Trentin Patrícia Gonçalves, Fernandes Marcília Baticy, D'Orléans-Juste Pedro, Rae Giles Alexander
Department of Pharmacology, Universidade Federal de Santa Catarina, Center of Biological Sciences, Block D, Trindade, Florianópolis, Santa Catarina 88040-900, Brazil.
Exp Biol Med (Maywood). 2006 Jun;231(6):1146-51.
Endothelin (ET)-1 evokes a burning pruritus sensation when injected intradermally in humans and nocifensive behavior when injected into the hind paw of rodents. Because pain and pruritus are clearly distinct nociceptive sensory modalities in humans, the current study evaluates the potential of ET-1 to elicit scratching behavior in mice. Mice received an intradermal injection of 1-30 pmol ET-1; 10 microg of the mast cell degranulator compound, 48/80; 100 nmol histamine; or vehicle into the scruff, and the number of scratching bouts displayed during the first 40 mins was recorded. ET-1 caused dose-dependent scratching bouts, which, like the responses to histamine and compound 48/80, occurred mainly during the first 5 to 10 mins of injection, but fewer episodes were also seen up to 35 mins. The effect of ET-1 was maximal at 10 pmol (total 40 +/- 7 bouts), a value similar to that caused by histamine (52 +/- 5 bouts) and compound 48/80 (53 +/- 6 bouts). The selective ET(B) receptor agonist, IRL-1620 (10 pmol), was not pruritic per se, and actually inhibited responses to histamine and ET-1. Pruritus induced by ET-1 was inhibited by the ET(A) receptor antagonists, 10 nmol BQ-123 (co-injected; net inhibition, 87%) and 10 mg/kg atrasentan (intraperitoneal administration; net inhibition, 83%), or the ET(B) receptor antagonist, 20 mg/kg A-192621 (intraperitoneal administration; net inhibition, 64%), but the response was augmented by co-injection of the ET(B) receptor antagonist, 3 nmol BQ-788 (net potentiation, 234%). Responses to compound 48/80 or responsiveness of vehicle-treated mice were unaffected by these antagonists. Thus, ET-1 displays potent pruritic actions in the mouse mediated to a substantial extent via local ET(A) receptors. The findings with IRL-1620 and BQ-788 suggest that local ET(B) receptors exert an antipruritic role, but, for reasons still unknown, the results obtained using systemic A-192621 injection are at variance with this view.
内皮素（ET）-1皮内注射于人体时会引起灼烧样瘙痒感，注射到啮齿动物后爪时会引发伤害防御行为。由于疼痛和瘙痒在人类中是明显不同的伤害性感觉模式，因此本研究评估了ET-1在小鼠中引发抓挠行为的可能性。给小鼠皮内注射1 - 30皮摩尔的ET-1；10微克肥大细胞脱颗粒剂化合物48/80；100纳摩尔组胺；或赋形剂于颈背部，并记录最初40分钟内出现的抓挠发作次数。ET-1引起剂量依赖性抓挠发作，与对组胺和化合物48/80的反应一样，主要发生在注射后的最初5至10分钟，但在35分钟内也可见较少发作次数。ET-1在10皮摩尔时作用最强（总共40±7次发作），该值与组胺（52±5次发作）和化合物48/80（53±6次发作）引起的值相似。选择性ET(B)受体激动剂IRL-1620（10皮摩尔）本身无瘙痒作用，实际上还抑制对组胺和ET-1的反应。ET-1诱导的瘙痒被ET(A)受体拮抗剂10纳摩尔BQ-123（联合注射；净抑制率87%）和10毫克/千克阿曲生坦（腹腔给药；净抑制率83%），或ET(B)受体拮抗剂20毫克/千克A-192621（腹腔给药；净抑制率64%）抑制，但联合注射ET(B)受体拮抗剂3纳摩尔BQ-788会增强反应（净增强率234%）。对化合物48/80的反应或赋形剂处理小鼠的反应不受这些拮抗剂影响。因此，ET-1在小鼠中表现出强大的瘙痒作用，在很大程度上是通过局部ET(A)受体介导的。IRL-1620和BQ-788的研究结果表明局部ET(B)受体发挥抗瘙痒作用，但由于仍不清楚的原因，使用全身性A-192621注射获得的结果与这一观点不一致。
