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PubMed1991

Regulatory peptide and serotonin content and brush-border enzyme activity in the rat gastrointestinal tract following neonatal treatment with capsaicin; lack of effect on epithelial markers.

The possible trophic influence of the capsaicin-sensitive extrinsic innervation of the gastrointestinal mucosa was investigated. Rats were treated neonatally with capsaicin. The gastrointestinal content of serotonin and glucagon-like immunoreactivity were used as a measure of the effect on the endocrine gut mucosa and gastrointestinal aminopeptidase and alkaline phosphatase activities were used as a measure of the effect on the gut brush-border. The gastrointestinal content of the neuropeptides substance P, VIP and CGRP were used to monitor effects on the innervation of the gut. The depletion of substance P-immunoreactivity(-IR) and calcitonin gene-related peptide(CGRP)-IR in extracts of urinary bladder and lung from the capsaicin-treated rats is evidence of the efficacy of capsaicin treatment in affecting a loss of C-fibre sensory nerves. The significant depletion of CGRP-IR measured in the stomach and duodenum of capsaicin-treated rats indicated the loss of the C-fibre sensory innervation to the gastrointestinal tract. The gastrointestinal content of VIP and substance P, which are predominantly within intrinsic gut neurones, were unaffected by capsaicin treatment. In all regions of the gastrointestinal tract of capsaicin-treated rats, the serotonin and glucagon-IR levels were not significantly different from those in controls. Similarly the levels of activity of the brush-border enzymes were not significantly effected by capsaicin treatment. This suggest the absence of any major trophic influence of capsaicin-sensitive sensory nerves on the gut endocrine mucosa and the brush border.

Alkaline Phosphatase↗
PubMedDate not supplied

Capsaicin application to central or peripheral vagal fibers attenuates CCK satiety.

Capsaicin treatment destroys small primary sensory neurons including a subpopulation of vagal afferents. Intraperitoneal, fourth ventricular or perivagal application of capsaicin attenuated or abolished cholecystokinin (CCK)-induced suppression of food intake. Capsaicin applied to the thoracolumbar spinal cord or to the pyloric region of the stomach did not alter CCK-induced reductions of food intake. Intraperitoneal capsaicin treatment reduced substance P-like immunoreactivity (SPLI) in the spinal dorsal horn and parts of the dorsal hindbrain. SPLI depletion, therefore, served as a histochemical indicator of the spread of capsaicin from its site of application. Capsaicin applied directly to the vagal trunks did not reduce SPLI in the spinal cord or hindbrain. Intraventricular capsaicin reduced SPLI in the hindbrain but not in the spinal cord. These data indicate that localized capsaicin application attenuates CCK-induced suppression of food intake by impairing the function of either central or peripheral portions of vagal afferent neurons. The data also support the conclusion that intraperitoneal capsaicin attenuates CCK-induced suppression of feeding by impairing vagal sensory function.

Afferent Pathways↗
PubMed1991

Capsaicin desensitization to plasma extravasation evoked by antidromic C-fiber stimulation is not associated with antinociception in the rat.

The relationship of capsaicin desensitization to the antinociception produced by acute capsaicin administration was studied in the rat. Cutaneous application of 1% capsaicin (3 x/day) for 1 day antagonized plasma extravasation evoked by either 5% capsaicin applied to the dorsal surface of the hindpaw or antidromic stimulation of the saphenous nerve. Treatment with either 1% or 5% capsaicin (3 x/day) for up to 4 days failed, however, to produce thermal antinociception as measured by the rat paw-withdrawal procedure. In contrast, intracutaneous injection of 100 micrograms capsaicin produced marked increases in paw-withdrawal response latencies for up to six hours after injection. These data demonstrate a dissociation between block of cutaneous plasma extravasation and thermal antinociception in the rat. The data provide in vivo evidence that desensitization of peripheral nociceptors by capsaicin cannot account for the antinociception observed following acute capsaicin administration. Finally, these data support the notion that some pharmacologic actions of capsaicin in the rat can be dissociated from frank neurotoxicity on the basis of concentration or dose.

Animals↗
PubMed1989

Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin.

