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PubMed1993

Intraurethral capsaicin produces reflex activation of the striated urethral sphincter in urethane-anesthetized male rats.

The effect of intraurethral application of capsaicin on the urethral motility of urethane anesthetized rats has been investigated. The urinary bladder and the urethra were surgically disconnected, and both organs were cannulated to record variations in intraluminal pressure (cystourethrogram). Urinary bladder reflex contractions in response to intravesical infusion of saline were paralleled by activation of the external striated urethral sphincter, resulting in intraluminal pressure high frequency oscillations (IPHFO) which were recorded at the urethral level. Intraurethral capsaicin (0.2 microgram./30 microliters.), produced an immediate enhancement of the IPHFO, the amplitude of which (70 +/- 9 mm.Hg) was significantly (p < 0.01) higher as compared with that recorded before drug administration (15 +/- 3 mm.Hg). The potentiation was followed (11 of 15 rats) by a period (5 to 12 minutes) characterized by a continuous low-amplitude urethral phasic activity. Throughout this period urinary bladder motility was inhibited. A second administration of capsaicin in the same animal was ineffective, and the response was absent in rats desensitized to capsaicin (50 mg./kg., subcutaneously, 4 days before), after application of tetrodotoxin (10 micrograms.) on the pudendal nerves, or after acute (3 hours before) sectioning, as well as in rats pretreated with d-tubocurarine (d-Tc, 100 micrograms./kg. intravenously). Intraurethral injection of capsaicin (0.2 microgram./30 microliters.), performed when the urinary bladder was empty, triggered IPHFO (12 +/- 3 mm.Hg) in 5 of 6 rats. This response was unaffected by hexamethonium (20 mg./kg., intravenously) or after removal (6 hours before) of the major pelvic ganglia, while it was absent after destruction of the lumbosacral spinal cord (3 to 6 hours before), in rats acutely spinalized (T13-L1), or after sectioning of the pudendal nerves. In rats receiving intrathecal (L5-S1) capsaicin (60 micrograms., 24 hours before), the capsaicin-induced IPHFO activation was lacking. Electrical field stimulation (EFS, 0.1 Hz, 30 microseconds, 20 to 30 v) of the rat isolated external urethral sphincter (EUS), elicited d-tubocurarine and tetrodotoxin-sensitive twitch contractions, the amplitude of which was unaffected by capsaicin (1 microM.). Altogether these results suggest a physiological interaction between capsaicin-sensitive primary afferents innervating the urethra and the somatic efferent innervation to the urethral rabdosphincter. Present findings suggest the existence of a chemonociceptive urethro-urethral neural loop which, via pudendal nerves, leads to a supraspinally-mediated activation of the external urethral sphincter.

Afferent Pathways↗
PubMed2001

Comparative effect of Phoneutria nigriventer spider venom and capsaicin on the rat paw oedema.

Capsaicin, the pungent component of hot peppers, and the venom of the spider Phoneutria nigriventer are able to activate sensory nerves resulting in cutaneous neurogenic plasma extravasation. This study was undertaken to compare the ability of these substances to evoke oedema in the rat hind-paw and mechanisms underlying this effect. Subplantar injection of either Phoneutria nigriventer venom (PNV; 1-100 microg/paw) or capsaicin (10-200 microg/paw) caused a significant paw oedema that was potentiated by CGRP (10 pmol/paw). In rats treated neonatally with capsaicin to deplete neuropeptides, the paw oedema induced by either PNV (100 microg/paw) or capsaicin (100 microg/paw) was partially reduced (P<0.05). The tachykinin NK1 receptor antagonist SR140333 (0.2 micromol/kg; i.v.) prevented the paw oedema induced by the tachykinin NK1 receptor agonist GR73632 (30 pmol/paw) and partially reduced paw oedema induced by PNV or capsaicin. Treatment of rats with compound 48/80 (5 mg/kg; s.c. 3 days) or with both H1 receptor antagonist (mepyramine; 1 nmol/paw) and 5-HT receptor antagonist (methysergide; 1 nmol/paw) significantly inhibited PNV- or capsaicin-induced paw oedema. The combined treatment with mepyramine and methysergide and SR140333 further reduced PNV- and capsaicin-induced paw oedema. The bradykinin B2 receptor antagonist Hoe 140 affected neither PNV- nor capsaicin-induced responses. Our results suggest that PNV and capsaicin each induce paw oedema that is partially mediated by activation of sensory fibers culminating in the release of substance P as well as by activation of mast cells which in turn release amines such as histamine and 5-HT.

