Pharmacology of Itch

Robin L. Thurmond, Kayvan Kazerouni, Sandra R. Chaplan, Andrew J. Greenspan

Histamine is one of the best-characterized pruritogens in humans. It is known to play a role in pruritus associated with urticaria as well as ocular and nasal allergic reactions. Histamine mediates its effect via four receptors. Antihistamines that block the activation of the histamine H1 receptor, H1R, have been shown to be effective therapeutics for the treatment of pruritus associated with urticaria, allergic rhinitis, and allergic conjunctivitis. However, their efficacy in other pruritic diseases such as atopic dermatitis and psoriasis is limited. The other histamine receptors may also play a role in pruritus, with the exception of the histamine H2 receptor, H2R. Preclinical evidence indicates that local antagonism of the histamine H3 receptor, H3R, can induce scratching perhaps via blocking inhibitory neuronal signals. The histamine H4 receptor, H4R, has received a significant amount of attention as to its role in mediating pruritic signals. Indeed, it has now been shown that a selective H4R antagonist can inhibit histamine-induced itch in humans. This clinical result, in conjunction with efficacy in various preclinical pruritus models, points to the therapeutic potential of H4R antagonists for the treatment of pruritus not controlled by antihistamines that target the H1R.