Endothelin-1 activates ETA receptors to cause reflex scratching in BALB/c mice

Abstract

Background and purpose: Endothelin-1 (ET-1) is present in murine and human skin and causes itch (pruritus) when injected in humans. This behavioural study examined the scratch reflex evoked by ET-1 in mice. Experimental approach: An automated detector was used to determine whether ET-1 causes reflex scratching, the behavioural correlate of itching, in BALB/c mice. Selective agonists and antagonists were used to probe the ET receptor(s) involved. Key results: ET-1 evoked dose-related reflex scratching lasting up to 20 min following intradermal injection (0.1-100 ng; 0.04-40 pmol). The ED 50 for ET-1 induced scratching was 2.1 ng and desensitization occurred with cumulative dosing. High doses of the ET B receptor agonist IRL1620 (10 μg; 5.5 nmol), also caused scratching (ED 50 1.3 μg, 0.7 nmol). The ET A receptor antagonist BQ123 significantly reduced scratching evoked by ET-1 and IRL 1620, suggesting that both agonists caused scratching via an ET A receptor-dependent mechanism. The ET B receptor antagonist BQ788 significantly reduced scratching evoked by IRL1620 but had no effect on scratching evoked by ET-1. This indicated that activation of ET B receptors by high doses of ET B agonist, but not ET-1, can trigger scratching. Conclusion and implications: ET-1 is a potent endogenous activator of reflex scratching (itch). Mechanisms for ET-induced scratching are considered, including direct action of ET-1 on pruriceptive nerve endings and indirect actions via release of endogenous mediators such as histamine from mast cells. ET-1 and ET A receptors, possibly also ET B receptors, are potential targets for developing specific anti-pruritic drugs to treat pruritic skin disorders such as atopic dermatitis. © 2007 Nature Publishing Group All rights reserved.