Animals↗
PubMed2003

Identification of QTLs for differential capsaicin sensitivity between mouse strains KJR and C57BL/6.

Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is the main compound of hot chili peppers that causes both a pungent sensation and physiological pain. Capsaicin activates vanilloid receptor 1, a multi-functional receptor for pain sensation. In our previous report, it was found that sensitivity for capsaicin varies among mouse strains. In the present study, we conducted a quantitative trait loci (QTL) analysis to characterize the genetic loci involved in the different sensitivities to capsaicin between C57BL/6 and KJR mouse strains. In the study, we generated F2 progeny from the intercross of F1 mice obtained from a cross of C57BL/6 and KJR. We applied a fluid intake test of a capsaicin solution to the F2 progeny and conducted a QTL analysis. In this mapping study, four QTLs for capsaicin sensitivity were detected. Each of these loci contributed to 18.7-27.87% of strain difference of capsaicin consumption between C57BL/6 and KJR at each concentration. Because the sensation for capsaicin is associated with perception of pain, this genetic study on different capsaicin sensitivities will help future analyses of endogenous analgesic pathway.

Animals↗
PubMed1996

Rapid recovery from capsaicin desensitization during recurrent stimulation.

Topical desensitization of the tongue was assessed during multiple bouts of exposure to capsaicin. In the first experiment subjects rated perceived irritation as 30 capsaicin stimuli (33 microM) were applied to the tongue tip in three blocks of 10, with 15 min breaks between blocks. Significant desensitization was measured at the beginning of the second and third blocks within each session. However, as stimulation continued within those blocks sensations of irritation grew toward undesensitized levels ('stimulus-induced recovery' (SIR)). Desensitization did not extend across days. The second experiment employed a 10-fold higher concentration of capsaicin (330 microM) to determine if SIR was limited to low levels of desensitization. SIR occurred as before within sessions, and the higher concentration produced desensitization across days that also exhibited recovery during the first block of stimuli on days 2 and 3. The third experiment included piperine, zingerone and citric acid as stimuli to determine if SIR was specific to capsaicin. Piperine produced SIR under conditions of both self- and cross-desensitization with capsaicin, whereas recovery failed to materialize with zingerone. Citric acid was not significantly cross-desensitized by capsaicin, so recovery could not be measured. Overall the results demonstrate that desensitization of the tongue produced by either capsaicin or piperine can be temporarily reversed if stimulation with either chemical is resumed for only a few minutes. The implications these findings may have for hypotheses about the mechanisms of capsaicin desensitization and sensitization as well as for clinical applications of capsaicin as a topical analgesic are discussed.

Administration, Oral↗
PubMed1999

Topical EMLA pre-treatment fails to decrease the pain induced by 1% topical capsaicin.

Topical capsaicin has been reported to be beneficial for the treatment of neurogenic pain. However, due to the burning pain associated with topical capsaicin, many patients discontinue treatment before therapeutic benefits are obtained. This study assessed the efficacy of EMLA (eutectic mixture of 2.5% prilocaine and 2.5% lidocaine) to block pain induced by the topical application of 1% capsaicin. Nine healthy subjects (five males and four females) participated in the study. High dose topical capsaicin (1%) was applied to a 2.5 x 2.5 cm region of both volar forearms for 6 h. One arm was pretreated (for 2 h) and cotreated with EMLA, and the other arm served as vehicle control. Average and peak pain ratings were recorded at 15-min intervals using a 0 (no pain) to 10 (worst possible pain) scale. Average and peak pain ratings were significantly lower at the EMLA site during the first 15-30 min of capsaicin treatment. However, for the remaining 5.5 h of capsaicin treatment, the pain ratings at the EMLA and vehicle sites were not significantly different. The 6 h treatment with high dose topical capsaicin (1%) produced significant desensitization to heat stimuli that was not affected by EMLA treatment. EMLA fails to produce a long lasting attenuation of the pain induced by topical application of 1% capsaicin. These results argue against the use of EMLA to block pain to topical capsaicin during the treatment of neurogenic pain.

Administration, Topical↗
PubMed2000

Intramuscular and intradermal injection of capsaicin: a comparison of local and referred pain.

