Endothelin‐1 activates ET A receptors to cause reflex scratching in BALB/c mice

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  μ g; 5.5 nmol), also caused scratching (ED 50 1.3 μ g, 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. British Journal of Pharmacology (2007) 151 , 278–284. doi: 10.1038/sj.bjp.0707216