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. 1992 Oct;107(2):544–552. doi: 10.1111/j.1476-5381.1992.tb12781.x

Capsazepine: a competitive antagonist of the sensory neurone excitant capsaicin.

S Bevan 1, S Hothi 1, G Hughes 1, I F James 1, H P Rang 1, K Shah 1, C S Walpole 1, J C Yeats 1
PMCID: PMC1907893  PMID: 1422598

Abstract

1. Capsazepine is a synthetic analogue of the sensory neurone excitotoxin, capsaicin. The present study shows the capsazepine acts as a competitive antagonist of capsaicin. 2. Capsazepine (10 microM) reversibly reduced or abolished the current response to capsaicin (500 nM) of voltage-clamped dorsal root ganglion (DRG) neurones from rats. In contrast, the responses to 50 microM gamma-aminobutyric acid (GABA) and 5 microM adenosine 5'-triphosphate (ATP) were unaffected. 3. The effects of capsazepine were examined quantitatively with radioactive ion flux experiments. Capsazepine inhibited the capsaicin (500 nM)-induced 45Ca2+ uptake in cultures of rat DRG neurones with an IC50 of 420 +/- 46 nM (mean +/- s.e.mean, n = 6). The 45Ca2+ uptake evoked by resiniferatoxin (RTX), a potent capsaicin-like agonist was also inhibited. (Log concentration)-effect curves for RTX (0.3 nM-1 microM) were shifted in a competitive manner by capsazepine. The Schild plot of the data had a slope of 1.08 +/- 0.15 (s.e.) and gave an apparent Kd estimate for capsazepine of 220 nM (95% confidence limits, 57-400 nM). 4. Capsazepine also inhibited the capsaicin- and RTX-evoked efflux of 86Rb+ from cultured DRG neurones. The inhibition appeared to be competitive and Schild plots yielded apparent Kd estimates of 148 nM (95% confidence limits, 30-332 nM) with capsaicin as the agonist and 107 nM (95% confidence limits, 49-162 nM) with RTX as agonist. 5. A similar competitive inhibition by capsazepine was seen for capsaicin-induced [14C]-guanidinium efflux from segments of adult rat vagus nerves (apparent Kd = 690 nM; 95% confidence limits, 63 nM-1.45 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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  1. Adams D. J., Takeda K., Umbach J. A. Inhibitors of calcium buffering depress evoked transmitter release at the squid giant synapse. J Physiol. 1985 Dec;369:145–159. doi: 10.1113/jphysiol.1985.sp015893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Amann R., Donnerer J., Lembeck F. Activation of primary afferent neurons by thermal stimulation. Influence of ruthenium red. Naunyn Schmiedebergs Arch Pharmacol. 1990 Jan-Feb;341(1-2):108–113. doi: 10.1007/BF00195066. [DOI] [PubMed] [Google Scholar]
  3. Amann R., Lembeck F. Ruthenium red selectively prevents capsaicin-induced nociceptor stimulation. Eur J Pharmacol. 1989 Feb 28;161(2-3):227–229. doi: 10.1016/0014-2999(89)90849-2. [DOI] [PubMed] [Google Scholar]
  4. Amann R., Maggi C. A. Ruthenium red as a capsaicin antagonist. Life Sci. 1991;49(12):849–856. doi: 10.1016/0024-3205(91)90169-c. [DOI] [PubMed] [Google Scholar]
  5. Bernath S., Vizi E. S. Inhibitory effect of ionized free intracellular calcium enhanced by ruthenium red and m-chloro-carbonylcyanide phenyl hydrazon on the evoked release of acetylcholine. Biochem Pharmacol. 1987 Nov 1;36(21):3683–3687. doi: 10.1016/0006-2952(87)90020-7. [DOI] [PubMed] [Google Scholar]
  6. Bevan S., Szolcsányi J. Sensory neuron-specific actions of capsaicin: mechanisms and applications. Trends Pharmacol Sci. 1990 Aug;11(8):330–333. doi: 10.1016/0165-6147(90)90237-3. [DOI] [PubMed] [Google Scholar]
  7. Bevan S., Yeats J. Protons activate a cation conductance in a sub-population of rat dorsal root ganglion neurones. J Physiol. 1991 Feb;433:145–161. doi: 10.1113/jphysiol.1991.sp018419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chahl L. A. The effects of ruthenium red on the response of guinea-pig ileum to capsaicin. Eur J Pharmacol. 1989 Oct 10;169(2-3):241–247. doi: 10.1016/0014-2999(89)90021-6. [DOI] [PubMed] [Google Scholar]