The present study compared capsaicin-induced muscle and skin pain in humans. Twelve healthy subjects received, in a randomised, balanced order, 3 intramuscular (i.m.) injections into the brachioradial muscle: capsaicin 100 microg/1 ml, capsaicin 100 microg/20 microl or 1 ml solvent (Tween 80), and one intradermal injection (i.d.): capsaicin 100 microg/20 microl. Local and referred pain intensities and areas were assessed from 0 to 60 min after injection. Intradermal capsaicin produced more intense local pain than i.m. capsaicin in the first min (skin: 68+/-6, muscle: 51+/-6 mm VASxmin, P<0.05). In contrast, the local pain offset was later (muscle: 38+/-5, skin: 23+/-5 min, P<0.05) and referred pain was more frequent (muscle: 9/12, skin: 1/12 subjects, P<0.01) following i.m. capsaicin compared with i.d. capsaicin. Capsaicin (1 ml) produced significantly more pain than 20 microl i.m. (pain in the first min: 1 ml: 71+/-6, 20 microl: 51+/-6 VASxmin, P<0.05, offset: 1 ml: 50+/-4, 20 microl: 38+/-5 min, P<0.05). The different local and referred pain following identical noxious stimulation of muscle and skin indicates that the neurophysiological mechanisms underlying skin and muscle pain differs. The model with identical noxious stimulation of muscle and skin may be suitable for the study of differences in deep and superficial pain as seen in the clinic.

Adult↗
PubMed2000

Differential effects of capsaicin on rat visceral sensory neurons.

Nodose neurons play an important role in the regulation of visceral function. Recent studies demonstrated that about 80% of these neurons contain messenger RNA for the capsaicin receptor, a heat-sensitive ion channel. Nodose neurons express voltage-sensitive sodium currents that can be differentiated based on their sensitivity to tetrodotoxin. Considering the potential role of tetrodotoxin-resistant sodium currents in somatosensory neurons, sodium channel expression and sodium currents were studied in nodose neurons. The results were correlated with the response to capsaicin. Nodose neurons contain messenger RNA for the tetrodotoxin-resistant sodium channel PN3. Consistent with these findings, about half of the neurons predominantly expressed tetrodotoxin-resistant sodium currents. In 54% (47/87) of the cells, capsaicin triggered an increase in intracellular calcium. Similarly, in 42% (18/43) of the cells, capsaicin elicited an inward current. There was no relationship between cell size (r=0.07) or sodium current properties (r=0.14) and the response to capsaicin. Micromolar concentrations of capsaicin inhibited voltage-dependent sodium, calcium and potassium currents. This effect was use dependent and did not involve the capsaicin receptor. In conclusion, capsaicin changed the excitability of visceral sensory neurons by blocking voltage-dependent ion channels, an effect that may contribute to the analgesic properties of capsaicin.

Action Potentials↗
PubMed2001

NMDA or non-NMDA receptor antagonists attenuate increased Fos expression in spinal dorsal horn GABAergic neurons after intradermal injection of capsaicin in rats.

GABAergic neurons play an important role in the generation of primary afferent depolarization, which results in presynaptic inhibition and, if large enough, triggers dorsal root reflexes. Recent electrophysiological studies by our group have suggested that increased excitation of spinal GABAergic neurons by activation of N-methyl-D-aspartate (NMDA) and non-NMDA receptors following intradermal injection of capsaicin results in the generation of DRRs that contribute to neurogenic inflammation. The present study was to determine if changes in the expression of Fos protein occur in GABAergic neurons in the lumbosacral spinal cord following injection of capsaicin into the glabrous skin of one hind paw of anesthetized rats and if pretreatment with an NMDA receptor antagonist, D-(-)-2-amino-7-phosphonoheptanoic acid (AP7) or a non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) blocks Fos expression in these neurons. The experiments used western blots and immunofluorescence double labeling staining following capsaicin or vehicle injection. Western blots showed that Fos protein was increased on the ipsilateral side in spinal cord tissue 0.5 h after capsaicin injection. Pretreatment with AP7 or CNQX caused a decrease in capsaicin-induced Fos expression. Immunofluorescence double labeling showed that the proportion of Fos-positive GABAergic neuronal profiles was significantly increased following capsaicin injection (48.8+/-4.8%) compared to the vehicle injection (23.8+/-5.1%) in superficial laminae on the ipsilateral side in lumbosacral spinal cord (P<0.05). However, when the spinal cord was pretreated with AP7 (5 microg) or CNQX (0.2 microg), only 9.1+/-0.6% or 7.1+/-0.8% of GABA-immunoreactive neuronal profiles were stained for Fos following capsaicin injection. The blockade of the capsaicin-evoked Fos staining was dose-dependent. These findings suggest that GABAergic neurons take part in dorsal horn circuits that modulate nociceptive information and that the function of GABAergic neurons following capsaicin injection is partially mediated by NMDA and non-NMDA receptors.

