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PubMed2001

Capsaicin inhibits activation of voltage-gated sodium currents in capsaicin-sensitive trigeminal ganglion neurons.

Capsaicin, the pungent ingredient in hot pepper, activates nociceptors to produce pain and inflammation. However, repeated exposures of capsaicin will cause desensitization to nociceptive stimuli. In cultured trigeminal ganglion (TG) neurons, we investigated mechanisms underlying capsaicin-mediated inhibition of action potentials (APs) and modulation of voltage-gated sodium channels (VGSCs). Capsaicin (1 microM) inhibited APs and VGSCs only in capsaicin-sensitive neurons. Repeated applications of capsaicin produced depolarizing potentials but failed to evoke APs. The capsaicin-induced inhibition of VGSCs was prevented by preexposing the capsaicin receptor antagonist, capsazepine (CPZ). The magnitude of the capsaicin-induced inhibition of VGSCs was dose dependent, having a K(1/2) = 0.45 microM. The magnitude of the inhibition of VGSCs was proportional to the capsaicin induced current (for -I(CAP) < 0.2 nA). Capsaicin inhibited activation of VGSCs without changing the voltage dependence of activation or markedly changing channel inactivation and use-dependent block. To explore the changes leading to this inhibition, it was found that capsaicin increased cAMP with a K(1/2) = 0.18 microM. At 1 microM capsaicin, this cAMP generation was inhibited 64% by10 microM CPZ, suggesting that activation of capsaicin receptors increased cAMP. The addition of 100 microM CPT-cAMP increased the capsaicin-activated currents but inhibited the VGSCs in both capsaicin-sensitive and -insensitive neurons. In summary, the inhibitory effects of capsaicin on VGSCs and the generation of APs are mediated by activation of capsaicin receptors. The capsaicin-induced activation of second messengers, such as cAMP, play a part in this modulation. These data distinguish two pathways by which neuronal sensitivity can be diminished by capsaicin: by modulation of the capsaicin receptor sensitivity, since the block of VGSCs is proportional to the magnitude of the capsaicin-evoked currents, and by modulation of VGSCs through second messengers elevated by capsaicin receptor activation. These mechanisms are likely to be important in understanding the analgesic effects of capsaicin.

Animals↗

PubMed1991

Selective antagonism of capsaicin by capsazepine: evidence for a spinal receptor site in capsaicin-induced antinociception.

1. Capsazepine has recently been described as a competitive capsaicin antagonist. We have used this compound to test the hypotheses that the in vitro and in vivo effects of capsaicin are due to interactions with a specific receptor. 2. In an in vitro preparation of the neonatal rat spinal cord with functionally connected tail, the activation of nociceptive afferent fibres by the application of capsaicin, bradykinin or noxious heat (48 degrees C) to the tail could be measured by recording a depolarizing response from a spinal ventral root. Application of capsaicin or substance P to the spinal cord also evoked a depolarizing response which was recorded in a ventral root. 3. When capsazepine (50 nM-20 microM) was administered to the tail or spinal cord it did not evoke any measurable response. However on the tail, capsazepine reversibly antagonized (IC50 = 254 +/- 28 nM) the responses to capsaicin but not to heat or bradykinin administered to the same site. Similarly capsazepine administration to the spinal cord antagonized the responses evoked by capsaicin (IC50 = 230 +/- 20 nM) applied to the cord but not responses evoked by substance P on the cord or by noxious heat and capsaicin on the tail. 4. In halothane anaesthetized rats, C-fibre responses evoked by transcutaneous electrical stimulation of the receptive field were recorded from single wide dynamic range neurones located in the spinal dorsal horn. C-fibre evoked discharges were consistently reduced by the systemic administration of capsaicin (20 mumol kg-1, s.c.) and this action of capsaicin was antagonized by capsazepine (100 mumol kg-1) administered by the same route. In addition the systemic effect of capsaicin was antagonized by a spinal intrathecal administration of capsazepine (5-50 nmol). 5. Intradermal injections of capsaicin, localized to the peripheral receptive field, usually one toe of the ipsilateral hind-paw, produced a transient increase in C-fibre-evoked activity followed by a prolonged period of localized insensitivity to transcutaneous C-fibre stimulation. These effects of capsaicin were significantly reduced by the concommitant administration of capsazepine to the same site. 6. These data demonstrate that capsazepine is a selective antagonist of capsaicin on nociceptive neurones in vitro and in vivo and suggest that the effects of capsaicin were mediated by activation of a specific receptor. Since the antinociceptive effect produced by systemically administered capsaicin was antagonised by spinal intrathecal capsazepine this further supports the hypothesis that capsaicin exerts its antinociceptive effect by acting on specific receptors localized to sensory nerve fibres in the spinal cord.