Psychophysical measurements of pain and mechanical hyperalgesia were obtained following different doses of capsaicin injected intradermally into the forearms of human subjects. Each subject received a 10 microliter injection of the vehicle and capsaicin doses of 0.01, 0.1, 1, 10 and 100 micrograms. The relationship between capsaicin dose and the magnitude and duration of pain was determined using the method of magnitude estimation. In addition to pain, capsaicin produced a flare and mechanical hyperalgesia. The area of flare and the area and time course of mechanical hyperalgesia were measured as a function of the dose of capsaicin. The magnitude and duration of pain, based on averaged responses of all subjects, increased as a negatively accelerating function of dose. The lowest dose of capsaicin to produce more pain than the vehicle was 0.1 micrograms. The area and duration of mechanical hyperalgesia also increased as a negatively accelerating function of dose. The lowest dose of capsaicin to produce an area of mechanical hyperalgesia was 0.1 micrograms. An area of hyperalgesia was present within seconds following injection. For doses of 10 and 100 micrograms, the area of hyperalgesia grew to reach a maximum within 5 and 7 min following the injection and gradually decreased, disappearing within 15 and 137 min, respectively. Capsaicin doses of 1, 10 and 100 micrograms produced successively greater areas of flare. The results demonstrate that humans can scale the magnitude of pain produced by capsaicin in a dose-dependent fashion. Further, the duration of pain, the area and duration of mechanical hyperalgesia, and the area of flare are dose-dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

Capsaicin↗
PubMed1991

The consequences of long-term topical capsaicin application in the rat.

Capsaicin has been used extensively as an experimental tool and in traditional and proprietary topical medications for acute soft tissue injuries. More recently it has been prescribed for several chronic pain conditions where it is usually administered topically for periods of several weeks. Here we have studied the consequences of this mode of application in the rat. Capsaicin cream (0.075% or 0.75%), or a vehicle cream, was applied twice daily to the hind paws of rats for a continuous period of 10 weeks. The hind paws treated with 0.75% capsaicin (but not 0.075%) because transiently hyperalgesic, but there were no signs of discomfort or distress associated with the treatment. After 10 weeks of capsaicin application, the ability of C fibres to produce neurogenic extravasation was markedly reduced. After 4 weeks of recovery this ability returned to normal in 0.075% capsaicin-treated animals, but remained impaired in the 0.75% group. This latter group showed a partial recovery 12 weeks after the end of treatment. The levels of substance P and CGRP in the sural nerve supplying the treated skin area were unchanged after both the 0.075% and 0.75% capsaicin treatments. The results suggest that the topical application of capsaicin at low concentration produces a reversible impairment of the terminals of C fibres in the skin without greatly exciting those fibres and without affecting the properties of cell soma. The number of afferent neurones in the L5 dorsal root ganglion projecting through the sural nerve was unchanged after 0.75% capsaicin treatment, suggesting that the topical capsaicin treatment does not produce any cell death in the adult animal.

Administration, Topical↗
PubMed1996

Independent effects of ischaemia and noradrenaline on thermal hyperalgesia in capsaicin-treated skin.