2-Amino-5-phosphonovalerate↗
PubMed1997

Systemic capsaicin in the adult rat differentially affects gene expression for neuropeptides and neurotrophin receptors in primary sensory neurons.

While systemic capsaicin in adult rats is known to reduce substance P and somatostatin in primary sensory nerves, it is still unknown if it also affects the production of these peptides at the genetic level. Therefore, we examined the effects of systemically administered capsaicin on the expression of the beta-preprotachykinin, gamma-preprotachykinin, somatostatin, calcitonin gene-related peptide, vasoactive intestinal polypeptide, galanin, neuropeptide Y and neurotrophin receptor family (trkA, trkB, trkC) genes in dorsal root ganglion neurons by in situ hybridization in adult rats. Nerve growth factor is thought to be involved in the regulation of some of these genes. In the control animals, beta-preprotachykinin, gamma-preprotachykinin, calcitonin gene-related peptide, somatostatin, trkA, trkB and trkC messenger RNAs were found in about 30%, 30%, 40%, 10%, 40%, 5% and 20% of the lumbar dorsal root ganglion neurons, respectively. The number of neurons expressing beta/gamma-preprotachykinin and calcitonin gene-related peptide messenger RNAs decreased to about 50% and 70% of the control values, respectively, six days after subcutaneous administration of capsaicin (950 mg/kg). Simultaneously, the number of trkA messenger RNA-expressing neurons also decreased to about 70% of the control level, while the number of neurons expressing trkB and trkC messenger RNAs was unaffected. On the other hand, vasoactive intestinal polypeptide and galanin messenger RNAs, but not neuropeptide Y messenger RNA, began to be expressed in about 10% of dorsal root ganglion neurons after administration of capsaicin, although their messenger RNAs were not detected in the controls. However, the expression of somatostatin messenger RNA was unaffected by the systemic administration of capsaicin. The somatostatin messenger RNA was not co-expressed with vasoactive intestinal polypeptide and galanin messenger RNAs in the sensory neurons of rats given capsaicin. Electron microscopic analysis revealed a few degenerating unmyelinated afferents in sural nerves of the treated rats. The number of small-sized dorsal root ganglion cells labeled with Fluoro-Gold, a retrograde-tracing dye which was injected into the sural nerve of the treated rats, decreased to half of the control number. Our results suggest that systemic administration of capsaicin in adult rats depresses the expression of beta/gamma-preprotachykinin, calcitonin gene-related peptide and trkA messenger RNAs, and induces expression of vasoactive intestinal polypeptide and galanin messenger RNAs in sensory neurons, which may be due to the capsaicin-induced degeneration of a subpopulation of sensory afferents. We also demonstrated that the regulation of somatostatin gene expression in mature sensory neurons is not affected by systemic capsaicin.

Animals↗
PubMed1999

Responses of primate spinomesencephalic tract cells to intradermal capsaicin.

