Histamine H₄ receptor antagonists are superior to traditional antihistamines in the attenuation of experimental pruritus

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.

Key words: Histamine, histamine H₁ receptor, histamine H₄ receptor, pruritus, mast cells

Abbreviations used: H₁R, Histamine H₁ receptor, H₂R, Histamine H₂ receptor, H₃R, Histamine H₃ receptor, H₄R, Histamine H₄ receptor, H₄R^−/−, Histamine H₄ receptor knockout, H₄R^+/+, Histamine H₄ receptor wild-type