Noradrenaline increases thermal hyperalgesia in skin previously sensitized by capsaicin. The aim of the present study was to determine whether a vasoconstrictor ischaemic effect of noradrenaline increases thermal hyperalgesia. Heat pain thresholds were measured in the capsaicin-treated and untreated skin on the forearms of 13 normal volunteers. The iontophoresis of noradrenaline induced thermal hyperalgesia in untreated skin (mean heat pain threshold at the noradrenaline site 42.2 +/- 4.2 degrees C compared with 47.3 +/- 3.5 degrees C at control sites, P < 0.001), and increased thermal hyperalgesia in capsaicin-treated skin (mean heat pain threshold at the noradrenaline site 38.6 +/- 2.1 degrees C compared with 45.7 +/- 5.6 degrees C at control sites, P < 0.001). Heat pain thresholds did not change during venous congestion, induced by applying a cuff pressure of 60 mmHg to the upper arm. Increasing the cuff pressure to 200 mmHg decreased the heat pain threshold by 2.4 +/- 2.3 degrees C at control sites in the capsaicin-treated skin (P < 0.01); nevertheless, thermal hyperalgesia was greater at the noradrenaline site than at control sites during arterial occlusion, both in capsaicin-treated and untreated skin (in the capsaicin-treated skin, mean heat pain threshold during arterial occlusion 38.1 +/- 3.3 degrees C at the noradrenaline site compared with 43.4 +/- 6.5 degrees C at control sites, P < 0.001; in the untreated skin, mean heat pain threshold at the noradrenaline site 44.3 +/- 3.6 degrees C compared with 47.9 +/- 3.1 degrees C at control sites, P < 0.001). Thermal hyperalgesia subsided in control sites in the capsaicin-treated skin after cuff pressure was released, but persisted at sites of noradrenaline iontophoresis (in the capsaicin-treated skin, mean heat pain threshold during reactive hyperaemia 45.2 +/- 5.1 degrees C at the noradrenaline site compared with 49.3 +/- 6.0 degrees C at control sites, P < 0.01; in the untreated skin, mean heat pain threshold at the noradrenaline site 46.5 +/- 3.3 degrees C compared with 48.8 +/- 3.0 degrees C at control sites, P < 0.001). Arterial occlusion could increase thermal hyperalgesia in capsaicin-treated skin by preventing the dispersal of nociceptive substances peripherally or through central summation of nociceptive signals. The hyperalgesic effect of noradrenaline is greater than the hyperalgesic effect of ischaemia, suggesting that some mechanism in addition to vasoconstriction contributes to the nociceptive effect of noradrenaline.

Adult↗
PubMed1988

Stimulation of afferent nerve endings by intragastric capsaicin protects against ethanol-induced damage of gastric mucosa.

Ablation of capsaicin-sensitive afferent neurons enhances experimentally induced ulceration in the rat gastric mucosa, which suggests that these neurons are involved in gastric mucosal protection. To provide direct evidence for such a function it was investigated whether stimulation of afferent nerve endings by the intragastric administration of capsaicin could counteract the ulcerogenic effect of 25% ethanol. Capsaicin (3.2-640 microM), administered together with ethanol, inhibited the development of haemorrhagic lesions in a concentration-dependent fashion but did not alter the ethanol-induced fall in the gastric potential difference. This suggests that capsaicin does not prevent ethanol from damaging gastric epithelial cells but can counteract the vascular lesions caused by ethanol. The anti-lesion effect of intragastric capsaicin was absent in adult rats which had been treated with a high dose of systemic capsaicin as neonates in order to achieve a permanent degeneration of unmyelinated afferent neurons. It would appear, therefore, that intragastric capsaicin reduces lesion formation by an action on afferent neurons. The protective effect of intragastric capsaicin was not altered following acute subdiaphragmatic vagotomy, acute removal of the coeliac-superior mesenteric ganglion complex, acute bilateral ligation of the adrenal glands, or pretreatment of the rats with atropine or guanethidine. These findings indicate that stimulation of afferent neurons by intragastric capsaicin affords protection of the rat gastric mucosa against ethanol-induced damage. As the autonomic nervous system is not involved gastroprotection appears to represent a local effector function of sensory nerve endings in the stomach.

Animals↗
PubMed1991

Capsaicin causes prolonged inhibition of voltage-activated calcium currents in adult rat dorsal root ganglion neurons in culture.

The effect of capsaicin on voltage-activated calcium currents was investigated in voltage-clamped somata of cultured adult rat dorsal root ganglion neurons. About half the neurons studied were sensitive to capsaicin, which induced an inward current at negative membrane potentials accompanied by an increase in membrane conductance. In the sensitive neurons capsaicin inhibited voltage-activated calcium current to an extent that depended on the size and duration of the capsaicin-induced inward current. Calcium channels were protected from the long-lasting inhibitory action of capsaicin by substituting extracellular Ca with Mg or Ba when capsaicin was applied, which suggests that the inhibition was dependent on the presence of extracellular Ca. Substituting Ca with Co did not prevent the prolonged block of calcium channels. It is concluded that the inhibition of voltage-activated calcium currents by capsaicin is secondary to increased intracellular Ca levels due to calcium entry through capsaicin-activated cation-specific ion channels in the plasma membrane. Long-lasting inhibition of voltage-activated calcium channels may contribute to the mechanism of the analgesic and anti-inflammatory effects of capsaicin through inhibition of neurotransmitter release from central and peripheral terminals of primary afferent nociceptive neurons.

