olvanil and capsazepine

Capsaicin produces pain by selectively activating polymodal nociceptive neurons. This involves a membrane depolarization and the opening of a unique, cation-selective, ion channel which can be blocked by ruthenium red. The capsaicin-induced activation is mediated by a specific membrane receptor which can be selectively and competitively antagonised by capsazepine. Repetitive administrations of capsaicin produces a desensitization and an inactivation of sensory neurons. Several mechanisms are involved. These include receptor inactivation, block of voltage activated calcium channels, intracellular accumulation of ions leading to osmotic changes and activation of proteolytic enzyme processes. Systemic and topical capsaicin produces a reversible antinociceptive and antiinflammatory action after an initial undesirable algesic effect. Capsaicin analogues, such as olvanil, have similar properties with minimal initial pungency. Systemic capsaicin produces antinociception by activating capsaicin receptors on afferent nerve terminals in the spinal cord. Spinal neurotransmission is subsequently blocked by a prolonged inactivation of sensory neurotransmitter release. Local or topical application of capsaicin blocks C-fibre conduction and inactivates neuropeptide release from peripheral nerve endings. These mechanisms account for localized antinociception and the reduction of neurogenic inflammation respectively.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Calcium Channels; Capsaicin; Cell Membrane; Humans; Neurons, Afferent; Nociceptors; Pain; Pain Threshold; Receptors, Drug

We examined the effects of TRPV1 agonists olvanil and piperine on glutamatergic spontaneous excitatory transmission in the substantia gelatinosa (SG) neurons of adult rat spinal cord slices with the whole-cell patch-clamp technique. Bath-applied olvanil did not affect the frequency and amplitude of spontaneous excitatory postsynaptic current (sEPSC), and unchanged holding currents at -70 mV. On the other hand, superfusing piperine reversibly and concentration-dependently increased sEPSC frequency (half-maximal effective concentration: 52.3 μM) with a minimal increase in its amplitude. This sEPSC frequency increase was almost repetitive at an interval of more than 20 min. Piperine at a high concentration produced an inward current in some neurons. The facilitatory effect of piperine was blocked by TRPV1 antagonist capsazepine. It is concluded that piperine but not olvanil activates TRPV1 channels in the central terminals of primary-afferent neurons, resulting in an increase in the spontaneous release of l-glutamate onto SG neurons.

Topics: Alkaloids; Animals; Benzodioxoles; Capsaicin; Excitatory Amino Acid Agents; Glutamates; Neurons; Patch-Clamp Techniques; Piperidines; Polyunsaturated Alkamides; Rats; Substantia Gelatinosa; Synaptic Transmission; TRPV Cation Channels

The contributions of brain cannabinoid (CB) receptors, typically CB1 (CB type 1) receptors, to the behavioral effects of nicotine (NC) have been reported to involve brain transient receptor potential vanilloid 1 (TRPV1) receptors, and the activation of candidate endogenous TRPV1 ligands is expected to be therapeutically effective. In the present study, the effects of TRPV1 ligands with or without affinity for CB1 receptors were examined on NC-induced depression-like behavioral alterations in a mouse model in order to elucidate the "antidepressant-like" contributions of TRPV1 receptors against the NC-induced "depression" observed in various types of tobacco abuse.. Repeated subcutaneous NC treatments (NC group: 0.3 mg/kg, 4 days), like repeated immobilization stress (IM) (IM group: 10 min, 4 days), caused depression-like behavioral alterations in both the forced swimming (reduced swimming behaviors) and the tail suspension (increased immobility times) tests, at the 2 h time point after the last treatment. In both NC and IM groups, the TRPV1 agonists capsaicin (CP) and olvanil (OL) administered intraperitoneally provided significant antidepressant-like attenuation against these behavioral alterations, whereas the TRPV1 antagonist capsazepine (CZ) did not attenuate any depression-like behaviors. Furthermore, the endogenous TRPV1-agonistic CB1 agonists anandamide (AEA) and N-arachidonyldopamine (NADA) did not have any antidepressant-like effects. Nevertheless, a synthetic "hybrid" agonist of CB1 and TRPV1 receptors, arvanil (AR), caused significant antidepressant-like effects. The antidepressant-like effects of CP and OL were antagonized by the TRPV1 antagonist CZ. However, the antidepressant-like effects of AR were not antagonized by either CZ or the CB1 antagonist AM 251 (AM).. The antidepressant-like effects of TRPV1 agonists shown in the present study suggest a characteristic involvement of TRPV1 receptors in NC-induced depression-like behaviors, similar to those caused by IM. The strong antidepressant-like effects of the potent TRPV1 plus CB1 agonist AR, which has been reported to cause part of its TRPV1-mimetic and cannabimimetic effects presumably via non-TRPV1 or non-CB1 mechanisms support a contribution from other sites of action which may play a therapeutically important role in the treatment of NC abuse.