Analgesics↗

PubMed2003

Novel expression of vanilloid receptor 1 on capsaicin-insensitive fibers accounts for the analgesic effect of capsaicin cream in neuropathic pain.

Here, we investigated the mechanism of the antihyperalgesic effect of capsaicin cream in the nerve injury-induced neuropathic pain model in mice. In naive mice, application of capsaicin cream onto footpad caused no significant changes in the thermal latency in contrast to the severe thermal hyperalgesia induced by a capsaicin ointment. On the other hand, application of the cream 3 h before test concentration dependently reversed both thermal and mechanical hyperalgesia observed after partial sciatic nerve injury in mice. In algogenic-induced nociceptive flexion (ANF) test, application of 0.1% capsaicin cream in naive mice blocked intraplantar (i.pl.) nociceptin- and ATP-induced flexion responses, whereas prostaglandin I(2) (PGI(2)) agonist-induced responses were unaffected. After nerve injury PGI(2) agonist-induced flexion responses were hypersensitized, and capsaicin cream concentration dependently blocked these hyperalgesic responses. Intraplantar injection of capsaicin solution in ANF test also produced potent flexion responses in naive mice that were lost after neonatal capsaicin-treatment. Partial sciatic nerve injury in neonatal capsaicin-treated mice caused reappearance of i.pl. capsaicin-induced flexion responses, suggesting novel expression of capsaicin receptors due to injury. The PGI(2) agonist-induced responses were also hypersensitized in such injured mice. Capsaicin cream completely reversed both i.pl. capsaicin- or i.pl. PGI(2) agonist-induced hyperalgesia in neonatal capsaicin-treated injured mice. Finally, novel expression of VR1 receptors on neonatal capsaicin-insensitive neurons after nerve injury was confirmed by immunohistochemistry. The newly expressed VR1 receptors after nerve injury were mainly confined to A-fibers. Together, our results suggest that novel expression of capsaicin receptors in neuropathic condition contributes to the analgesic effects of the capsaicin cream.

Analgesia↗

PubMed1997

Inhibition of substance P release from spinal cord tissue after pretreatment with capsaicin does not mediate the antinociceptive effect of capsaicin in adult mice.

Substance P (SP) is released from primary afferent fibers in response to nociceptive stimuli. Capsaicin, which produces an initial hyperalgesic response followed by persistent antinociception, also elicits release of SP from primary afferent fibers. Capsaicin pretreatment decreases the content and release of SP from primary afferent fibers. This effect on SP has been hypothesized to mediate the antinociceptive effect of capsaicin. To test this hypothesis, mice were injected intrathecally (i.t.) with antinociceptive doses of capsaicin or SP(1-7) before superfusion of spinal cord tissue with 3 microM capsaicin 24, 48, 96 or 168 h later. N-terminal metabolic fragments of SP that accumulate after capsaicin-induced SP release and are involved in the antinociceptive effect of capsaicin, were also tested. Like capsaicin SP(1-3), SP(1-4) and SP(1-7) were each antinociceptive when injected 24 h before nociceptive testing. However, at this time there was no decrease in capsaicin-evoked release of SP in tissue from capsaicin- and SP(1-7)-pretreated animals compared to those injected with vehicle. In contrast, capsaicin-evoked SP release decreased significantly in tissue from mice pretreated with capsaicin or SP(1-7) 48 h prior to testing. D-Substance P(1-7), which prevents antinociception, blocked capsaicin- and SP(1-7)-induced decreases in SP release, indicating that these effects are mediated by SP N-terminal activity. Total spinal cord content of SP did not differ amongst treatment groups. These data indicate that antinociception does not appear to depend on decreases in SP release or content as antinociception precedes decreases in SP release.