Animals↗
PubMed1988

Nerve growth factor (NGF) regulates adult rat cultured dorsal root ganglion neuron responses to the excitotoxin capsaicin.

An overlap between subpopulations of nerve growth factor (NGF)-responsive and capsaicin-sensitive dorsal root ganglion (DRG) sensory neurons has been suggested from a number of in vivo studies. To examine this apparent link in more detail, we compared the effects of capsaicin on adult rat DRG neurons cultured in the presence or absence of NGF. Capsaicin sensitivity was assessed histochemically by a cobalt staining method, by measuring capsaicin-induced 45Ca2+ uptake, and by electrophysiological recording of capsaicin-evoked membrane currents. When cultured with NGF, approximately 50% of these adult DRG neurons were capsaicin-sensitive, whereas adult sympathetic neurons or ganglionic nonneuronal cells were insensitive. DRG cultures grown in the absence of NGF, however, were essentially unresponsive to capsaicin. Capsaicin sensitivity could be regained fully within 4-6 days of replacement of NGF. These results indicate that, at least in vitro, NGF can modify the capsaicin sensitivity of adult DRG neurons.

Animals↗
PubMed2004

Activation of protein kinase C reverses capsaicin-induced calcium-dependent desensitization of TRPV1 ion channels.

Ca2+ selective ion channels of vanilloid receptor subtype-1 (TRPV1) in capsaicin-sensitive dorsal root ganglion (DRG) neurons and TRPV1 transfected Chinese hamster ovarian (CHO) cells are desensitized following calcium-dependent tachyphylaxis induced by successive applications of 100 nM capsaicin. Tachyphylaxis of TRPV1 to 100 nM capsaicin stimuli was not observed in the absence of extracellular calcium. Capsaicin sensitivity of desensitized TRPV1 ion channels recovered on application of phorbol-12-myristate-13-acetate (PMA). PMA-induced recovery of desensitized TRPV1 was primarily due to influx of extracellular calcium observed during re-application of capsaicin following desensitization. Capsazepine blocked the re-sensitization to capsaicin by PMA. Protein kinase C (PKC) inhibitory peptide PKC fragment 19-36 also inhibited re-sensitization to capsaicin by PMA. Reversal of capsaicin-induced desensitization by PMA was prevented by a mutation of TRPV1 where phosphorylation sites serine502 and serine800 were replaced with alanine. This study provides evidence for a role of PKC in reversing capsaicin-induced calcium-dependent desensitization of TRPV1 ion channels.

Amino Acid Substitution↗
PubMed2005

Inducible nitric oxide synthase evoked nitric oxide counteracts capsaicin-induced airway smooth muscle contraction, but exacerbates plasma extravasation.

The contribution of nitric oxide (NO) to capsaicin-evoked airway responses was investigated in rats. The measurement of plasma NO level, airway dynamics, airway smooth muscle electromyogram, and plasma extravasation by India ink and Evans blue leakage technique was adapted. Capsaicin-evoked hypotension, bronchoconstriction, trachea plasma extravasation as well as increases in plasma NO level in a dose-dependent manner. L-732138 (NK1 receptor antagonist) or SR-48968 (NK2 receptor antagonist) pretreatment reduced capsaicin-enhanced hypotension, bronchoconstriction, plasma extravasation, and plasma NO level. N(G)-nitro-L-Arginine methyl ester (L-NAME, 10 mg/kg, i.v.), a non-selective NO synthase (NOS) inhibitor, or aminoguanidine (10 mg/kg, i.v.), a selective inducible NOS (iNOS) inhibitor, reduced capsaicin-induced increases in plasma NO level and protected against capsaicin-induced plasma extravasation, whereas L-arginine (150 mg/kg, i.v.), a NO precursor, enhanced capsaicin-evoked plasma NO level and plasma extravasation. L-Arginine pretreatment ameliorated capsaicin-induced bronchoconstriction, whereas L-NAME and aminoguanidine exaggerated capsaicin-induced bronchoconstriction. In summary, NK1 and NK2 receptors and iNOS play a role in NO formation and on capsaicin-induced bronchoconstriction and plasma extravasation. NO generated by iNOS counteracts tachykinin-mediated bronchoconstriction, but exacerbates tachykinin-mediated plasma extravasation.