  9. Davidson J. S., Wakefield I. K., King J. A., Mulligan G. P., Millar R. P. Dual pathways of calcium entry in spike and plateau phases of luteinizing hormone release from chicken pituitary cells: sequential activation of receptor-operated and voltage-sensitive calcium channels by gonadotropin-releasing hormone. Mol Endocrinol. 1988 Apr;2(4):382–390. doi: 10.1210/mend-2-4-382. [DOI] [PubMed] [Google Scholar]
  10. Dickenson A. H., Dray A. Selective antagonism of capsaicin by capsazepine: evidence for a spinal receptor site in capsaicin-induced antinociception. Br J Pharmacol. 1991 Dec;104(4):1045–1049. doi: 10.1111/j.1476-5381.1991.tb12547.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Docherty R. J., Robertson B., Bevan S. Capsaicin causes prolonged inhibition of voltage-activated calcium currents in adult rat dorsal root ganglion neurons in culture. Neuroscience. 1991;40(2):513–521. doi: 10.1016/0306-4522(91)90137-d. [DOI] [PubMed] [Google Scholar]
  12. Donnerer J., Lembeck F. Analysis of the effects of intravenously injected capsaicin in the rat. Naunyn Schmiedebergs Arch Pharmacol. 1982 Jul;320(1):54–57. doi: 10.1007/BF00499072. [DOI] [PubMed] [Google Scholar]
  13. Dray A., Bettaney J., Forster P. Resiniferatoxin, a potent capsaicin-like stimulator of peripheral nociceptors in the neonatal rat tail in vitro. Br J Pharmacol. 1990 Feb;99(2):323–326. doi: 10.1111/j.1476-5381.1990.tb14702.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Dray A., Forbes C. A., Burgess G. M. Ruthenium red blocks the capsaicin-induced increase in intracellular calcium and activation of membrane currents in sensory neurones as well as the activation of peripheral nociceptors in vitro. Neurosci Lett. 1990 Mar 2;110(1-2):52–59. doi: 10.1016/0304-3940(90)90786-9. [DOI] [PubMed] [Google Scholar]
  15. Dubois J. M. Capsaicin blocks one class of K+ channels in the frog node of Ranvier. Brain Res. 1982 Aug 12;245(2):372–375. doi: 10.1016/0006-8993(82)90820-4. [DOI] [PubMed] [Google Scholar]
  16. Erdélyi L., Such G. The effects of capsaicin on the early outward current in identified snail neurones. Neurosci Lett. 1984 Aug 10;48(3):349–353. doi: 10.1016/0304-3940(84)90063-6. [DOI] [PubMed] [Google Scholar]
  17. Fenwick E. M., Marty A., Neher E. Sodium and calcium channels in bovine chromaffin cells. J Physiol. 1982 Oct;331:599–635. doi: 10.1113/jphysiol.1982.sp014394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Flynn D. L., Rafferty M. F., Boctor A. M. Inhibition of human neutrophil 5-lipoxygenase activity by gingerdione, shogaol, capsaicin and related pungent compounds. Prostaglandins Leukot Med. 1986 Oct;24(2-3):195–198. doi: 10.1016/0262-1746(86)90126-5. [DOI] [PubMed] [Google Scholar]
  19. Franco-Cereceda A., Lou Y. P., Lundberg J. M. Ruthenium red differentiates between capsaicin and nicotine effects on cardiac sensory nerves. Acta Physiol Scand. 1989 Nov;137(3):457–458. doi: 10.1111/j.1748-1716.1989.tb08748.x. [DOI] [PubMed] [Google Scholar]
  20. Geppetti P., Del Bianco E., Patacchini R., Santicioli P., Maggi C. A., Tramontana M. Low pH-induced release of calcitonin gene-related peptide from capsaicin-sensitive sensory nerves: mechanism of action and biological response. Neuroscience. 1991;41(1):295–301. doi: 10.1016/0306-4522(91)90218-d. [DOI] [PubMed] [Google Scholar]
  21. Grasso P., Reichert L. E., Jr Follicle-stimulating hormone receptor-mediated uptake of 45Ca2+ by proteoliposomes and cultured rat sertoli cells: evidence for involvement of voltage-activated and voltage-independent calcium channels. Endocrinology. 1989 Dec;125(6):3029–3036. doi: 10.1210/endo-125-6-3029. [DOI] [PubMed] [Google Scholar]
  22. Holzer P. Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol Rev. 1991 Jun;43(2):143–201. [PubMed] [Google Scholar]