Animals↗

PubMed1987

Capsaicin-induced inhibition of motility of the rat isolated vas deferens: do multiple neuropeptides mediate the visceromotor effects of capsaicin?

1 The effects of capsaicin have been investigated in the field-stimulated (0.1 Hz) or unstimulated rat isolated vas deferens and compared with those of some neuropeptides (neurokinins, calcitonin gene-related peptide (CGRP) putatively stored in capsaicin-sensitive sensory fibres. 2 Capsaicin (0.01-3 microM) produced a concentration-related transient inhibition of the field-stimulation-induced twitches. This effect was characterized by marked desensitization and could not be elicited in preparations excised from capsaicin-pretreated rats (50 mg/kg s.c., 4 days before). The amplitude of the nerve-mediated twitches was unaffected by capsaicin-desensitization. 3 Neurokinins (substance P, Kassinin) produced a potentiation of the nerve-mediated contractions while CGRP had a potent inhibitory effect. In the presence of Kassinin, CGRP still inhibited twitches although the time course of this inhibitory effect was delayed as compared to controls. 4 In the unstimulated rat vas deferens neither capsaicin (3 microM) nor CGRP (0.1 microM) had any significant motor effect. However, when phasic contractions were initiated by previous exposure to Kassinin (0.2 microM), both capsaicin (3 microM) or CGRP (10-100 nM) had a prompt inhibitory effect. Capsaicin inhibition exhibited a marked desensitization while the effect of CGRP was still evident after capsaicin-desensitization. 5 The inhibitory effect of capsaicin or CGRP on the Kassinin-stimulated rhythmic contractions of the rat isolated vas deferens was unaffected by a previous exposure to tetrodotoxin (0.5 microM). 6 Storage at 4 degrees C for 24 h produced a 65% reduction of the response of the rat isolated vas deferens to nerve-stimulation. The residual response was tetrodotoxin-sensitive and could be potentiated by Kassinin (0.2 microM) or inhibited by CGRP (10-100 nM) as observed in controls. In these preparations the inhibitory effect of capsaicin (3 microM) was significantly reduced (approximately equal to 50%) and in some preparations abolished, as compared to controls. 7 These findings indicate the existence, in the rat isolated vas deferens, of capsaicin-sensitive sensory innervation which, upon chemical stimulation, releases, through a tetrodotoxin-insensitive mechanism, a substance(s) which inhibits motility at postjunctional level. CGRP is a possible candidate for the role of inhibitory sensory transmitter released from capsaicin-sensitive nerve endings in this preparation.

Animals↗

PubMed2001

Four response stages of capsaicin-sensitive primary afferent neurons to capsaicin and its analog: gastric acid secretion, gastric mucosal damage and protection.

Capsaicin is the active component of red hot peppers, which modifies specifically the capsaicin-sensitive sensory afferent nerves. The action of capsaicin is an initial short-lasting stimulation, which is followed by desensitization to capsaicin itself, and to other stimuli of afferent sensory nerves. Four response stages of capsaicin-sensitive primary afferents exist to capsaicin, depending on the dose and duration of exposure to the drug. These are excitation, a sensory blocking effect, long-term selective neurotoxic impairment, and irreversible cell destruction. The possible roles of four stages of capsaicin-sensitive primary afferents can be evaluated in relation to gastric acid secretion, and to the details of the defensive side of gastric mucosa against different chemicals, physical agents, drugs and other pathological stress. Capsaicin inhibited the gastric acid secretion in pylorus-ligated rats when it was given intragastrically at a dose of 0.4-1.8 microg/kg. Small doses of capsaicin (up to 800 microg, i.g.) produced a dose-dependent inhibition (ID50 = 400 microg), and its inhibitory effect was exerted for 1 h in healthy human subjects. While a small dose (5 microg/kg) of capsaicin caused inhibition, a high dose (50-100 mg/kg) enhanced the gastric mucosal lesions productivity by causing hyperacidity in pylorus-ligated animals. Capsaicin and its analog inhibited the development of different chemically induced gastric mucosal damage in various experimental models if they were given intragastric doses (microg/kg). The final effects of capsaicin depend on the dosage and timing. The different effects are excitation, a sensory-blocking effect, long-term selective neurotoxic impairment and irreversible cell destruction.

