Food allergy, anaphylaxis, dermatology, and drug allergy
Histamine H4 receptor antagonists are superior to traditional antihistamines in the attenuation of experimental pruritus

https://doi.org/10.1016/j.jaci.2006.08.034Get rights and content

Background

Histamine is a potent mediator of itch in humans, yet histamine H1 receptor antagonists have been shown to be of limited use in the treatment of certain chronic pruritic diseases. The histamine H4 receptor is a recently described histamine receptor, expressed on hematopoietic cells, linked to the pathology of allergy and asthma.

Objective

The contribution of the novel histamine H4 receptor to histaminergic and allergic pruritus was investigated.

Results

Histamine and a selective histamine H4 receptor agonist caused scratching responses in mice, which were almost completely attenuated in histamine H4 receptor knockout mice or by pretreatment with the selective histamine H4 receptor antagonist, JNJ 7777120. Pruritus induced by allergic mechanisms was also potently inhibited with histamine H4 receptor antagonist treatment or in histamine H4 receptor knockout mice. In all cases, the inhibitory effect of histamine H4 receptor antagonist was greater than those observed with histamine H1 receptor antagonists. The histamine H4 receptor–mediated pruritus was shown to be independent of mast cells or other hematopoietic cells and may result from actions on peripheral neurons.

Conclusion

These results demonstrate that the histamine H4 receptor is involved in pruritic responses in mice to a greater extent than the histamine H1 receptor.

Clinical implications

Histamine H4 receptor antagonists may have therapeutic utility for treating chronic pruritic diseases in humans where histamine H1 receptor antagonists are not effective.

Section snippets

Animals

All experiments and procedures were performed according to on-site Institutional Animal Care and Use Committee standards and regulations. Female CD-1 mice (Charles River, Hollister, Calif) approximately 10 to 12 weeks old, H4R knockout (−/−) and littermate, wild-type (+/+) mice (c57bl/6 sv129),23 or mast cell-deficient (WBBF1-W/Wv) and sufficient control (WBB6F1-+/+) mice 10 to 12 weeks of age (Jackson Laboratories, Bar Harbor, Maine) were used. H4R−/−/+/+ bone marrow chimera mice were produced

Histamine-mediated pruritus

Pruritic responses to histamine were examined in H4R−/− mice in comparison with wild-type controls. Histamine injected intradermally induced a pruritic response in a dose-dependent fashion in H4R+/+ mice, whereas H4R−/− mice showed a significantly reduced (P < .001 vs +/+) response at all doses (Fig 1, A). To confirm the role of the H4R in this response, intradermal injection of histamine also induced itch in a dose-dependent fashion in CD-1 mice (data not shown), with a dose of 300 nmol used

Discussion

The ability of histamine to produce pruritic responses in humans is incontrovertible. However, its involvement in various chronic pruritic diseases has been debated, largely because of the ineffectiveness of existing H1R and H2R antagonists in the clinic. Here we demonstrate the definitive role of the histamine H4 receptor in murine itch and investigate the possible mechanisms involved in H4R-mediated pruritus using clinically relevant pruritogens and allergic mechanisms.

The pruritic response

References (41)

  • Y. Sugimoto et al.

    Evaluation of the effects of anti-pruritic drugs on scratch responses using histamine H1 receptor-deficient mice

    Eur J Pharmacol

    (2003)
  • N. Inagaki et al.

    Involvement of unique mechanisms in the induction of scratching behavior in BALB/c mice by compound 48/80

    Eur J Pharmacol

    (2002)
  • K. Ishizaka et al.

    Biologic function of the Fc fragments of E myeloma protein

    Immunochemistry

    (1970)
  • F. Coge et al.

    Structure and expression of the human histamine H4-receptor gene

    Biochem Biophys Res Commun

    (2001)
  • J. Kamei et al.

    Effects of first- and second-generation histamine-H1-receptor antagonists on the pentobarbital-induced loss of the righting reflex in streptozotocin-induced diabetic mice

    J Pharmacol Sci

    (2005)
  • S.M. Carlton et al.

    Localization and activation of substance P receptors in unmyelinated axons of rat glabrous skin

    Brain Res

    (1996)
  • L. Kraus et al.

    Mechanism of action of antipruritic drugs

    BMJ (Clin Res Ed)

    (1983)
  • N.T. Watson et al.

    Famotidine in the treatment of acute urticaria

    Clin Exp Dermatol

    (2000)
  • M.G. Davies et al.

    Sensory responses of human skin to synthetic histamine analogues and histamine

    Br J Clin Pharmacol

    (1980)
  • Y. Sugimoto et al.

    Pruritus-associated response mediated by cutaneous histamine H3 receptors

    Clin Exp Allergy

    (2004)
  • Cited by (263)

    • Neuron‒Mast Cell Cross-Talk in the Skin

      2022, Journal of Investigative Dermatology
    • The Pharmacology of Antihistamines

      2022, Comprehensive Pharmacology
    • Itch: Pathogenesis and treatment

      2022, Journal of the American Academy of Dermatology
    View all citing articles on Scopus

    Disclosure of potential conflict of interest: P. J. Dunford, K. N. Williams, P. J. Desai, L. Karlsson, and R. L. Thurmond are employed by Johnson & Johnson Pharmaceutical Research & Development, LLC. D. McQueen has declared that he has no conflict of interest.

    View full text