SR 48968 selectively blocked the bronchoconstriction induced by neurokinin 2 (NK2) receptor agonists and also depressed that induced either by vagal stimulation or capsaicin, with no prejunctional effect on the overflow of calcitonin gene-related peptide (CGRP). Furthermore, SR 48968 inhibited the bronchoconstriction to citric acid aerosol. The NK1 antagonist CP 96345 had only marginal effects on NANC bronchoconstriction. Tetrodotoxin (TTX) and omega-conotoxin (CTX) inhibited neuropeptide release and bronchoconstriction caused by vagal stimulation or a low concentration of capsaicin but only marginally attenuated the effects evoked by a high concentration of capsaicin, or nicotine. Prejunctional alpha 2-adrenoceptor or opiate receptor activation inhibited the neuropeptide release and bronchoconstriction induced by vagal stimulation or a low concentration of capsaicin. Ruthenium red had a selective inhibitory effect on the overflow of neuropeptides [CGRP, neurokinin A (NKA)] and bronchoconstriction induced by capsaicin and its analogue RTX but not on responses induced by vagal stimulation, nicotine, bradykinin and histamine. It also inhibited CGRP and NKA release and bronchoconstriction caused by pH 5 buffer in lung, as well as cough and nasal irritation provoked by citric acid in vivo. The capsaicin receptor antagonist capsazepine inhibited peptide (CGRP, NKA) release and bronchoconstriction produced by capsaicin but not that evoked by vagal stimulation, nicotine and bradykinin, suggesting selectivity. Citric acid (in vivo) and pH 5 buffer (in vitro) produced bronchoconstriction via activation of capsaicin-sensitive sensory nerves. Interestingly, capsazepine also markedly depressed peptide overflow and bronchoconstriction caused by pH 5 buffer in isolated guinea-pig lung.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Regulation of jejunal arterioles by capsaicin-sensitive nerves in Nippostrongylus brasiliensis-sensitized rats.

The mechanisms by which sensory nerves elicit dilation of serosal arterioles in the jejunum of rats sensitized to the nematode Nippostrongylus brasiliensis were studied using intravital microscopy. Capsaicin (0.002-2 micrograms), applied as a bolus topically to the serosa, produced a substantially larger dilation in the sensitized rats than in unsensitized rats. Abolition of the primary afferent nerves by neonatal treatment with capsaicin and blockade of capsaicin with the antagonist ruthenium red reduced markedly the dilator actions of capsaicin. Mast cell products are important in the actions of capsaicin, because pretreatment with dexamethasone (4 mg/kg), to eliminate mast cells by a macrophage-dependent mechanism, abrogated the actions of capsaicin. In addition, superfusion of the H1 receptor antagonist diphenhydramine (2 microM) blocked the actions of capsaicin. Neither cyclooxygenase products nor platelet-activating factor was involved in capsaicin-induced dilation. The actions of capsaicin and histamine were mediated via a nitric oxide (NO)-dependent mechanism, because superfusion of an inhibitor of NO synthase (NG-nitro L-arginine methyl ester, 10 microM) blocked their effects. This inhibition of capsaicin-elicited dilation by NG-nitro L-arginine methyl ester was prevented by L-arginine (100 microM), the substrate for NO synthase. Thus the arteriolar dilation evoked by capsaicin activation of primary afferent nerves in N. brasiliensis-sensitized rats involves predominantly the release from mast cells of histamine, which then dilates the vessels by a NO-dependent mechanism.

Animals↗
PubMed1997

A single capsaicin injection partially depletes neuropeptides but does not ameliorate inflammation severity in established feline antigen induced arthritis.

OBJECTIVE: To investigate the effect of the neuropeptide depleting agent capsaicin on neuropeptides in both synovial and nonsynovial articular tissues and on the relative degree of joint inflammation in established antigen induced arthritis (AIA). METHODS: AIA was created in both knees in 3 cats. Once AIA was established, the left knee of each animal received a single 0.5 ml injection of capsaicin (0.3 mg/ml). Three days later, the knees were harvested and dissected into 11 regions. Eleven articular cartilage tissues from both the experimental (capsaicin) and control (non-capsaicin) knees were examined for the immunocytochemical presence of substance P (SP) and calcitonin gene related peptide (CGRP). Additionally, the synovium was examined to determine the severity of joint inflammation. RESULTS: Nerve fibers immunoreactive for SP or CGRP were found in all 11 tissues in each of the non-capsaicin treated AIA knees. Both perivascular and "free" SP and CGRP immunoreactive fibers were present in all 11 articular structures. In the knees treated with capsaicin, however, 48% of the joint tissues examined completely lacked SP immunoreactivity, while 12% had no CGRP immunoreactivity. Inflammatory disease severity was not ameliorated by the single intraarticular injection of capsaicin used in this study. CONCLUSION: These data indicate that SP and CGRP immunoreactivity is maintained in synovial and nonsynovial articular tissues of non-capsaicin treated knees during subacute joint inflammation. In the capsaicin treated AIA knees, however, there was partial neuropeptide depletion. Nerve fibers containing SP were more sensitive to the peptide depleting effects of capsaicin than were CGRP positive fibers. Depletion of SP and CGRP from some joint tissues did not correlate with a decrease in joint inflammation. Studies incorporating a broad range of dosages will be required to determine whether intraarticular treatment with capsaicin can effectively deplete neuropeptides and thereby ameliorate established inflammatory arthritis.

Animals↗
PubMed1990

Capsaicin-induced neuronal degeneration in the brain and retina of preweanling rats.

Capsaicin is a neurotoxin known for its ability to cause degeneration of small unmyelinated primary sensory neurons in both spinal and cranial nerves. Although lower motor neurons do not degenerate following capsaicin treatment, the extent to which capsaicin may damage neurons in the brain has not been thoroughly evaluated. This study examines the effects of systemic capsaicin (50-150 mg/kg) on the central nervous system of 10-day-old rats. Rat pups were injected with capsaicin or the injection vehicle and sacrificed 6 hours-10 days later. Brains, spinal cords, and retinas were stained with cupric silver to label degenerating neurons. As previously reported for capsaicin-treated rats, degenerating nerve terminals were present in areas receiving primary afferent input: the spinal cord dorsal horn, spinal trigeminal nucleus, nucleus of the solitary tract, and area postrema. However, degenerating terminals were also present in areas not known to receive primary sensory innervation: the inferior olivary nucleus, sphenoid nucleus, medial and olivary pretectal nuclei, interpeduncular nucleus, interfascicular nucleus, caudal linear, dorsal, median, and paramedian raphe nuclei, supramammillary area, lateral habenula, ventrolateral geniculate nucleus, ventral reuniens nucleus, ventromedial hypothalamic nucleus, lateral hypothalamic and preoptic areas, suprachiasmatic nucleus, septohypothalamic nucleus, bed nucleus of the stria terminalis, lateral septal nucleus, accumbens shell, olfactory bulb, and retina. Some areas where capsaicin caused degeneration in rat pups do not appear to be capsaicin-sensitive in adult rats. Results indicate that (1) capsaicin's neurotoxicity is not limited to primary sensory neurons and (2) developmental factors may alter the capsaicin sensitivity of some neuronal projections within the brain.

Animals↗