Endothelin-1 induces itch and pain in the mouse cheek model

AbstractAimsTo 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.Main methodsMice 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.Key findingsHistamine 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 ETB receptor antagonist) and reduced by co-injection of BQ-788 plus BQ-123 (an ETA 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.SignificanceThese 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 ETA receptors and subjected to limitation by simultaneous ETB 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