The responses of 32 spinomesencephalic tract cells to intradermal capsaicin were examined in anesthetized monkeys. Wide dynamic range (n = 20) and nociceptive specific (n = 6) cells showed two types of excitatory responses to intradermal injection of capsaicin. The first excitatory response shown by the majority of wide dynamic range (n = 13) and nociceptive specific (n = 4) cells was consistent with their sensitization by capsaicin. The cells showed an acute and prolonged increase in ongoing activity with capsaicin injection. Responses to mechanical stimuli were substantially increased after capsaicin and an expansion of receptive field was often observed. The responses of the same cells to excitatory amino acid agonists applied locally by iontophoresis also increased. All cells showing sensitization were antidromically activated from periaqueductal gray regions dorsal to the sulcus limitans. Electrical stimulation at these sites did not affect the ongoing or evoked discharges of these cells. The second excitatory response of wide dynamic range (n = 5) and nociceptive specific (n = 1) cells was a novel pattern not consistent with sensitization. These cells nevertheless showed an acute and prolonged increase in background activity after capsaicin injection. Yet, there was no change or a decrease in responses to cutaneous stimuli, no evidence for change in receptive field size and no increase in responses to locally released excitatory amino acids. These cells projected to regions in the periaqueductal gray ventral to the sulcus limitans. Electrical stimulation at these sites produced a decrease in spontaneous activity of the same cell. Low threshold mesencephalic-projecting neurons (n = 6) showed a single inhibitory pattern (n = 4) of responses to capsaicin. The injection produced an acute decrease in spontaneous activity that was sustained for at least 30 min after injection. The responses to cutaneous stimuli and to excitatory amino acids were also substantially reduced. Low threshold cells were found that projected to both dorsal-lateral and ventral-lateral regions of the periaqueductal gray. In summary, three patterns of responses shown by primate spinomesencephalic tract cells to intradermal capsaicin appear dependent on the functional regions of the periaqueductal gray to which they project. These results suggest that inputs of spinomesencephalic tract neurons to the periaqueductal gray may evoke important components of the systemic response to the neurogenic hyperalgesia produced by intradermal capsaicin.

Animals↗
PubMed2003

Capsaicin exhibits anti-inflammatory property by inhibiting IkB-a degradation in LPS-stimulated peritoneal macrophages.

Capsaicin, a major ingredient of hot pepper, was considered to exhibit an anti-inflammatory property. In order to clarify the signalling mechanism underlying the anti-inflammatory action of capsaicin, we investigated the effect of capsaicin on the production of inflammatory molecules in lipopolysaccharide (LPS)-stimulated murine peritoneal macrophages. The level of PGE2 was measured by EIA. The expression levels of COX-2, iNOS, IkB-a, and vanilloid receptor-1 (VR-1) were determined at the protein and mRNA levels. Significant inhibition of the production of LPS-induced PGE2 by capsaicin was observed in a dose-dependent manner. Capsaicin did not affect the COX-2 expression at either the protein or mRNA level, but inhibited the enzyme activity of COX-2 and the expression of the iNOS protein. Capsaicin completely blocked LPS-induced disappearance of IkB-a and therefore inactivated NF-kB. The inhibitory action of capsaicin on PGE2 production was not abolished by capsazepine, a specific antagonist to VR-1. A high expression level of the VR-1 like protein (VRL-1) was observed in peritoneal macrophages, while the expression of VR-1 was not detected. These findings suggest that the anti-inflammatory action of capsaicin may occur through a novel mechanism, not by a VR-1 receptor-mediated one. Both capsaicin and capsazepine may be a promising drug candidates for ameliorating inflammatory diseases and cancer.

Animals↗
PubMed1991

Mechanism of capsaicin action: recent learnings.

Capsaicin has long been known to act selectively on a subpopulation of neurons to produce initial excitation, followed by a prolonged neuroinhibitory action commonly referred to as 'capsaicin desensitization'. This property has been exploited extensively as a tool with which to investigate the role of these nerves in the normal and pathophysiology of the airways. However, the cellular basis for these effects is only now beginning to be understood. The purpose of this review is to summarize recent findings that provide new insights into the mechanisms by which capsaicin acts to exert its effects. These findings suggest that capsaicin acts at a receptor that is either tightly coupled to, or indeed is, a relatively non-selective cation channel. Binding of capsaicin to this receptor allows both sodium and calcium (and possibly potassium) ions to flow down their concentration gradients, causing initial depolarization and neurotransmitter release. Prolonged exposure to capsaicin produces a subsequent desensitization or neuroinhibition. The neuroinhibition has now been shown to be of two types: capsaicin-specific and non-specific. The former is characterized by a loss of the acute excitatory response evoked by application of capsaicin, but maintained responses to other stimuli. The latter is characterized by a loss of responsiveness to all stimuli and is probably associated with the neurotoxic effect of this agent. Despite these recent findings, many questions remain regarding the nature and physiological role of the capsaicin receptor. The availability of two new probes for this receptor, ruthenium red and resiniferatoxin, promises to provide at least some of the answers to these intriguing questions.

Action Potentials↗
PubMed2003

Stimulation by capsaicin of duodenal HCO3(-) secretion via afferent neurons and vanilloid receptors in rats: comparison with acid-induced HCO3(-) response.