Animals↗
PubMed2005

Differential effects of bupivacaine and tetracaine on capsaicin-induced currents in dorsal root ganglion neurons.

Capsaicin opens the TRPV1 channel, a cation channel that depolarizes and activates nociceptive neurons. Following this initial activation, neurons become desensitized to subsequent applications of capsaicin as well as to other noxious stimuli, a phenomenon attributed primarily to the entry of Ca2+ ions through the open TRPV1 channel. This ability of capsaicin to desensitize nociceptors has led to its use as an analgesic in the treatment of a variety of chronic pain states. Because treatment with capsaicin is initially quite painful, local anesthetics are sometimes used to block axonal conduction in nociceptive neurons and thus minimize pain. However, local anesthetics might also block TRPV1 and prevent the Ca2+ entry required for capsaicin-induced desensitization. We have studied the direct effect of local anesthetics on currents induced by capsaicin (1 microM) in acutely isolated rat dorsal root ganglion neurons using the whole cell patch clamp technique. At the highest concentration tested (1 mM), bupivacaine only moderately inhibited the capsaicin-induced current to 55 +/- 27% of control (mean +/- S.D.; n=12, p<0.01). Tetracaine (1 mM), on the other hand, enhanced the capsaicin-induced current to 151 +/- 34% of control (mean +/- S.D.; n=7, p<0.01). These results show that local anesthetics can be used to prevent the initial pain induced by application of capsaicin without abolishing, and perhaps even enhancing, its desensitizing actions.

Anesthetics, Local↗
PubMed2004

Forty years in capsaicin research for sensory pharmacology and physiology.

Capsaicin, the pungent ingredient of chilli peppers has become a "hot" topic in neuroscience with yearly publications over half thousand papers. It is outlined in this survey how this exciting Hungarian research field emerged from almost complete ignorance. From the initial observation of the phenomenon of "capsaicin desensitization", a long-lasting chemoanalgesia and impairment in thermoregulation against heat, the chain of new discoveries which led to the formulation of the existence of a "capsaicin receptor" on C-polymodal nociceptors is briefly summarized. Neurogenic inflammation is mediated by these C-afferents which are supplied by the putative capsaicin receptor and were termed as "capsaicin sensitive" chemoceptive afferents. They opened new avenues in local peptidergic regulation in peripheral tissues. It has been suggested that in contrast to the classical axon reflex theory, the capsaicin-sensitive sensory system subserves a "dual sensory-efferent" function whereby initiation of afferent signals and neuropeptide release are coupled at the same nerve endings. Furthermore, in the skin at threshold stimuli which do not evoke sensation elicit already maximum efferent response as enhanced microcirculation. In isolated organ preparations large scale of new type of peptidergic capsaicin-sensitive neurogenic smooth muscle responses were revealed after the first one was described by ourselves on the guinea-pig ileum in 1978. Recently the "capsaicin receptor" has been cloned and it is now named as the "transient receptor potential vanilloid 1" (TRPV1). Hence, capsaicin research led to the discovery of the first temperature-gated ion channel gated by noxious heat, protons, vanilloids and endogenous ligands as anandamide, N-oleoyldopamine and lipoxygenase products. Another recent achievement is the discovery of a novel "unorthodox" neurohumoral regulatory mechanism mediated by somatostatin. Somatostatin released from the TRPV1-expressing nerve endings reaches the circulation and elicits systemic antiinflammatory and analgesic "sensocrine" functions with counter-regulatory influence e.g. in Freund's adjuvant-induced chronic arthritis. Nociceptors supplied by TRPV1 and sst4 somatostatin receptors has become nowadays promising targets for drug development.

Animals↗
PubMed1997

Intraintestinal capsaicin transiently reduces CGRP-like immunoreactivity in rat submucosal plexus.