Topics: Animals; Antidepressive Agents; Arachidonic Acids; Capsaicin; Depression; Dopamine; Endocannabinoids; Hindlimb Suspension; Ligands; Male; Mice; Mice, Inbred ICR; Nicotine; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptor, Cannabinoid, CB1; Stress, Psychological; Swimming; TRPV Cation Channels

This investigation was conducted to provide further insight into the effects of vanilloid (subtype 1) receptor (VR1) drugs at voltage-gated sodium channels and examine the potential of this interaction to influence release of neurotransmitters from synaptosomes prepared from mammalian brain. The VR1 modulatory drugs capsaicin, olvanil and capsazepine inhibited the binding of batrachotoxinin-A 20-alpha-benzoate ([(3)H]BTX-B) to receptor site 2 of voltage-gated sodium channels. All drugs reduced the affinity of radioligand for sodium channels, and capsazepine also decreased the number of [(3)H]BTX-B binding sites. In kinetic experiments, no reduction in radioligand association rate was found, but capsaicin, olvanil and capsazepine all enhanced the dissociation rate of [(3)H]BTX-B. All drugs inhibited veratridine-evoked release of L-glutamic acid, gamma-amino butyric acid and L-aspartic acid from synaptosomes; however, their inhibitory effects on transmitter release were much weaker when 35 mM potassium chloride was used to depolarize synaptosomes. The study compounds, in common with other central nervous system depressants, interact with a region on the voltage-gated sodium channel that permits negative allosteric coupling with receptor site 2 and this mechanism likely accounts for blockade of sodium channel-activated transmitter release.

Topics: Animals; Aspartic Acid; Batrachotoxins; Brain; Capsaicin; gamma-Aminobutyric Acid; Glutamic Acid; Male; Mice; Mice, Inbred Strains; Potassium Chloride; Sodium Channels; Synaptosomes; Tritium; TRPV Cation Channels; Veratridine

The transient receptor potential (TRP) vanilloid receptor subtype 1 (TRPV1) is a ligand-gated, Ca(2+)-permeable ion channel in the TRP superfamily of channels. We report the establishment of the first neuronal model expressing recombinant human TRPV1 (SH-SY5Y(hTRPV1)). SH-SY5Y human neuroblastoma cells were stably transfected with hTRPV1 using the Amaxa Biosystem (hTRPV1 in pIREShyg2 with hygromycin selection). Capsaicin, olvanil, resiniferatoxin and the endocannabinoid anandamide increased [Ca(2+)](i) with potency (EC(50)) values of 2.9 nmol/L, 34.7 nmol/L, 0.9 nmol/L and 4.6 micromol/L, respectively. The putative endovanilloid N-arachidonoyl-dopamine increased [Ca(2+)](i) but this response did not reach a maximum. Capsaicin, anandamide, resiniferatoxin and olvanil mediated increases in [Ca(2+)](i) were inhibited by the TRPV1 antagonists capsazepine and iodo-resiniferatoxin with potencies (K(B)) of approximately 70 nmol/L and 2 nmol/L, respectively. Capsaicin stimulated the release of pre-labelled [(3)H]noradrenaline from monolayers of SH-SY5Y(hTRPV1) cells with an EC(50) of 0.6 nmol/L indicating amplification between [Ca(2+)](i) and release. In a perfusion system, we simultaneously measured [(3)H]noradrenaline release and [Ca(2+)](i) and observed that increased [Ca(2+)](i) preceded transmitter release. Capsaicin treatment also produced a cytotoxic response (EC(50) 155 nmol/L) that was antagonist-sensitive and mirrored the [Ca(2+)](I) response. This model displays pharmacology consistent with TRPV1 heterologously expressed in standard non-neuronal cells and native neuronal cultures. The advantage of SH-SY5Y(hTRPV1) is the ability of hTRPV1 to couple to neuronal biochemical machinery and produce large quantities of cells.

