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


METHODS
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.


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 microg; 5.5 nmol), also caused scratching (ED(50) 1.3 microg, 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.


CONCLUSIONS
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.
McQueen
D S
DS
Division of Neuroscience, School of Biomedical Sciences, University of Edinburgh College of Medicine & Veterinary Medicine, University of Edinburgh, Edinburgh, UK. d.s.mcqueen@ed.ac.uk
Noble
M A H
MA
Bond
S M
SM
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000008:administration & dosage / Q000494:pharmacology*; D016232:Endothelins / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D007271:Injections, Intradermal; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D011537:Pruritus / Q000503:physiopathology*; D044022:Receptor, Endothelin A / Q000819:agonists / Q000502:physiology*; D044023:Receptor, Endothelin B / Q000819:agonists / Q000502:physiology; D012018:Reflex / Q000187:drug effects*
D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D009842:Oligopeptides; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C074308:sovateltide; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)