  23. Holzer P. Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides. Neuroscience. 1988 Mar;24(3):739–768. doi: 10.1016/0306-4522(88)90064-4. [DOI] [PubMed] [Google Scholar]
  24. Juan H., Lembeck F., Seewann S., Hack U. Nociceptor stimulation and PGE release by capsaicin. Naunyn Schmiedebergs Arch Pharmacol. 1980 Jun;312(2):139–143. doi: 10.1007/BF00569722. [DOI] [PubMed] [Google Scholar]
  25. Maggi C. A. Capsaicin and primary afferent neurons: from basic science to human therapy? J Auton Nerv Syst. 1991 Apr;33(1):1–14. doi: 10.1016/0165-1838(91)90013-s. [DOI] [PubMed] [Google Scholar]
  26. Maggi C. A., Giuliani S., Meli A. Effect of ruthenium red on responses mediated by activation of capsaicin-sensitive nerves of the rat urinary bladder. Naunyn Schmiedebergs Arch Pharmacol. 1989 Nov;340(5):541–546. doi: 10.1007/BF00260609. [DOI] [PubMed] [Google Scholar]
  27. Maggi C. A., Meli A. The sensory-efferent function of capsaicin-sensitive sensory neurons. Gen Pharmacol. 1988;19(1):1–43. doi: 10.1016/0306-3623(88)90002-x. [DOI] [PubMed] [Google Scholar]
  28. Maggi C. A., Patacchini R., Santicioli P., Giuliani S., Geppetti P., Meli A. Protective action of ruthenium red toward capsaicin desensitization of sensory fibers. Neurosci Lett. 1988 May 26;88(2):201–205. doi: 10.1016/0304-3940(88)90126-7. [DOI] [PubMed] [Google Scholar]
  29. Maggi C. A., Santicioli P., Geppetti P., Parlani M., Astolfi M., Pradelles P., Patacchini R., Meli A. The antagonism induced by ruthenium red of the actions of capsaicin on the peripheral terminals of sensory neurons: further studies. Eur J Pharmacol. 1988 Sep 1;154(1):1–10. doi: 10.1016/0014-2999(88)90356-1. [DOI] [PubMed] [Google Scholar]
  30. Mapp C. E., Boniotti A., Graf P. D., Chitano P., Fabbri L. M., Nadel J. A. Bronchial smooth muscle responses evoked by toluene diisocyanate are inhibited by ruthenium red and by indomethacin. Eur J Pharmacol. 1991 Jul 23;200(1):73–76. doi: 10.1016/0014-2999(91)90667-f. [DOI] [PubMed] [Google Scholar]
  31. Mapp C. E., Fabbri L. M., Boniotti A., Maggi C. A. Prostacyclin activates tachykinin release from capsaicin-sensitive afferents in guinea-pig bronchi through a ruthenium red-sensitive pathway. Br J Pharmacol. 1991 Sep;104(1):49–52. doi: 10.1111/j.1476-5381.1991.tb12383.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. McBurney R. N., Neering I. R. The measurement of changes in intracellular free calcium during action potentials in mammalian neurones. J Neurosci Methods. 1985 Mar;13(1):65–76. doi: 10.1016/0165-0270(85)90044-5. [DOI] [PubMed] [Google Scholar]
  33. McCleskey E. W., Almers W. The Ca channel in skeletal muscle is a large pore. Proc Natl Acad Sci U S A. 1985 Oct;82(20):7149–7153. doi: 10.1073/pnas.82.20.7149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Ong J., Kerr D. I., Johnston G. A. Calcium dependence of baclofen- and GABA-induced depression of responses to transmural stimulation in the guinea-pig isolated ileum. Eur J Pharmacol. 1987 Feb 24;134(3):369–372. doi: 10.1016/0014-2999(87)90372-4. [DOI] [PubMed] [Google Scholar]
  35. Petersen M., Pierau F. K., Weyrich M. The influence of capsaicin on membrane currents in dorsal root ganglion neurones of guinea-pig and chicken. Pflugers Arch. 1987 Aug;409(4-5):403–410. doi: 10.1007/BF00583794. [DOI] [PubMed] [Google Scholar]
  36. Petersen M., Wagner G., Pierau F. K. Modulation of calcium-currents by capsaicin in a subpopulation of sensory neurones of guinea pig. Naunyn Schmiedebergs Arch Pharmacol. 1989 Jan-Feb;339(1-2):184–191. doi: 10.1007/BF00165142. [DOI] [PubMed] [Google Scholar]
  37. Raess B. U., Vincenzi F. F. Calmodulin activation of red blood cell (Ca2+ + Mg2+)-ATPase and its antagonism by phenothiazines. Mol Pharmacol. 1980 Sep;18(2):253–258. [PubMed] [Google Scholar]