Topics: Arachidonic Acids; Calcium; Calcium Signaling; Capsaicin; Cell Culture Techniques; Cell Death; Cell Line, Tumor; Cell Proliferation; Diterpenes; Dopamine; Endocannabinoids; Humans; Models, Biological; Neuroblastoma; Neurons; Norepinephrine; Polyunsaturated Alkamides; Recombinant Proteins; Synaptic Transmission; Transfection; TRPV Cation Channels; Up-Regulation

The endocannabinoid anandamide is an emerging potential signalling molecule in the cardiovascular system. Anandamide causes vasodilatation, bradycardia and hypotension in animals and has been implicated in the pathophysiology of endotoxic, haemorrhagic and cardiogenic shock, but its vascular effects have not been studied in man. Human forearm blood flow and skin microcirculatory flow were recorded using venous occlusion plethysmography and laser-Doppler perfusion imaging (LDPI), respectively. Each test drug was infused into the brachial artery or applied topically on the skin followed by a standardized pin-prick to disrupt the epidermal barrier. Anandamide failed to affect forearm blood flow when administered intra-arterially at infusion rates of 0.3-300 nmol min(-1). The highest infusion rate led to an anandamide concentration of approximately 1 microM in venous blood as measured by mass spectrometry. Dermal application of anandamide significantly increased skin microcirculatory flow and coapplication of the transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine inhibited this effect. The TRPV1 agonists capsaicin, olvanil and arvanil all induced concentration-dependent increases in skin blood flow and burning pain when administered dermally. Coapplication of capsazepine inhibited blood flow and pain responses to all three TRPV1 agonists. This study shows that locally applied anandamide is a vasodilator in the human skin microcirculation. The results are consistent with this lipid being an activator of TRPV1 on primary sensory nerves, but do not support a role for anandamide as a circulating vasoactive hormone in the human forearm vascular bed.

Topics: Adult; Arachidonic Acids; Benzylamines; Capsaicin; Endocannabinoids; Female; Forearm; Humans; Laser-Doppler Flowmetry; Male; Microcirculation; Middle Aged; Muscle, Skeletal; Plethysmography; Polyunsaturated Alkamides; Regional Blood Flow; Skin; TRPV Cation Channels

Vanilloid receptors (VR) are molecular integrators of painful chemical and physical stimuli. Olvanil is an agonist of the vanilloid receptor; capsazepine is a competitive VR antagonist. The authors were interested in investigated the effects of these compounds on anxiety-like behaviors in rats using the elevated plus maze. In addition, the authors examined the effects of olvanil on the Porsolt swim test. Doses of 0, 0.2, 1.0 and 5.0 mg/kg olvanil, respectively, yielded percent open arm entries at 5 min of 25+/-10.1, 19.3+/-7.1, 14.9+/-5.9 and 0+/-0. We demonstrated a drug effect by showing that the mean of the 0.2, 1 and 5 mg/kg doses was significantly lower than the 0 mg/kg dose at P<.05. In addition, the authors examined the effect of olvanil on the ability of rats to perform in the Porsolt swim test. Float time for rats was tested with 0.1 or 2 mg/kg olvanil and differences between the float times for the lower and higher doses were significant at P<.05. In addition, the effects of various doses of the vanilloid antagonist capsazepine was examined on elevated plus maze behavior. Doses of 0, 1, 5 and 10 mg/kg yielded percent time in the open arms at 5 min of 1.46+/-1.38, 15.05+/-10.42, 11.54+/-10.57, and 14.56+/-7.86. The mean of the 1, 5 and 10 mg/kg doses was significantly greater than the percent time in the open arms for the vehicle, consistent with a drug effect. The results suggest that the vanilloid agonists and antagonists may impact on behaviors involving anxiety and affect. However, it cannot be ruled that the findings could be due to nonspecific motor effect.

