Department of Pharmacology, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
Life Sci. 2012 Oct 15;91(13-14):628-33. doi: 10.1016/j.lfs.2012.03.020. Epub 2012 Mar 28.
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 (3-60 pmol) promoted dose-dependent bouts of both behaviors. While scratching and wipe responses to ET-1 (30 pmol) 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 H(1) 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 H(1) receptors, contributes importantly to the nociceptive effect of ET-1 in this model.
迄今为止，关于内皮素-1（ET-1）引起疼痛和瘙痒的观点是基于临床前模型中的结果，在这些模型中，无法区分对瘙痒和疼痛刺激的反应。本研究在新的小鼠脸颊模型中重新检查了 ET-1 的这些感觉效应，在该模型中，瘙痒原和致痛原引发了不同的行为反应。
将测试物质皮内（i.d.）注射到左脸颊，向注射部位定向进行后肢搔抓或前肢擦拭，分别被认为是瘙痒和疼痛的指征。
组胺和辣椒素分别选择性地诱发搔抓和擦拭，而 ET-1（3-60 pmol）促进了两种行为的剂量依赖性发作。虽然 ET-1（30 pmol）引起的搔抓和擦拭反应被 BQ-788（ET（B）受体拮抗剂）增强，并被 BQ-788 与 BQ-123（ET（A）受体拮抗剂）的共同注射所减少，但 BQ-123 本身仅抑制搔抓反应。CTOP（μ-阿片受体选择性拮抗剂）仅增强 ET-1 引起的搔抓反应，而 DAMGO（μ-阿片受体选择性激动剂）减少了这两种行为。氯雷他定（组胺 H1 受体拮抗剂）轻微减少搔抓，但显著抑制擦拭。
这些结果表明，ET-1 在小鼠脸颊模型中引起瘙痒和疼痛行为。ET-1 的这两种反应似乎都通过 ET（A）受体介导，并受到同时的 ET（B）受体激活的限制。局部内源性阿片样物质作用于 μ-阿片受体选择性调节 ET-1 的瘙痒反应，而组胺可能来自肥大细胞并作用于 H1 受体，在该模型中对 ET-1 的疼痛效应有重要贡献。
