Abstract
We examined the involvement of substance P (SP) in mouse ear oedema induced by topical application of capsaicin (250 µg/ear). Reapplication of capsaicin at 4h, 24h, and 48h after initial treatment did not induce a second oedema response. Oedema induced after the second application was significantly (p<0.01 orp<0.001) suppressed for up to 30 days but was observed when capsaicin was applied 40 days after initial treatment. Topical pretreatment of ears with capsaicin at 4h, 24h and 48h before i.v. injection of SP (5 µg/kg) did not cause a significant inhibition of plasma extravasation in ear skin. NK1 receptor antagonists such as RP 67580 (ED50:0.19 mg/kg, i.v.), spantide II (ED50:0.33 mg/kg, i.v.), and GR 82334 (ED50:0.26 mg/kg, i.v.), inhibited capsaicin-induced ear oedema, whereas SR 48968 (2.0 mg/kg, i.v.), a NK2 receptor antagonist, had no effect. Furthermore, RP 67580 (0.5 kg/mg, i.v.) inhibited the oedema response induced by reapplication of capsaicin at 50 days after initial treatment. These results indicate that tachyphylaxis of capsaicin-induced oedema is reversible and suggest that this response may be due mainly to a reduction of SP in sensory neurones but not to any loss of responsiveness of NK1 receptors. We also conclude that SP and NK1 receptors are involved predominantly in the development of capsaicin-induced mouse ear oedema.
Similar content being viewed by others
References
Holzer P. Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol Rev 1991;43:143–201.
Kenins P. Responses of single nerve fibres to capsaicin applied to the skin. Neurosci Lett 1982;29:83–8.
Lynn B, Ye W, Cotsell B. The actions of capsaicin applied topically to the skin of the rat on C-fibre afferents, antidromic vasodilatation and substance P levels. Br J Pharmacol 1992;107:400–6.
Jancsó N. Desensitization with capsaicin and related acylamides as a tool for studying the function of pain receptors. In: Lim PKS, Armstrong D, Pardo EG editors. Pharmacology of Pain. Oxford: Pergamon, 1968:33–5.
Bernstein JE, Swift RM, Soltani K, Lorincz AL. Inhibition of axon reflex vasodilatation by topically applied capsaicin. J Invest Dermatol 1981;76:394–5.
Carpenter SE, Lynn B. Vascular and sensory responses of human skin to mild injury after topical treatment with capsaicin. Br J Pharmacol 1981;73:755–8.
Carter RB. Topical capsaicin in the treatment of cutaneous disorders. Drug Develop Res 1991;22:109–23.
Guard S, Watson SP. Tachykinin receptor types: classification and membrane signalling mechanisms. Neurochem Int 1991;18:149–65.
Lembeck F, Holzer P. Substance P as neurogenic mediator of antidromic vasodilation and neurogenic plasma extravasation. Naunyn-Schmied Arch Pharmacol 1979;310:175–83.
Foreman JC, Jordan CC, Oehme P, Renner H. Structure-activity relationships for some substance P-related peptides that cause wheal and flare reactions in human skin. J Physiol 1983;335:449–65.
Wallengren J, Ekman R, Möller H. Substance P and vasoactive intestinal peptide in bullous and inflammatory skin disease. Acta Dermatol Venereol 1986;66:23–8.
Garret C, Carruette A, Fardin V, Moussaoui S, Peyronel JF, Blanchard JC, et al. Pharmacological properties of a potent and selective nonpeptide substance P antagonist. Proc Natl Acad Sci USA 1991;88:10208–12.
Lembeck F, Donnerer J, Tsuchiya M, Nagahisa A. The non-peptide tachykinin antagonist, CP-96,345, is a potent inhibitor of neurogenic inflammation. Br J Pharmacol 1992;105:527–30.
Moussaoui SM, Montier F, Carruette A, Blanchard JC, Laduron PM, Garret C. A non-peptide NK1-receptor antagonist, RP 67580, inhibits neurogenic inflammation post-synaptically. Br J Pharmacol 1993;109:259–64.
Mantione CR, Rodriguez R. A bradykinin (BK)1 receptor antagonist blocks capsaicin-induced ear inflammation in mice. Br J Pharmacol 1990;99:516–8.
