Archives of Dermatological Research

, Volume 274, Issue 1–2, pp 29–37 | Cite as

Potentiation of histamine-induced itch and flare responses in human skin by the enkephalin analogue FK 33-824, β-endorphin and morphine

  • B. Fjellner
  • Ö. Hägermark
Original Contributions


The effect of various opioid or putative neurotransmitter peptides on histamine-induced itch and flare responses was studied in humans after intradermal injection. Significant enhancement of the histamine responses was induced by the stable methionine-enkephalin analogue FK 33-824, β-endorphin and morphine. The putative neurotransmitters substance P and vasoactive intestinal polypeptide (VIP) — which moreover are potent histamine liberators — had no enhancing effect. The potentiation induced by FK 33-824 was induced neither by local pretreatment with Compound 48/80 to deplete the local stores of mast-cell-bound histamine, nor by oral pretreatment with indomethacin to inhibit prostaglandin formation in the skin. Thus, the enhancement did not seem to be due to histamine release or to prostaglandin formation and the mechanism of the effect remains to be shown. The specific morphine antagonist naloxone did not inhibit the potentiation by FK 33-824, which might indicate that ordinary opiate receptors were not involved. The results support the idea that pain and itch are qualitatively separate processes, and suggest possible mechanisms of morphine-induced pruritus. The findings are of particular interest in view of recent reports on the presence of methionineenkephalin in Merkel cells.

Key words

Pruritus Histamine Opioid peptides Morphine 


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  1. 1.
    Adler MW (1980) Opioid peptides. Minireview. Life Sci 26:497–510Google Scholar
  2. 2.
    Beamont A, Hughes J (1979) Biology of opioid peptides. Ann Rev Pharmacol Toxicol 19:245–267Google Scholar
  3. 3.
    Bernstein JE (1979) Relief of intractable pruritus with naloxone. Arch Dermatol 115:1366–1367Google Scholar
  4. 4.
    Black AK, Greaves MW, Hensby CN, Plummer NA, Warin AP (1978) The effects of indomethacin on arachidonic acid and prostaglandins E2 and F levels in human skin 24 h after U. V. B. and U. V. C. irradiation. Br J Clin Pharmacol 6:261–266Google Scholar
  5. 5.
    Feldberg W, Paton WDM (1951) Release of histamine from skin and muscle in the cat by opium alkaloids and other histamine liberators. J Physiol 114:490–509Google Scholar
  6. 6.
    Ferreira SH, Nakamura M (1979) II. Prostaglandin hyperalgesia: the peripheral analgesic activity of morphine, enkephalins and opioid antagonists. Prostaglandins 18:191–200Google Scholar
  7. 7.
    Fjellner B, Hägermark Ö (1981) Studies on pruritogenic and histamine-relasing effects of some putative peptide neurotransmitters. Acta Derm Venereol (Stockh) 61:245–250Google Scholar
  8. 8.
    Graffenried B, del Pozo E, Roubicek J, Krebs E, Pöldinger W, Burmeister P, Kerp L (1978) Effect of the synthetic enkephalin analogue FK 33-824 in man. Nature 272: 729–730Google Scholar
  9. 9.
    Greaves MW, McDonald-Gibson W (1973) Itch: role of prostaglandins. Br Med J iii:608–609Google Scholar
  10. 10.
    Hägermark Ö, Fjellner B (1980) Enhancement of histamine-induced pruritus by enkephalin and morphine. J Invest Dermatol 74:459Google Scholar
  11. 11.
    Hägermark Ö, Hökfelt T, Pernow B (1978) Flare and itch induced by substance P in human skin. J Invest Dermatol 71:233–235Google Scholar
  12. 12.
    Hägermark Ö, Strandberg K (1977) Pruritogenic activity of prostaglandin E2. Acta Derm Venereol (Stockh) 57:37–43Google Scholar
  13. 13.
    Hägermark Ö, Strandberg K, Hamberg M (1977) Potentiation of itch and flare responses in human skin by prostaglandins E2 and H2 and a prostaglandin endoperoxide analog. J Invest Dermatol 69:527–530Google Scholar
  14. 14.
    Hartschuh W, Weihe E, Büchler M, Helmstaedter V, Feurle GE, Forssmann WG (1979) Metenkephalin-like immunoreactivity in Merkel cells. Cell Tissue Res 201:343–348Google Scholar
  15. 15.
    Hartschuh W, Weihe E (1980) Fine structural analysis of the synaptic junction of Merkel cell-axon-complexes. J Invest Dermatol 75:159–165Google Scholar
  16. 16.
    Jaques R (1977) Inhibitory effect of enkephalins on contractions of the guinea-pig ileum elicited by PGE1. Agents Actions 7:317–319Google Scholar
  17. 17.
    Keele CA, Armstrong D (1964) Substances producing pain and itch, chap 15. Arnold, London, pp 288–304Google Scholar
  18. 18.
    Koenigstein H (1948) Experimental study of itch stimuli in animals. Arch Dermatol 57:828–849Google Scholar
  19. 19.
    Lembeck L, Beubler E (1979) Inhibition of PGE1 induced intestinal secretion by the synthetic enkephalin analogue FK 33-824. Naunyn-Schmiedeberg's Arch Pharmacol 308:261–264Google Scholar
  20. 20.
    Lovell CR, Burton PA, Duncan EHL, Burton JL (1976) Prostaglandins and pruritus. Br J Dermatol 94:273–275Google Scholar
  21. 21.
    McKnight AT, Kosterlitz HW (1980) Opioid peptides and pituitary function. J Reprod Fertil 58:513–519Google Scholar
  22. 22.
    Roemer D, Buescher HH, Hill RC, Pless J, Bauer W, Cardinaux F, Closse A, Hauser D, Huguening R (1977) A synthetic enkephalin analogue with prolonged parenteral and oral analgesic activity. Nature, 268:547–549Google Scholar
  23. 23.
    Rothman S (1941) Physiology of itching. Physiol Rev 21:357–381Google Scholar
  24. 24.
    Stacher G, Bauer P, Steinringer H, Schreiber E, Schmierer G (1979) Effect of the synthetic enkephalin analogue FK 33-824 on pain threshold and pain tolerance in man. Pain 7:159–172Google Scholar
  25. 25.
    Summerfield JA (1980) Naloxone modulates the perception of itch in man. Br J Clin Pharmacol 10:180–183Google Scholar
  26. 26.
    Terenius L (1979) Endorphins — the first three years. Am Heart J. 98:681–683Google Scholar

Copyright information

© Springer-Verlag 1982

Authors and Affiliations

  • B. Fjellner
    • 1
  • Ö. Hägermark
    • 1
  1. 1.Department of DermatologyKarolinska HospitalStockholmSweden

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