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Keywords:

  • endothelin-1;
  • ETA receptors;
  • ETB receptors;
  • BQ123;
  • BQ788;
  • pruritus;
  • itch;
  • IRL1620;
  • BALB/c mice;
  • pruriceptors

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 ED50 for ET-1 induced scratching was 2.1 ng and desensitization occurred with cumulative dosing. High doses of the ETB receptor agonist IRL1620 (10 μg; 5.5 nmol), also caused scratching (ED50 1.3 μg, 0.7 nmol). The ETA receptor antagonist BQ123 significantly reduced scratching evoked by ET-1 and IRL 1620, suggesting that both agonists caused scratching via an ETA receptor-dependent mechanism. The ETB receptor antagonist BQ788 significantly reduced scratching evoked by IRL1620 but had no effect on scratching evoked by ET-1. This indicated that activation of ETB receptors by high doses of ETB 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 ETA receptors, possibly also ETB 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