Topics: Analysis of Variance; Animals; Behavior, Animal; Capsaicin; Dose-Response Relationship, Drug; Maze Learning; Rats; Rats, Sprague-Dawley; Receptors, Drug; Swimming

The vanilloid receptor 1 (VR1 or TRPV1) ion channel is activated by noxious heat, low pH and by a variety of vanilloid-related compounds. The antagonist, capsazepine is more effective at inhibiting the human TRPV1 response to pH 5.5 than the rat TRPV1 response to this stimulus. Mutation of rat TRPV1 at three positions in the S3 to S4 region, to the corresponding human amino acid residues I514M, V518L, and M547L decreased the IC(50) values for capsazepine inhibition of the pH 5.5 response from >10,000 nm to 924 +/- 241 nm in [Ca(2+)](i) assays and increased capsazepine inhibition of the capsaicin response to levels seen for human TRPV1. We have previously noted that phorbol 12-phenylacetate 13-acetate 20-homovanillate (PPAHV) is a strong agonist of rat TRPV1 but not human TRPV1 in [Ca(2+)](i) assays (1). Mutation of methionine 547 in S4 of rat TRPV1 to leucine, found in human TRPV1 (M547L), reduced the ability of PPAHV to activate TRPV1 by approximately 20-fold. The reciprocal mutation of human TRPV1 (L547M) enabled the human receptor to respond to PPAHV. These mutations did not significantly affect the agonist activity of capsaicin, resiniferatoxin (RTX) or olvanil in [Ca(2+)](i) assays. Introducing the equivalent mutation into guinea pig TRPV1 (L549M) increased the agonist potency of PPAHV by > 10-fold in the [Ca(2+)](i) assay and increased the amplitude of the evoked current. The rat M547L mutation reduced the affinity of RTX binding. Thus, amino acids within the S2-S4 region are important sites of agonist and antagonist interaction with TRPV1.

Topics: Amino Acid Sequence; Animals; Calcium; Capsaicin; CHO Cells; Cricetinae; Diterpenes; DNA, Complementary; Dose-Response Relationship, Drug; Electrophysiology; Guinea Pigs; Humans; Hydrogen-Ion Concentration; Inhibitory Concentration 50; Ions; Kinetics; Ligands; Methionine; Models, Chemical; Molecular Sequence Data; Mutagenesis, Site-Directed; Mutation; Phenotype; Phorbol Esters; Protein Structure, Tertiary; Rats; Receptors, Drug; Species Specificity; Time Factors

The amiloride-sensitive epithelial Na+ channel (ENaC) regulates Na+ homeostasis into cells and across epithelia. So far, four homologous subunits of mammalian ENaC have been isolated and are denoted as alpha, beta, gamma, and delta. The chemical agents acting on ENaC are, however, largely unknown, except for amiloride and benzamil as ENaC inhibitors. In particular, there are no agonists currently known that are selective for ENaCdelta, which is mainly expressed in the brain. Here we demonstrate that capsazepine, a competitive antagonist for transient receptor potential vanilloid subfamily 1, potentiates the activity of human ENaCdeltabetagamma (hENaCdeltabetagamma) heteromultimer expressed in Xenopus oocytes. The inward currents at a holding potential of -60 mV in hENaCdeltabetagamma-expressing oocytes were markedly enhanced by the application of capsazepine (> or =1 microM), and the capsazepine-induced current was mostly abolished by the addition of 100 microM amiloride. The stimulatory effects of capsazepine on the inward current were concentration-dependent with an EC50 value of 8 microM. Neither the application of other vanilloid compounds (capsaicin, resiniferatoxin, and olvanil) nor a structurally related compound (dopamine) modulated the inward current. Although hENaCdelta homomer was also significantly activated by capsazepine, unexpectedly, capsazepine had no effect on hENaCalpha and caused a slight decrease on the hENaCalphabetagamma current. In conclusion, capsazepine acts on ENaCdelta and acts together with protons. Other vanilloids tested do not have any effect. These findings identify capsazepine as the first known chemical activator of ENaCdelta.