Intraintestinal infusion of the sensory neurotoxin, capsaicin, transiently abolishes behavioral responses to chemical stimulation of the intestine. This desensitizing action of capsaicin may be due to an action on CGRP-containing nerve terminals, which are postulated to serve a sensory function in the enteric plexuses. To determine whether intraintestinal capsaicin treatment alters CGRP-like immunoreactivity (CGRP-li) in the enteric plexuses, we performed immunohistochemical analyses of the small intestinal submucosal and myenteric plexuses of rats at various times after intestinal infusion of capsaicin (5 mg) or its vehicle. Intestinal capsaicin treatment, but not vehicle treatment, reduced CGRP-li, but not substance-P-like immunoreactivity (SP-li), in nerve fibers of the submucosal plexus. CGRP-li was reduced in submucosal interganglionic connectives and in nerve fibers associated with submucosal blood vessels. CGRP-li of submucosal connectives was reduced by 1 h post-infusion. Reduction of CGRP-li in the submucosal fibers also was pronounced 24 h after intraintestinal capsaicin treatment. By 48 h after intestinal capsaicin infusion, CGRP-li was not distinguishable from vehicle-treated animals. There were no consistent immunohistochemical changes in CGRP-li or SP-li in the myenteric plexus at any time. These results indicate that intestinal capsaicin selectively induces transient reduction of CGRP-li in nerve fibers of the submucosal plexus. The chronology of depletion and reappearance of CGRP-li is congruent with previously reported, transient impairment of sensory function observed following intestinal capsaicin infusion.

Animals↗
PubMed2001

Capsaicin potentiates 1,25-dihydoxyvitamin D3- and all-trans retinoic acid-induced differentiation of human promyelocytic leukemia HL-60 cells.

Human promyelocytic leukemia HL-60 cells are differentiated into monocytic or granulocytic lineage when treated with 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] or all-trans retinoic acid, respectively. In this study, the effect of capsaicin, an active component of the red pepper of the genus Capsocum, on cell differentiation was investigated in a HL-60 cell culture system. Treatment of HL-60 cells with 5-30 microg/ml capsaicin for 72 h inhibited cell proliferation and induced a small increase in cell differentiation. Interestingly, synergistic induction of HL-60 cell differentiation was observed when capsaicin was combined with either 5 nM 1,25-(OH)2D3 or 50 nM all-trans retinoic acid. Flow cytometric analysis indicated that combinations of 1,25-(OH)2D3 and capsaicin stimulated differentiation predominantly to monocytes whereas combinations of all-trans retinoic acid and capsaicin stimulated differentiation predominantly to granulocytes. Capsaicin enhanced protein kinase C activity in 1,25-(OH)2D3- and all-trans retinoic acid-treated HL-60 cells. In addition, inhibitors for protein kinase C [bisindolylmaleimide (GF-109203X), chelerythrine, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7)] and an inhibitor for extracellular signal-regulated kinase [2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one (PD-098059)] significantly inhibited HL-60 cell differentiation induced by capsaicin in combination with either 1,25-(OH)2D3 or all-trans retinoic acid. These results indicate that capsaicin potentiates 1,25-(OH)2D3- or all-trans retinoic acid-induced HL-60 cell differentiation and that both protein kinase C and extracellular signal-regulated kinase are involved in the cell differentiation synergistically enhanced by capsaicin.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1998

Capsaicin-induced desensitization is prevented by capsazepine but not by ruthenium red in guinea pig bronchi.

In isolated guinea pig bronchi, the influence of ruthenium red, capsazepine and extracellular Ca2+ on capsaicin-induced desensitization was examined to investigate whether this desensitization was mediated via a specific receptor coupled with an ion channel. Pre-exposure of tissues to capsaicin (1, 3 or 10 microM) caused a dose-dependent desensitization to the second application of capsaicin. However, the contractile responses to exogenous tachykinins were not changed after pre-exposure of tissues to capsaicin. This capsaicin-induced desensitization was prevented by capsazepine (30 microM), but not by ruthenium red added to tissues 20 min before pretreatment with capsaicin (3 microM). While the excitatory contractile response to capsaicin was markedly reduced in the absence of extracellular Ca2+, the desensitization induced by capsaicin was not changed by the removal of extracellular Ca2+. In summary, the results from the present study suggest that in vitro functional desensitization induced by capsaicin in guinea pig bronchi may involve changes in the vanilloid receptor and occur through a ruthenium red-insensitive pathway.

Animals↗
PubMed1999

Endothelin-1 affects capsaicin-evoked release of neuropeptides from rat vas deferens.