Gabór M, Rázga Z. Development and inhibition of mouse ear oedema induced with capsaicin. Agents Actions 1992;36:83–6.
Inoue H, Nagata N, Koshihara Y. Profile of capsaicininduced mouse ear oedema as neurogenic inflammatory model: comparison with arachidonic acid-induced ear oedema. Br J Pharmacol 1993;110:1614–20.
Maggi CA, Patacchini R, Rovero P, Giachetti A. Tachykinin receptors and tachykinin receptor antagonists. J Auton Pharmacol 1993;13:23–93.
Emonds-Alt X, Vilain P, Goulaouic P, Proietto V, Van Broeck D, Advenier C, et al. A potent and selective non-peptide antagonist of the neurokinin A (NK2) receptor. Life Sci 1992;50:PL101–6.
Cochran WG, Cox GM. Experimental Designs. 2nd ed. New York: Wiley, 1957.
Alber G, Scheuber PH, Reck B, Sailer-Kramer B, Hartmann A, Hammer DK. Role of substance P in immediatetype skin reactions induced by staphylococcal enterotoxin B in unsensitized monkeys. J Allergy Clin Immunol 1989;84:880–5.
Lynn B. Capsaicin: actions of C fibre afferents that may be involved in itch. Skin Pharmacol 1992;5:9–13.
Dray A. Neuropharmacological mechanisms of capsaicin and related substances. Biochem Pharmacol 1992;44:611–5.
Håkanson R, Leander S, Asona N, Feng DM, Folkers K. Spantide II, a novel tachykinin antagonist having high potency and low histamine-releasing effect. Regul Peptides 1990;31:75–82.
Hagan RM, Ireland SJ, Bailey F, McBridge C, Jordan CC, Ward P. A spirolactam conformationally-constrained analogue of physalaemin which is a peptidase-resistant, selective neurokinin NK-1 receptor antagonist. Br J Pharmacol 1991;102:168P.
Tousignant C, Chan CC, Guevremont D, Brideau C, Hale JJ, MacCoss M, et al. NK2 receptors mediate plasma extravasation in guinea-pig lower airways. Br J Pharmacol 1993;108:383–6.
Dalsgaard CJ, Haegerstrand A, Theodorsson-Norheim E, Brodin E, Hökfelt T. Neurokinin A-like immunoreactivity in rat primary sensory neurons; coexistence with substance P. Histochem 1985;83:37–9.
Nawa H, Hirose T, Takashima H, Inayama S, Nakanishi A. Nucleotide sequences of cloned cDNAs for two types of bovine brain substance P precursor. Nature 1983;306:32–6.
O'Flynn NM, Helme RD, Watkins DJ, Burcher E. Autoradiographic localization of substance P binding sites in rat footpad skin. Neurosc Lett 1989;106:43–8.
Tsuchida K, Shigemoto R, Yokota Y, Nakanishi S. Tissue distribution and quantitation of the mRNAs for three rat tachykinin receptors. Eur J Biochem 1990;193:751–7.
Fuller RW, Conradson TB, Dixon CMS, Crossman DC, Barnes PJ. Sensory neuropeptide effects in human skin. Br J Pharmacol 1987;92:781–8.
Hirayama Y, Yasumitsu R, Kawamura A, Fujii T. NK1 receptors mediate tachykinin-induced plasma extravasation in the rat knee joint. Agents Actions 1993;40:171–5.
Xu XJ, Hao JX, Wiesenfeld-Hallin Z, Håkanson R, Folkers K, Hökfelt T. Spantide II, a novel tachykinin antagonist, and galanin inhibit plasma extravasation induced by antidromic C-fiber stimulation in rat hindpaw. Neurosc 1991;42:731–7.
Szallasi A. The vanilloid (capsaicin) receptor: receptor types and species differences. Gen Pharmacol 1994;25:223–43.
Amann R, Maggi CA. Ruthenium red as a capsaicin antagonist. Life Sci 1991;49:849–56.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Inoue, H., Nagata, N. & Koshihara, Y. Involvement of substance P as a mediator in capsaicin-induced mouse ear oedema. Inflamm Res 44, 470–474 (1995). https://doi.org/10.1007/BF01837912
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01837912