Afferent Pathways↗

PubMed1997

Capsaicin inhibits detrusor contractility but not the micturition reflex in capsaicin-desensitized rats.

Intravesical capsaicin at high concentration (1 mmol/L) inhibits the micturition reflex and detrusor contractility. To investigate the mechanism, we compared rats that had been desensitized by capsaicin at birth with control rats. In vivo cystometrography was performed with normal saline (n = 5) or 1 mmol/L capsaicin (n = 5), then an isolated whole bladder contractility study with electrical field stimulation, bethanechol, and KCl was carried out. In the bladders with normal saline cystometrography and after isolated bladder study, 0.5 mL of 1 mmol/L capsaicin was instilled into the bladders and another set of stimulations by electrodes, bethanechol, and KCl was given. The bladders of capsaicin-desensitized rats showed the presence of detrusor reflexes but diminished amplitudes of detrusor contractions. There was no urinary retention or increased intravesical pressure in these desensitized bladders after capsaicin cystometrography. The detrusor contractility in the isolated whole bladder study showed no significant difference between the control and experimental bladders. After 1 mmol/L capsaicin cystometrography the bladders had little contractility compared with bladders after saline cystometrography. The bladders of the desensitized rats increased in weight compared to the controls. Intravesical administration of 1 mmol/L capsaicin induced an initial excitatory effect on the micturition reflex and final urinary retention in control rats. After capsaicin treatment at birth, these effects no longer existed but the depressant effect of capsaicin on detrusor contractility persisted. We conclude that a high concentration of intravesical capsaicin acutely inhibits the micturition reflex and detrusor contractility. Neonatal desensitization by capsaicin can depress the detrusor contractility in rats but the micturition reflex is not affected.

Animals↗

PubMed1988

Effect of capsaicin pretreatment on capsaicin-induced catecholamine secretion from the adrenal medulla in rats.

The effect of capsaicin pretreatment on adrenal catecholamine secretion induced by intravenously administered capsaicin was investigated in alpha-chloralose and urethane anesthetized rats. In neonatal vehicle pretreated rats, capsaicin (200 micrograms/kg, iv) caused a rapid and significant increase in adrenal epinephrine secretion, but neonatal capsaicin pretreatment (50 mg/kg, sc, on the 2nd day of life) significantly reduced both the basal and capsaicin-induced epinephrine secretion from the adrenal medulla. Adult capsaicin pretreatment (6 increasing doses/6 days, total 310 mg/kg, sc) also reduced both the basal and capsaicin-stimulated adrenal epinephrine secretion, though it was less effective compared with the neonatal capsaicin pretreatment. These results suggest the participation of capsaicin-sensitive neurons in capsaicin-induced catecholamine secretion from the adrenal medulla.

Adrenal Medulla↗

PubMed1987

The contribution of capsaicin-sensitive innervation to activation of the spinal vesico-vesical reflex in rats: relationship between substance P levels in the urinary bladder and the sensory-efferent function of capsaicin-sensitive sensory neurons.