Capsaicin-sensitive neurones release a number of neuropeptides, such as substance P, neurokinin A, somatostatin and calcitonin gene-related peptide (CGRP), which exert a number of effects on smooth muscle tissues. Endothelin-1 was thought to potentiate the capsaicin-evoked release of neuropeptides from sensory neurones of the rat. We have investigated the neuromodulatory effects of endothelin-1 on capsaicin-induced release of neurotransmitters from rat vas deferens. Capsaicin and human alpha calcitonin gene-related peptide (human alphaCGRP) reduced the rat vas deferens twitch responses induced by electrical field stimulation. Human beta calcitonin gene-related peptide-(8-37) [human betaCGRP-(8-37)] (1 microM), a selective alphaCGRP receptor antagonist, antagonized the inhibitory effects of both drugs. Endothelin-1 concentration dependently evoked an increase in basal tone of the musculature and potentiated the amplitude of the electrically stimulated responses, blocking inhibitory effects of capsaicin but not of human alphaCGRP. Moreover, endothelin-1 did not markedly change the inhibitory effects of papaverine (0.1-100 microM) or isoprenaline (1 nM-100 microM) on responses to electrical field stimulation. FR 139317 [(N,N-hexamethylene) carbamoyl-Leu-D-Trp(N-Me)-D-2-Pya], a selective endothelin ET(A) receptor antagonist, administered 30 min before endothelin-1 restored the capsaicin effects whereas BQ 788 [Dmpc-gamma-MeLeu-D-Trp-(1-methoxycarbonyl)-D-Nle], a selective endothelin ET(B) receptor antagonist, was completely ineffective. The endothelin-1-induced block of the capsaicin effect was resistant to tetrodotoxin (1 microM) and 30-min pre-treatment with MEN 10.627 (cyclo[(Met-Asp-Trp-Phe-Dap-Leu) cyclo (2beta-5beta)]), a selective tachykinin NK2 receptor antagonist, did not abolish the endothelin-1 effect on the inhibitory response to capsaicin. These results suggest that endothelin-1 selectively inhibits the capsaicin-induced release of neurotransmitters from rat vas deferens and these effects are mediated via endothelin ET(A) receptors but not by tachykinin release.

Animals↗
PubMed1999

Connections between P2 purinoceptors and capsaicin-sensitive afferents in the intestine and other tissues.

Relations between P2 purinoceptors and capsaicin-sensitive sensory neurons include an excitatory action of P2 purinoceptor agonists on spinal afferent neurons, as well as release of ATP from afferents at their central and peripheral endings, and a possible participation of ATP in nociception and/or in 'local efferent' responses mediated by sensory nerves at the periphery. The present paper briefly summarizes available evidence on these interrelations. Ample evidence shows that ATP and other P2 purinoceptor agonists can activate primary afferent neurons, through P2X3 receptors and probably other purinoceptors as well, but evidence for an involvement of P2 purinoceptors in nociception or in 'local efferent' responses due to activation of primary afferents is, at best, circumstantial. The possibility is also dealt with that P2 purinoceptor activation may cause small intestinal contraction with the mediation of capsaicin-sensitive sensory neurons and that the motor response to capsaicin in this tissue may involve the release of a P2 purinoceptor stimulant from sensory nerves. Our data show that cholinergic contractions of the guinea-pig ileum in response to the P2 purinoceptor agonist alpha,beta-methylene ATP (alpha,beta-meATP) are blocked by atropine, but not by in vitro capsaicin pretreatment (which completely blocks the contractile action of capsaicin). Cholinergic ileum contractions due to capsaicin (2 microM) are insensitive to suramin (a P2 purinoceptor antagonist; 100 microM). In the presence of antagonists acting at tachykinin NK1 and NK2 receptors, however, suramin (100 microM) causes a significant inhibition of the capsaicin-evoked contraction. These data indicate that capsaicin-sensitive nerves are not involved in the excitatory effect of alpha,beta-methylene ATP on myenteric neurons. On the other hand, ATP is probably involved in the 'non-tachykininergic' component of the capsaicin-induced excitatory response of the small intestine. ATP may originate from sensory neurons and probably acts as activator of myenteric nerves.

Adenosine Triphosphate↗