We compared the HCO3(-) secretory response to capsaicin and mucosal acidification in rat duodenums, especially the relation to vanilloid receptor type 1 (VR1). A proximal duodenal loop was perfused with saline, and the HCO3(-) secretion was measured at pH 7.0 using a pH-stat method and by adding 10 mM HCl. The secretion was stimulated by exposing the loop to capsaicin (0.03-0.3 mg/ml) or 10 mM HCl for 10 min. Indomethacin subcutaneously or ruthenium red intravenously, a nonspecific VR1 antagonist, was given 60 or 10 min, respectively, before exposure to capsaicin or acid, while L-NAME was given intravenously 3 hr before these treatments. Capsazepine, another VR1 antagonist, was coapplied to the loop for 10 min with capsaicin or acid. Luminal application of capsaicin increased the secretion of HCO3(-) in a dose-dependent manner; this effect was markedly attenuated by chemical ablation of capsaicin-sensitive afferent neurons (CSN) as well as pretreatment with ruthenium red or capsazepine, and significantly mitigated by indomethacin or L-NAME (in an L-arginine-sensitive manner). The HCO3(-) secretion was also stimulated by mucosal acidification, and this response was attenuated by both capsaicin pretreatment, indomethacin and L-NAME, but not ruthenium red or capsazepine. Mucosal application of capsaicin as well as acid increased the mucosal PGE2 content, and these effects were both significantly attenuated by indomethacin and L-NAME. These results suggest that both capsaicin and acid cause the CSN-dependent increase in duodenal HCO3(-) secretion mediated by NO and PG, yet the mode of their action differs in terms of the ruthenium red or capsazepine sensitivity. Although luminal H+ plays a modulatory role in duodenal HCO3(-) secretion, it is unlikely that the action results from the interaction of H+ with the ruthenium red- or capsazepine-sensitive site of VR1.

Animals↗
PubMed1983

Dissociation between peripheral and central heat loss mechanisms induced by neonatal capsaicin.

Fifty-eight 4-day-old male rats were studied. Peripheral desensitization was induced in 36 rats by sc administration of capsaicin in increasing doses (350, 700, 1,400, 2,100, and 2,800 micrograms) on 5 consecutive days. When adult, 9 treated and 5 control rats were chronically implanted with a lateral intracerebroventricular (icv) guide cannula. This tube was used for icv capsaicin injection. Eleven treated rats and 6 controls were implanted with a hypothalamic thermode. Hypothalamic heating was activated with the aid of this water-perfused thermode. Twenty-eight rats, 12 control and 16 treated, were injected ip and sc with capsaicin. Results showed that in control rats, icv, ip, and sc capsaicin injections produced a fall in body (core) temperature and an increase in cutaneous temperature. These changes are attributed to cutaneous vasodilation. In capsaicin-treated rats, sc and ip injections had no effect on body temperature. However, neonatal treatment did not inhibit the effect of capsaicin on body temperature. Furthermore, in these rats thermoregulatory behavior for fresh air was identical to that of controls at all ambient temperatures before and during hypothalamic heating. These results suggest that the central heat receptors responsible for autonomic and behavioral thermoregulation in the treated rats function normally when icv capsaicin is injected or when the hypothalamus is heated. In contrast, neonatal injection of capsaicin produced an inhibition of the heat loss mechanisms induced by ip or sc capsaicin, i.e., by stimulation of the peripheral nervous system.

Animals↗
PubMed1997

Effects of tachykinins and capsaicin on the mechanical and electrical activity of the guinea-pig isolated trachea.