In acute spinal rats (C2-C3) the transvesical infusion of saline activates a vesico-vesical excitatory reflex (Brain Res., 380 (1986) 83-93). In bladders containing a subthreshold amount of fluid the topical application of capsaicin on the outer surface of the bladder dome activated this spinal reflex and also produced a transient rise in blood pressure and heart rate. The effects of systemic capsaicin desensitization (50 mg/kg s.c. 5 min, 60 days before) on the sensory (activation of the spinal vesico-vesical reflex) and 'efferent' (tetrodotoxin-insensitive capsaicin-induced contraction) functions mediated by the capsaicin-sensitive sensory fibers were correlated to changes in substance P-like immunoreactivity (SP-LI) content of the urinary bladder in adult rats. Blockade of both sensory and efferent functions was observed at a time (60 min from capsaicin administration) when the SP-LI content of the urinary bladder was unaffected. Four days after capsaicin desensitization the SP-LI levels of the bladder are almost depleted indicating that the neuropeptide(s) are entirely stored in sensory structures. At this time the sensory-efferent functions mediated by these fibers are still blocked. At 15-60 days from systemic capsaicin desensitization there was a progressive, time-related recovery of SP-LI levels in the bladder as well as of the sensory-efferent functions. These findings indicate a role of the capsaicin-sensitive innervation of the urinary bladder in activating the spinal vesico-vesical reflex. The present findings suggest that measurement of SP-LI levels in the rat bladder may be a useful biochemical index for monitoring the function(s) of the capsaicin-sensitive, peptidergic sensory neurons.

Animals↗

PubMed1992

Different ion channel mechanisms between low concentrations of capsaicin and high concentrations of capsaicin and nicotine regarding peptide release from pulmonary afferents.

Vagal nerve stimulation (1 Hz for 1 min), capsaicin (10(-8) M and 10(-6) M), resiniferatoxin (3 x 10(-10) M) and nicotine (10(-4) M) evoked a non-cholinergic bronchoconstriction in the isolated perfused guinea-pig lung preparation. Simultaneously there was an increase in the perfusate levels of calcitonin gene-related peptide-like immunoreactivity, suggesting release from sensory nerves. Both the bronchoconstriction and peptide release evoked by a low concentration of capsaicin (10(-8) M) and that evoked by nerve stimulation were depressed by tetrodotoxin, suggesting involvement of Na+ channel dependent depolarization. Since the effects of capsaicin (10(-8) M) and vagal nerve stimulation were inhibited by omega-conotoxin but not influenced by nifedipine, the Ca(2+)-channel dependent is probably of N-type. Furthermore, the capsaicin analogue resiniferatoxin also evoked omega-conotoxin sensitive peptide release and bronchoconstriction. At the higher capsaicin concentration (10(-6) M), the functional response was only slightly inhibited by omega-conotoxin or tetrodotoxin indicating that capsaicin at this concentration evoked peptide release and functional effects through other mechanisms, probably involving Ca2+ fluxes in the non-selective cation channel associated with the proposed capsaicin receptor. The nicotine (10(-4) M) evoked peptide release and bronchoconstriction were only marginally influenced by omega-conotoxin or tetrodotoxin. It is concluded that the ion-channel mechanisms underlying the peptide releasing properties of antidromic nerve stimulation and low concentrations of capsaicin are similar and depend on action potential propagation, whereas capsaicin in high, toxic concentration and nicotine mainly act via receptor operated channels.

Animals↗

PubMed1986

Capsaicin-induced beta-adrenergic action on energy metabolism in rats: influence of capsaicin on oxygen consumption, the respiratory quotient, and substrate utilization.

The mode of action of capsaicin on energy metabolism was investigated in rats. The oxygen consumption was higher when capsaicin (6.0 mg/kg) was intraperitoneally injected than when it was not injected. The respiratory quotient (R.Q.) increased and then decreased after the administration of capsaicin. The levels of serum glucose and immunoreactive insulin rapidly increased after the administration of capsaicin. Also, liver glycogen rapidly decreased, in contrast to the serum glucose concentration which rapidly increased. The serum-free fatty acid level gradually increased after the administration of capsaicin. These alterations in energy metabolism on the administration of capsaicin were similar to those in the metabolism of epinephrine, and were specifically inhibited by various beta-adrenergic blockers. On the other hand, the alterations were not affected by pretreatment with alpha-adrenergic or ganglion blockers. These results suggest that the mode of action of capsaicin on the enhancement of energy metabolism in rats comprises a direct (as an agonist) and/or an indirect (via catecholamine) beta-adrenergic action. Therefore, it was speculated that the adrenergic action of capsaicin resulted, at least in part, in a decrease in the perirenal adipose tissue weight and serum triglyceride concentration in rats fed a high fat diet supplemented with capsaicin (T. Kawada et al., J Nutr 116:1272-1278, 1986).