  38. Robertson B., Wann K. T. On the action of ruthenium red and neuraminidase at the frog neuromuscular junction. J Physiol. 1987 Jan;382:411–423. doi: 10.1113/jphysiol.1987.sp016375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Rossi C. S., Vasington F. D., Carafoli E. The effect of ruthenium red on the uptake and release of Ca 2+ by mitochondria. Biochem Biophys Res Commun. 1973 Feb 5;50(3):846–852. doi: 10.1016/0006-291x(73)91322-3. [DOI] [PubMed] [Google Scholar]
  40. Ryves W. J., Garland L. G., Evans A. T., Evans F. J. A phorbol ester and a daphnane ester stimulate a calcium-independent kinase activity from human mononuclear cells. FEBS Lett. 1989 Mar 13;245(1-2):159–163. doi: 10.1016/0014-5793(89)80212-1. [DOI] [PubMed] [Google Scholar]
  41. Szallasi A., Blumberg P. M. Resiniferatoxin and its analogs provide novel insights into the pharmacology of the vanilloid (capsaicin) receptor. Life Sci. 1990;47(16):1399–1408. doi: 10.1016/0024-3205(90)90518-v. [DOI] [PubMed] [Google Scholar]
  42. Szallasi A., Blumberg P. M. Resiniferatoxin, a phorbol-related diterpene, acts as an ultrapotent analog of capsaicin, the irritant constituent in red pepper. Neuroscience. 1989;30(2):515–520. doi: 10.1016/0306-4522(89)90269-8. [DOI] [PubMed] [Google Scholar]
  43. Szallasi A., Blumberg P. M. Specific binding of resiniferatoxin, an ultrapotent capsaicin analog, by dorsal root ganglion membranes. Brain Res. 1990 Jul 30;524(1):106–111. doi: 10.1016/0006-8993(90)90498-z. [DOI] [PubMed] [Google Scholar]
  44. Szolcsányi J., Barthó L. New type of nerve-mediated cholinergic contractions of the guinea-pig small intestine and its selective blockade by capsaicin. Naunyn Schmiedebergs Arch Pharmacol. 1978 Oct;305(1):83–90. doi: 10.1007/BF00497009. [DOI] [PubMed] [Google Scholar]
  45. Tapia R., Arias C., Morales E. Binding of lanthanum ions and ruthenium red to synaptosomes and its effects on neurotransmitter release. J Neurochem. 1985 Nov;45(5):1464–1470. doi: 10.1111/j.1471-4159.1985.tb07213.x. [DOI] [PubMed] [Google Scholar]
  46. Wang J. P., Hsu M. F., Hsu T. P., Teng C. M. Antihemostatic and antithrombotic effects of capsaicin in comparison with aspirin and indomethacin. Thromb Res. 1985 Mar 15;37(6):669–679. doi: 10.1016/0049-3848(85)90196-3. [DOI] [PubMed] [Google Scholar]
  47. Wang J. P., Hsu M. F., Teng C. M. Antiplatelet effect of capsaicin. Thromb Res. 1984 Dec 15;36(6):497–507. doi: 10.1016/0049-3848(84)90189-0. [DOI] [PubMed] [Google Scholar]
  48. Williams P. F., Caterson I. D., Cooney G. J., Zilkens R. R., Turtle J. R. High affinity insulin binding and insulin receptor-effector coupling: modulation by Ca2+. Cell Calcium. 1990 Sep;11(8):547–556. doi: 10.1016/0143-4160(90)90031-o. [DOI] [PubMed] [Google Scholar]
  49. Winter J., Dray A., Wood J. N., Yeats J. C., Bevan S. Cellular mechanism of action of resiniferatoxin: a potent sensory neuron excitotoxin. Brain Res. 1990 Jun 18;520(1-2):131–140. doi: 10.1016/0006-8993(90)91698-g. [DOI] [PubMed] [Google Scholar]
  50. Wood J. N., Winter J., James I. F., Rang H. P., Yeats J., Bevan S. Capsaicin-induced ion fluxes in dorsal root ganglion cells in culture. J Neurosci. 1988 Sep;8(9):3208–3220. doi: 10.1523/JNEUROSCI.08-09-03208.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Yamanaka K., Kigoshi S., Muramatsu I. Conduction-block induced by capsaicin in crayfish giant axon. Brain Res. 1984 May 21;300(1):113–119. doi: 10.1016/0006-8993(84)91345-3. [DOI] [PubMed] [Google Scholar]
  52. Zernig G., Holzer P., Lembeck F. A study of the mode and site of action of capsaicin in guinea-pig heart and rat uterus. Naunyn Schmiedebergs Arch Pharmacol. 1984 May;326(1):58–63. doi: 10.1007/BF00518779. [DOI] [PubMed] [Google Scholar]
  53. de Vries D. J., Blumberg P. M. Thermoregulatory effects of resiniferatoxin in the mouse: comparison with capsaicin. Life Sci. 1989;44(11):711–715. doi: 10.1016/0024-3205(89)90382-2. [DOI] [PubMed] [Google Scholar]

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