1. The effects of tachykinins and capsaicin were studied by means of intracellular membrane potential and isometric tension recordings in the isolated trachea of the guinea-pig. 2. The basal membrane potential averaged -51 mV, and most preparations demonstrated spontaneous slow waves. Tetraethylammonium (TEA), a potassium channel blocker (8 x 10(-3) M), depolarized the membrane potential to -44 mV and induced a rhythmic activity. 3. In control solution, substance P (10(-8)-10(-6) M), [Nle10]-neurokinin A(4-10) (10(-8)-10(-6) M) and capsaicin (10(-7)-10(-6) M) induced concentration-dependent depolarizations which were statistically significant at the highest concentration tested (depolarization by 10(-6) M: 8, 11 and 16 mV for the NK1 agonist, the NK2 agonist and capsaicin, respectively). 4. In the presence of TEA (8 x 10(-3) M), the three substances induced depolarizations which were statistically significant at the highest concentration tested for substance P (10(-6) M) and at 10(-7) and 10(-6) M for both [Nle10]-neurokinin A(4-10) and capsaicin (depolarization by 10(-6) M: 11, 17 and 10 mV for substance P, [Nle10]neurokinin A(4-10) and capsaicin, respectively). 5. In the presence or absence of tetraethylammonium, [MePhe7]-neurokinin B (10(-8)-10(-6) M) did not induce any significant changes in membrane potential. 6. The depolarizing effects of substance P (10(-6) M) and [Nle10]-neurokinin A(4-10) (10(-6) M) were blocked only by the specific antagonists for NK1 and NK2 receptors, SR 140333 (10(-7) M) and SR 48968 (10(-7) M), respectively. The effects of capsaicin (10(-6) M) were partially inhibited by each antagonist and fully blocked by their combination. 7. Substance P (10(-9) to 10(-4) M), [Nle10]-neurokinin A(4-10) (10(-10) to 10(-5) M), [MePhe7]-neurokinin B and capsaicin (10(-7) to 10(-5) M) evoked concentration-dependent contractions. 8. The contractions to substance P were significantly inhibited by SR 140333 (10(-8) to 10(-6) M) but unaffected by SR 48968 (10(-8) to 10(-6) M). Furthermore, the response to [Nle10]-neurokinin A(4-10) was significantly inhibited by SR 48968 and unaffected by SR 140333 at the same concentrations. Although SR 48968 (10(-7) M) alone did not influence the effects of substance P, it potentiated the inhibitory effect of SR 140333 (10(-7) M). A similar synergetic effect of these two compounds was observed in the inhibition of the contractile response to [Nle10]-neurokinin A(4-10). 9. Neither SR 140333 (10(-7) M) nor SR 48968 (10(-7) M) alone influenced the contractions to [MePhe7]-neurokinin B and capsaicin. However, the combination of the two antagonists abolished the contractions to either peptide. 10. These results demonstrate that the stimulation of both NK1 and NK2 tachykinin-receptors induced contraction and depolarization of the guinea-pig tracheal smooth muscle and that both receptors were stimulated during the endogenous release of tachykinins by capsaicin. There was no evidence for a major role of NK3 receptors in the contractile and electrical activity of the guinea-pig isolated trachea.

Animals↗
PubMed2002

Taste suppression following lingual capsaicin pre-treatment in humans.

The effect of oral capsaicin on taste sensations in humans was reinvestigated with attention to methodological issues raised in previous studies, including the mode of presentation and temperature of the tastant stimulus, as well as the sensitizing and desensitizing properties of capsaicin. One-half of the dorsal anterior tongue was pre-treated with capsaicin, followed by bilateral tastant application (sucrose, NaCl, quinine, monosodium glutamate and citric acid). Subjects indicated on which side the taste intensity was greater in a two-alternative, forced-choice procedure and also rated taste intensity independently on each side of the tongue. Each of the five tastants was tested sequentially, with reapplication of capsaicin between trials in order to maintain a constant level of burn. Four experiments were conducted: (i) a high concentration (33 p.p.m.) (109 microM) capsaicin effect on taste intensity elicited by high tastant concentrations; (ii) a high concentration capsaicin effect on taste intensity elicited by low tastant concentrations; (iii) a low concentration (1.5 p.p.m.) (4.9 microM) capsaicin effect on taste intensity elicited by low tastant concentrations; and (iv) validation of the method for localizing taste by pre-treating one side of the tongue with Gymnema sylvestre, followed by bilateral application of sucrose. In the first experiment, a significant proportion of the subjects chose the non-treated side in the two-alternative, forced-choice procedure and assigned significantly higher ratings to that side for sucrose-induced sweetness, quinine-induced bitterness and glutamate-induced umami sensations. Salty and sour sensations were not different between sides. A 15 min break was imposed in order to allow the capsaicin burn to disappear and desensitization to set in, followed by reapplication of the tastant test solutions. There were no bilateral differences in the intensity of the sensations elicited by any of the five tastants. Similar results were obtained in experiments 2 and 3. In the fourth experiment, all 15 subjects tested chose the side not treated with Gymnema sylvestre as having a stronger sweet taste and assigned significantly higher ratings to that side, thereby validating the method for taste localization. These results indicate that oral capsaicin reduces certain but not all taste sensations and are discussed in terms of possible physiological and cognitive interactions.