Adrenergic beta-Agonists↗

PubMed2006

Characterization of capsaicin synthase and identification of its gene (csy1) for pungency factor capsaicin in pepper (Capsicum sp.).

Capsaicin is a unique alkaloid of the plant kingdom restricted to the genus Capsicum. Capsaicin is the pungency factor, a bioactive molecule of food and of medicinal importance. Capsaicin is useful as a counterirritant, antiarthritic, analgesic, antioxidant, and anticancer agent. Capsaicin biosynthesis involves condensation of vanillylamine and 8-methyl nonenoic acid, brought about by capsaicin synthase (CS). We found that CS activity correlated with genotype-specific capsaicin levels. We purified and characterized CS ( approximately 35 kDa). Immunolocalization studies confirmed that CS is specifically localized to the placental tissues of Capsicum fruits. Western blot analysis revealed concomitant enhancement of CS levels and capsaicin accumulation during fruit development. We determined the N-terminal amino acid sequence of purified CS, cloned the CS gene (csy1) and sequenced full-length cDNA (981 bp). The deduced amino acid sequence of CS from full-length cDNA was 38 kDa. Functionality of csy1 through heterologous expression in recombinant Escherichia coli was also demonstrated. Here we report the gene responsible for capsaicin biosynthesis, which is unique to Capsicum spp. With this information on the CS gene, speculation on the gene for pungency is unequivocally resolved. Our findings have implications in the regulation of capsaicin levels in Capsicum genotypes.

Amino Acid Sequence↗

PubMed1981

Effect of capsaicin pretreatment on capsaicin-evoked release of immunoreactive somatostatin and substance P from primary sensory neurons.

Release of immunoreactive somatostatin (I-SRIF) and immunoreactive substance P (I-SP) was studied from slices prepared from upper dorsal horn (UDH) and lower dorsal plus ventral horn (LDH-VH) of rat spinal cord. Superfusion with capsaicin (10 microM) led to release of I-SRIF and I-SP from UDH slices but not from LDH-VH slices. The capsaicin-evoked release of I-SP was 6 fold higher than that of I-SRIF. A pulse of 60 mM K+ applied after the capsaicin pulse caused release of I-SRIF and I-SP from UDH as well as LDH-VH slices. Pretreatment of rats with capsaicin (125 mg/kg, s.c.) led to a nearly 40% depletion of I-SP in slices from UDH only. Capsaicin-evoked release from these slices was reduced by 81% for I-SRIF and by 79% for I-SP. Release evoked by K+ remained unchanged. These results indicate that capsaicin causes release of both I-SRIF and-I-SP and that this release is most likely restricted to primary sensory neurons. The marked reduction of the release of I-SP after systemic capsaicin pretreatment may well represent one of the, or even the reason for the insensitivity of capsaicin pretreated rats towards chemogenic pain.

Animals↗

PubMed1991

Capsaicin-induced release of neurokinin A from muscle and mucosa of gastric corpus: correlation with capsaicin-evoked release of calcitonin gene-related peptide.

It has been proposed that capsaicin-sensitive nerves might participate in a gastric defence mechanism, possibly via a local release of sensory neuropeptides. In this study, it was examined whether capsaicin might induce the release of neurokinin A (NKA), substance P (SP) and calcitonin gene-related peptide (CGRP) from different regions of rat stomach. Firstly, the tissue content of NKA-, SP- and CGRP-like immunoreactivity (LI) was measured in the fundus, in the corpus, in the muscle layer and in the mucosa of corpus of control rats and rats pre-treated with systemic capsaicin, s.c. (50 mg/kg as newborn). A large depletion (about 80%) of CGRP-LI following capsaicin treatment was observed in all regions examined, while no difference was observed for NKA-LI and SP-LI. NKA-LI, SP-LI and CGRP-LI release induced by capsaicin was measured in different regions of the rat stomach. Both in the gastric fundus and in the corpus, capsaicin (10 microM) produced a remarkable release of of CGRP-LI and NKA-LI, but not of SP-LI. A second administration of the drug had no longer effect, indicating desensitization. In the gastric corpus, the capsaicin-induced NKA-LI and CGRP-LI release was larger from the muscle layer than from the mucosa. The present findings provide neurochemical evidence that both NKA-LI and CGRP-LI are released from different regions of the rat stomach and both peptides should therefore be taken into account when considering the efferent function of capsaicin-sensitive primary afferents at gastric level.