Topics: Amiloride; Animals; Anti-Inflammatory Agents, Non-Steroidal; Capsaicin; Diterpenes; Diuretics; Dopamine; Dose-Response Relationship, Drug; Electrophysiology; Epithelial Sodium Channels; Humans; Hydrogen-Ion Concentration; Neurotoxins; Oocytes; Protein Structure, Tertiary; Protons; Receptors, Drug; Sodium Channels; Xenopus

A full pharmacological characterisation of the recently cloned human vanilloid VR1 receptor was undertaken. In whole-cell patch clamp studies, capsaicin (10 microM) elicited a slowly activating/deactivating inward current in human embryonic kidney (HEK293) cells stably expressing human vanilloid VR1 receptor, which exhibited pronounced outward rectification (reversal potential -2.1+/-0.2 mV) and was abolished by capsazepine (10 microM). In FLIPR-based Ca(2+) imaging studies the rank order of potency was resiniferatoxin>olvanil>capsaicin>anandamide, and all were full agonists. Isovelleral and scutigeral were inactive (1 nM-30 microM). The potencies of capsaicin, olvanil and resiniferatoxin, but not anandamide, were enhanced 2- to 7-fold at pH 6.4. Capsazepine, isovelleral and ruthenium red inhibited the capsaicin (100 nM)-induced Ca(2+) response (pK(B)=6.58+/-0.02, 5.33+/-0.03 and 7.64+/-0.03, respectively). In conclusion, the recombinant human vanilloid VR1 receptor stably expressed in HEK293 cells acted as a ligand-gated, Ca(2+)-permeable channel with similar agonist and antagonist pharmacology to rat vanilloid VR1 receptor, although there were some subtle differences.

Topics: Alkaloids; Aniline Compounds; Arachidonic Acids; Benzophenanthridines; Calcium; Capsaicin; Cell Line; Diterpenes; Dose-Response Relationship, Drug; Endocannabinoids; Enzyme Inhibitors; Fluorescence; Fluorometry; Humans; Hydrogen-Ion Concentration; Membrane Potentials; Phenanthridines; Polycyclic Sesquiterpenes; Polyunsaturated Alkamides; Protein Kinase C; Receptors, Drug; Ruthenium Red; Sesquiterpenes; Time Factors; Xanthenes

The effects of capsaicin analogs on adrenaline secretion were investigated in rats. Capsaicin (20-100 microg/kg, i.v.) caused biphasic adrenaline secretion. Capsazepine (20 mg/kg, i.v.), a specific competitive antagonist of the vanilloid (capsaicin) receptor, strongly inhibited both phases of adrenaline secretion by capsaicin (50 microg/kg). Next, the effects of two capsaicin analogs on the adrenal catecholamine secretion were examined. Resiniferatoxin (20-200 ng/kg, i.v.), a naturally occurring phorbolester-like compound, provoked slow onset adrenaline secretion in a dose-dependent manner. Olvanil (2.46-246 microg/kg, i.v.), a synthesized non pungent capsaicin analog, also stimulated delayed catecholamine secretion dose-dependently. Capsazepine (20 mg/kg, i.v.) pretreatment prevented the resiniferatoxin (50 ng/kg)- and olvanil (24.6 microg/kg)-induced catecholamine secretion. These results suggest that some vanilloids (capsaicin, resiniferatoxin, olvanil) excite adrenaline secretion and such excitation is via the vanilloid receptor.

Topics: Adrenal Glands; Animals; Capsaicin; Diterpenes; Epinephrine; Rats; Rats, Sprague-Dawley; Receptors, Drug

The vanilloid receptor (VR1) is a ligand-gated ion channel, which plays an important role in nociceptive processing. Therefore, a pharmacological characterization of the recently cloned rat VR1 (rVR1) was undertaken. HEK293 cells stable expressing rVR1 (rVR1-HEK293) were loaded with Fluo-3AM and then incubated at 25 degrees C for 30 min with or without various antagonists or signal transduction modifying agents. Then intracellular calcium concentrations ([Ca(2+)](i)) were monitored using FLIPR, before and after the addition of various agonists. The rank order of potency of agonists (resiniferatoxin (RTX)>capsaicin>olvanil>PPAHV) was as expected, and all were full agonists. The potencies of capsaicin and olvanil, but not RTX or PPAHV, were enhanced at pH 6.4 (pEC(50) values of 7.47+/-0.06, 7.16+/-0.06, 8.19+/-0.06 and 6.02+/-0.03 respectively at pH 7.4 vs 7.71+/-0.05, 7.58+/-0.14, 8.10+/-0.05 and 6.04+/-0.08 at pH 6.4). Capsazepine, isovelleral and ruthenium red all inhibited the capsaicin (100 nM)-induced Ca(2+) response in rVR1-HEK293 cells, with pK(B) values of 7.52+/-0.08, 6.92+/-0.11 and 8.09+/-0.12 respectively (n=6 each). The response to RTX and olvanil were also inhibited by these compounds. None displayed any agonist-like activity. The removal of extracellular Ca(2+) abolished, whilst inhibition of protein kinase C with chelerythrine chloride (10 microM) partially (approximately 20%) inhibited, the capsaicin (10 microM)-induced Ca(2+) response. However, tetrodotoxin (3 microM), nimodipine (10 microM), omega-GVIA conotoxin (1 microM), thapsigargin (1 microM), U73122 (3 microM) or H-89 (3 microM) had no effect on the capsaicin (100 nM)-induced response. In conclusion, the recombinant rVR1 stably expressed in HEK293 cells acts as a ligand-gated Ca(2+) channel with the appropriate agonist and antagonist pharmacology, and therefore is a suitable model for studying the effects of drugs at this receptor.