Adolescent↗
PubMed2003

Fentanyl decreases Ca2+ currents in a population of capsaicin-responsive sensory neurons.

BACKGROUND: Neuraxial opioids produce analgesia in part by decreasing excitatory neurotransmitter release from primary nociceptive neurons, an effect that may be due to inhibition of presynaptic voltage-activated Ca2+ channels. The purpose of this study was to determine whether opioids decrease Ca2+ currents (I Ca ) in primary nociceptive neurons, identified by their response to the algogenic agent capsaicin. METHODS: I was recorded from acutely isolated rat dorsal root ganglion neurons using the whole cell patch clamp technique before, during, and after application of the micro -opioid agonist fentanyl (0.01-1 micro m). Capsaicin was applied to each cell at the end of the experiment. RESULTS: Fentanyl reduced I Ca in a greater proportion of capsaicin-responsive cells (62 of 106, 58%) than capsaicin-unresponsive cells (2 of 15, 13%; P < 0.05). Among capsaicin-responsive cells, the decrease in I Ca was 38 +/- 3% (n = 36, 1 micro m) in fentanyl-sensitive cells just 7 +/- 1% (n = 15, 1 micro m; P < 0.05) in fentanyl-insensitive cells. Among capsaicin-responsive cells, I Ca inactivated more rapidly in fentanyl-sensitive cells (tau, 52 +/- 4 ms, n = 22) than in fentanyl-insensitive cells (93 +/- 14 ms, n = 24; P < 0.05). This was not due to differences in the types of Ca2+ channels expressed as the magnitudes of omega-conotoxin GVIA-sensitive (N-type), nifedipine-sensitive (L-type), and GVIA/nifedipine-resistant (primarily P-/Q-type) components of I Ca were similar. CONCLUSIONS: The results show that opioid-sensitive Ca2+ channels are expressed by very few capsaicin-unresponsive neurons but by more than half of capsaicin-responsive neurons. The identity of the remaining capsaicin-responsive (and therefore presumed nociceptive) neurons that express opioid-insensitive Ca2+ channels is unknown but may represent a potential target of future non-opioid-based therapies for acute pain.

Agatoxins↗
PubMed2004

Urodynamic and immunohistochemical evaluation of intravesical capsaicin delivery using thermosensitive hydrogel and liposomes.

PURPOSE: Aqueous insolubility of the vanilloids such as capsaicin is a major disincentive in their intravesical therapy of detrusor hyperreflexia. We sought to overcome the delivery of this hydrophobic neurotoxin by entrapping it in a lipid bilayer of positively charged multilamellar lipid vesicles (liposomes) or in a hydrophobic polymer matrix of thermosensitive hydrogel. MATERIALS AND METHODS: Liposomes, hydrogel and 30% ethanol/normal saline were prepared with or without 1 mM capsaicin (0.5 ml) and administered intravesically for 30 minutes to 7 groups of age matched, normal female adult Sprague-Dawley rats under halothane anesthesia. At 48 hours after intravesical instillation cystometric studies were performed using urethane anesthesia (0.04 ml per minute). The animals were subsequently sacrificed and whole bladders were harvested for histology and immunohistochemistry. RESULTS: In normal urethane anaesthetized rats capsaicin in 30% ethanol and liposomes completely blocked micturition reflexes. Capsaicin in hydrogel did not completely block the micturition reflex but it significantly decreased bladder contraction frequency compared with vehicle controls. The results of cystometry with capsaicin in liposomes and capsaicin in 30% ethanol correlated with a significant decrease in calcitonin gene-related peptide staining of afferent nerves in the bladder wall. Photographs taken after hematoxylin and eosin staining of the bladder treated with liposomes and hydrogel in the absence of capsaicin did not reveal any adverse histological changes. There were significant histological changes in bladders treated with 30% ethanol alone. CONCLUSIONS: In comparison with 30% ethanol liposomes are a superior vehicle for the intravesical administration of capsaicin, producing comparable efficacy with less tissue damage. Hydrogel can also serve as safe alternative option for capsaicin delivery.

Administration, Intravesical↗