Animals↗

PubMed2001

Hypolocomotor effects in rats of capsaicin and two long chain capsaicin homologues.

Capsaicin and its analogue N-arachidonoyl-vanillyl-amine (arvanil) are agonists of vanilloid VR1 receptors, and suppress spontaneous activity in mice through an unknown mechanism. Here, we tested in rats the effect on motor behavior of: (1) capsaicin; (2) N-linoleoyl-vanillyl-amine (livanil) and N-alpha-linolenoyl-vanillyl-amine (linvanil), which, unlike arvanil, have very little affinity for cannabinoid CB1 receptors; and (3) the endocannabinoid anandamide (N-arachidonoyl-ethanolamine), which is a full agonist at both cannabinoid CB1 and vanilloid VR1 receptors. All compounds, administered i.p., dose-dependently (0.1-10 mg/kg) inhibited ambulation and stereotypic behavior and increased inactivity in the open field test. The rank of potency observed in vivo (livanil>capsaicin>linvanil>anandamide) bore little resemblance with the relative potencies in a functional assay for rat vanilloid VR1 receptors (livanil=linvanil>capsaicin>anandamide) and even less with the relative affinities in rat CB1 receptor binding assays (anandamide>livanil>linvanil>capsaicin). The vanilloid VR1 receptor antagonist capsazepine (10 mg/kg, i.p.) blocked the effect of capsaicin but not of livanil or anandamide, whereas the CB1 receptor antagonist (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide.HCl (SR141716A, 3 mg/kg, i.p.) antagonized the actions of the CB1 receptor agonist Delta9-tetrahydrocannabinol, but not of livanil, anandamide or capsaicin. Anandamide occluded the effects of livanil on locomotion, possibly suggestive of a common mechanism of action for the two compounds. Finally, stimulation with capsaicin of cells expressing rat vanilloid VR1 receptors led to anandamide formation. These data suggest that motor behavior can be suppressed by the activation of: (1) vanilloid receptors, possibly via the intermediacy of anandamide; or (2) capsazepine- and SR141716A-insensitive sites of action for anandamide, livanil and linvanil, possibly the same that were previously suggested to mediate arvanil hypokinetic effects in mice.

Animals↗

PubMed1998

A capsaicin-receptor antagonist, capsazepine, reduces inflammation-induced hyperalgesic responses in the rat: evidence for an endogenous capsaicin-like substance.

In the present study, the presence of an endogenous capsaicin-like substance and the role of capsaicin receptors in nociception during inflammation were assessed using Fos immunohistochemistry and the paw-withdrawal test in rats. Intradermal injection of carrageenan in the hind-paw produced inflammation in the foot pad, increased the number of cells exhibiting Fos-like immunoreactivity in the dorsal horn of the spinal cord, and decreased the paw-withdrawal latency. Intradermal injection of capsazepine, a capsaicin-receptor antagonist, significantly reduced the number of cells exhibiting Fos-like immunoreactivity, significantly increased the paw-withdrawal latency, but did not decrease inflammation induced by carrageenan injection. Intradermal injection of capsaicin or formalin also increased Fos-positive neurons. Capsaicin- or formalin-induced Fos expression was reduced in both cases by pretreatment of capsazepine, but to a much lesser extent for formalin. The capsazepine inhibition of carrageenan inflammation-induced hyperalgesic responses strongly suggests that an endogenous capsaicin-like substance is released in inflamed tissues and produces nociceptive neural impulses by acting on capsaicin receptors present on sensory neurons. Furthermore, our results indicate that capsaicin receptors take part only in generating nociceptive signals in sensory neurons, but not in activating the inflammation-promoting cells.