Topics: Animals; Calcium; Capsaicin; Cell Line; Diterpenes; DNA, Recombinant; Dose-Response Relationship, Drug; Fluorometry; Humans; Hydrogen-Ion Concentration; Ligands; Phorbol Esters; Polycyclic Sesquiterpenes; Rats; Receptors, Drug; Ruthenium Red; Sesquiterpenes; Transfection

The structural similarities between the anandamide transport inhibitor N-(4-hydroxyphenyl)-arachidonylamide (AM404) and the synthetic vanilloid agonist olvanil [(N-vanillyl)-9-oleamide], prompted us to investigate the possibility that olvanil may interfere with anandamide transport. The intracellular accumulation of [3H]anandamide by human astrocytoma cells was prevented by olvanil with a Ki value of 14.1+/-7.1 microM. By contrast, capsaicin [(8-methyl-N-vanillyl)-6-noneamide], a plant-derived vanilloid agonist, and capsazepine (N-[2-(4-chlorophenyl)ethyl]-1,3,4,5-tetrahydro-7,8-dihydroxy-2 H-2-benzazepine-2-carbothioamide), a vanilloid antagonist, had no such effect (Ki > 100 microM). These results indicate that, although less potent than AM404 (Ki 2.1+/-0.2 microM), olvanil may reduce anandamide clearance at concentrations similar to those needed for vanilloid receptor activation.

Topics: Amidohydrolases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acids; Astrocytoma; Biological Transport; Brain; Capsaicin; Depression, Chemical; Endocannabinoids; Humans; Polyunsaturated Alkamides; Rats; Receptors, Drug; Tumor Cells, Cultured

Capsaicin, the pungent ingredient in hot pepper, activates and subsequently desensitizes a subset of polymodal nociceptors. Because its initial application to skin produces pain, nonpungent analogs such as olvanil and glyceryl nonivamide (GLNVA) were synthesized to enhance its clinical use. To explore how these nonpungent analogs differ from capsaicin, whole-cell patch-clamp recordings were performed on cultured rat trigeminal ganglion neurons. In neurons held at -60 mV, capsaicin, olvanil, and GLNVA were found to activate one or two kinetically distinct inward currents. Two inward currents were also activated when extracellular Ca2+ was replaced with Ba2+ and also when intracellular chloride was replaced by aspartate. The reversal potentials of the rapidly and slowly activating currents were 15.3 +/- 6 and -4.0 +/- 2.5 mV, respectively. These data provide strong evidence for subtypes of vanilloid receptors. One difference among these agonists is that, on average, the activation kinetics of the currents evoked by 1 microM olvanil and 30 microM GLNVA are considerably slower than those evoked by 1 microM capsaicin. Measurements of the peak current, Ip, versus agonist concentration were fit to the Hill equation to yield values of the half maximal concentrations (K1/2), and the Hill coefficients (n). For capsaicin, olvanil, and GLNVA, K1/2 = 0.68, 0.59, and 27.0 microM and n = 1.38, 1.32, and 1.24, respectively. We propose that olvanil and GLNVA are nonpungent because they activate different subtypes of receptors and/or because of their activation kinetics (compared with capsaicin) are, on average, slower than the rate they inhibit action potentials from polymodal nociceptors.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Capsaicin; Cells, Cultured; Dose-Response Relationship, Drug; Glycerol; Neurons; Pain; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Receptors, Drug; Tachyphylaxis; Taste; Trigeminal Ganglion