To date, suggestions that endothelin-1 (ET-1) causes nociception and pruritus are based on results in preclinical models in which responses to pruritic and nociceptive stimuli cannot be distinguished. This study reexamines these sensory effects of ET-1 in the new mouse cheek model, in which pruritogens and algogens evoke distinct behavioral responses.

Mice received intradermal (i.d.) injections of test substances into the left cheek and bouts of hind limb scratches or forepaw wipes, directed to the injection site, were considered indicative of pruritus and nociception, respectively.

Histamine and capsaicin selectively evoked scratching and wipes, respectively, whereas ET-1 (3–60pmol) promoted dose-dependent bouts of both behaviors. While scratching and wipe responses to ET-1 (30pmol) were potentiated by BQ-788 (an ET_B receptor antagonist) and reduced by co-injection of BQ-788 plus BQ-123 (an ET_A receptor antagonist), BQ-123 alone inhibited scratching responses only. CTOP (μ-opioid receptor selective antagonist) only augmented scratching responses to ET-1, whereas DAMGO (μ-opioid receptor selective agonist) reduced both behaviors. Loratadine (histamine H₁ receptor antagonist) marginally reduced scratching, but markedly suppressed wipes.

These results demonstrate that ET-1 evokes pruritic and nociceptive behaviors in the mouse cheek model. Both responses to ET-1 appear to be mediated via ET_A receptors and subjected to limitation by simultaneous ET_B receptor activation. Local endogenous opioids acting on μ-opioid receptors selectively modulate the pruritic response to ET-1, whereas histamine, possibly derived from mast cells and acting on H₁ receptors, contributes importantly to the nociceptive effect of ET-1 in this model.