Piovezan A P, D'Orléans-Juste P, Souza G E, Rae G A
Department of Pharmacology, CCB, Universidade Federal de Santa Catarina, Rua Ferreira Lima 82, Florianópolis, 88015-420, Brazil.
Br J Pharmacol. 2000 Mar;129(5):961-8. doi: 10.1038/sj.bjp.0703154.
Endothelin-1 causes ET(A) receptor-mediated enhancement of capsaicin-induced nociception in mice. We have assessed if this hyperalgesic effect of endothelin-1 is also accompanied by other pro-inflammatory effects, namely nociception and oedema, and characterized the endothelin ET receptors involved. Intraplantar (i. pl.) hind-paw injection of endothelin-1 (0.3 - 30 pmol) induced graded nociceptive responses (accumulated licking time: vehicle, 20. 5+/-3.3 s; endothelin-1 at 30 pmol, 78.1+/-9.8 s), largely confined to the first 15 min. Endothelin-1 (1 - 10 pmol) potentiated ipsilateral capsaicin-induced (0.1 microgram, i.pl.; at 30 min) nociception (vehicle, 40.2+/-2.6 s; endothelin-1 at 10 pmol, 98.4+/-5.8 s, but 30 pmol was inactive), and caused oedema (increase in paw weight 5 min after capsaicin: vehicle, 46.3+/-2.3 mg; endothelin-1 at 30 pmol, 100.3+/-6.1 mg). Selective ET(B) receptor agonists sarafotoxin S6c (up to 30 pmol) and IRL 1620 (up to 100 pmol) were inactive, whereas endothelin-3 (up to 30 pmol) induced only modest oedema. ET(A) receptor antagonists BQ-123 (1 nmol, i.pl. ) or A-127722-5 (6 micromol kg(-1), i.v.) prevented all effects of endothelin-1 (10 pmol), but the ET(B) receptor antagonist BQ-788 (1 or 10 nmol, i.pl.) was ineffective. BQ-788 (10 nmol, i.pl.) unveiled hyperalgesic effects of 30 pmol endothelin-1 and endothelin-3. Sarafotoxin S6c (30 pmol, i.pl.) did not modify endothelin-1-induced (10 pmol) nociception or oedema, but abolished hyperalgesia. Thus, endothelin-1 triggers ET(A) receptor-mediated nociception, hyperalgesia and oedema in the mouse hind-paw. Simultaneous activation of ET(B) receptors by endothelin-1 or selective agonists can limit the hyperalgesic, but not the nociceptive or oedematogenic, effects of the peptide.
内皮素 -1 可引起小鼠体内内皮素 A（ET(A)）受体介导的辣椒素诱导的伤害感受增强。我们评估了内皮素 -1 的这种痛觉过敏效应是否还伴有其他促炎效应，即伤害感受和水肿，并对所涉及的内皮素 ET 受体进行了表征。足底（i.pl.）后爪注射内皮素 -1（0.3 - 30 pmol）可诱导分级伤害性反应（累积舔舐时间：溶剂对照组为 20.5±3.3 秒；30 pmol 内皮素 -1 组为 78.1±9.8 秒），主要局限于最初的 15 分钟。内皮素 -1（1 - 10 pmol）增强同侧辣椒素诱导的（0.1 微克，i.pl.；30 分钟时）伤害感受（溶剂对照组为 40.2±2.6 秒；10 pmol 内皮素 -1 组为 98.4±5.8 秒，但 30 pmol 时无活性），并引起水肿（辣椒素注射后 5 分钟爪重量增加：溶剂对照组为 46.3±2.3 毫克；30 pmol 内皮素 -1 组为 100.3±6.1 毫克）。选择性内皮素 B（ET(B)）受体激动剂沙拉沙星 S6c（高达 30 pmol）和 IRL 1620（高达 100 pmol）无活性，而内皮素 -3（高达 30 pmol）仅引起轻微水肿。ET(A)受体拮抗剂 BQ - 123（1 nmol，i.pl.）或 A - 127722 - 5（6 μmol kg⁻¹，i.v.）可预防内皮素 -1（10 pmol）的所有效应，但 ET(B)受体拮抗剂 BQ - 788（1 或 1０ nmol，i.pl.）无效。BQ - 788（10 nmol，i.pl.）揭示了 30 pmol 内皮素 -1 和内皮素 -3 的痛觉过敏效应。沙拉沙星 S6c（30 pmol，i.pl.）未改变内皮素 -1 诱导的（10 pmol）伤害感受或水肿，但消除了痛觉过敏。因此，内皮素 -1 在小鼠后爪引发 ET(A)受体介导的伤害感受、痛觉过敏和水肿。内皮素 -1 或选择性激动剂同时激活 ET(B)受体可限制该肽的痛觉过敏效应，但不能限制其伤害感受或致水肿效应。