Animals↗

PubMed1992

Involvement of capsaicin-sensitive neurones in the haemodynamic effects of exogenous vasoactive peptides: studies in conscious, adult Long Evans rats treated neonatally with capsaicin.

1. The regional haemodynamic effects of i.v. bolus injections of bradykinin (0.05 or 0.5 nmol), cholecystokinin (0.175 or 1.75 nmol), substance P (0.01 or 0.1 nmol) and calcitonin gene-related peptide (0.05 or 0.5 nmol) were assessed in conscious, adult Long Evans rats that had been treated neonatally with either capsaicin (50 mg kg-1, s.c.) or vehicle. 2. In vehicle-treated rats, both doses of bradykinin were without effect on blood pressure, but caused tachycardia and hindquarters vasodilatation. Moreover, after the higher dose there were dilatations in the renal and superior mesenteric vascular beds. In capsaicin-treated rats the hindquarters vasodilator effects elicited by both doses of bradykinin were significantly reduced, while the tachycardia and responses in the renal and superior mesenteric vascular beds were unchanged. 3. In vehicle-treated rats, cholecystokinin caused dose-dependent increases in blood pressure accompanied by renal, superior mesenteric and hindquarters vasoconstriction followed, after the higher dose, by a hindquarters vasodilatation. The lower dose produced a tachycardia, while there was a bradycardia followed by a tachycardia after the higher dose. In capsaicin-treated rats, the pressor response, as well as the renal vasoconstrictor effects of cholecystokinin, were greater than in vehicle-treated rats, while the heart rate, superior mesenteric or hindquarters responses were not different. 4. In vehicle-treated rats, substance P produced a dose-dependent depressor response and tachycardia accompanied by dilatations in the renal and hindquarters vascular beds and constriction in the superior mesenteric vascular bed. In capsaicin-treated rats, the responses to the lower dose of substance P were not different from those in vehicle-treated rats, while the depressor response to the higher dose of substance P was slightly less than in vehicle-treated rats and the renal vasodilatation was absent.5. In vehicle-treated rats, calcitonin gene-related peptide caused dose-dependent hypotensive and tachycardic effects associated with dilatations in renal and hindquarters vascular beds and a constriction in the superior mesenteric vascular bed. After the higher dose, the renal vasodilatation was followed by a modest vasoconstriction. In capsaicin-treated rats, the depressor responses to both doses of calcitonin generelated peptide were slightly more prolonged than in vehicle-treated animals, whereas the heart rate and renal and mesenteric vascular conductance changes were not significantly different. However, there was a more sustained hindquarters vasodilator response to the higher dose of calcitonin gene-related peptide in the capsaicin-treated rats.6. The results suggest that peripheral, capsaicin-sensitive neurones are involved in the cardiovascular responses to exogenous bradykinin and cholecystokinin in conscious rats. It does not appear that the extent of involvement of these neurones is underestimated on account of development of marked supersensitivity to the peptides they normally release, since responses to such peptides (e.g. substance P and calcitonin gene-related peptide) are relatively normal in capsaicin-treated rats.

Analysis of Variance↗

PubMed1991

The role of capsaicin-sensitive afferent nerves in protective effect of capsaicin against absolute ethanol-induced gastric lesions in rats.

The role of capsaicin-sensitive afferent nerves in gastroprotection by capsaicin was investigated in the absolute ethanol-induced gastric lesion model in rats. Capsaicin (0.1 and 0.5 mg/kg, p.o.) inhibited the lesion formation dose-dependently. The protective effect of capsaicin was attenuated by indomethacin-pretreatment and disappeared in capsaicin-sensitive nerve degenerated rats. Capsaicin did not induce the distension of gastric mucosal folds. These results suggested that stimulation of capsaicin-sensitive afferent nerves by capsaicin would enhance the prostaglandin formation, leading to an inhibition of gastric lesions.

Animals↗