Interleukin-18 induces mechanical hypernociception in rats via endothelin acting on ETB receptors in a morphine-sensitive manner
Interleukin-18 induces mechanical hypernociception in rats via endothelin acting on ETB receptors in a morphine-sensitive manner
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DOI：
10.1124/jpet.103.063990
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发表时间：
2004-08-01
影响因子：
3.5
通讯作者：
Cunha, FQ
中科院分区：
文献类型：
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作者：
Verri, WA;Schivo, IRS;Cunha, FQ
白细胞介素18(IL-18)在关节炎的发病机制中起着重要作用，关节炎继发于炎症性关节伤害性感觉而伴有运动受限。因此，我们采用大鼠足爪恒压实验和电子压力计实验，研究了IL-18对大鼠机械伤害性反应的可能作用。在这两个实验中，足底注射IL-18(20-60 ng PAW(-1))引起剂量和时间依赖的机械性痛觉过敏，在注射后3h达到峰值，并在24h达到对照水平。预先给予吲哚美辛(2.5 mg kg(-1))、阿替洛尔(1 mg kg(-1))或3-[1-(p-chlorobenzyl)-5-(isopropyl)-3-t-butylthioindol-2-yl]-2；2-dimethylpropanoic酸(5-脂氧合酶激活蛋白抑制剂MK886，1 mg kg(-1))不能抑制IL-18诱发的过敏性痛觉(40 ng PAW(-1))，而地塞米松(2 mg kg(-1))可抑制这一过程。大鼠肿瘤坏死因子-α(50 mU PAW(-1))或IL-1受体拮抗剂(300 pg PAW(-1))抗血清不能抑制IL-18诱发的过敏性伤害性反应。预先给予N-半胱氨酸-2，6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D-1-methoxycarboyl-D-norleucine(BQ788)(ETB受体拮抗剂，3-30nmolpaw(-1))可剂量依赖性地抑制IL-18诱导的过敏性伤害性感受。吗啡(3-12杯爪(-1))可剂量依赖性地抑制IL-18诱导的过敏性伤害性感受。此外，BQ788也能抑制内皮素-1诱导的机械性伤害性感觉，但BQ123、吲哚美辛或阿替洛尔不能。综上所述，我们首次证明了IL-18是一种前伤害性细胞因子，可通过ETB受体诱导内皮素介导的机械性伤害性感觉。因此，抑制内皮素ETB受体可能有助于控制炎症过度伤害性感觉，而IL-18在其发病机制中起着重要作用。
Interleukin (IL)-18 has an important role in the pathogenesis of arthritis, which is accompanied by movement limitation secondary to inflammatory articular nociception. Therefore, we investigated the possible mechanical hypernociceptive effect of IL-18 in rats using the paw constant pressure and the electronic pressure-meter tests. In both tests, intraplantar administration of IL-18 (20-60 ng paw(-1)) caused a dose- and time-dependent mechanical hypernociception, which peaked 3 h and reached control levels 24 h after injection. Pretreatments with indomethacin (2.5 mg kg(-1)), atenolol (1 mg kg(-1)), or 3-[1-(p-chlorobenzyl)-5-(isopropyl)-3-t-butylthioindol-2-yl]-2;2-dimethylpropanoic acid; Na (MK886) (5-lipoxygenase-activating protein inhibitor; 1 mg kg(-1)) did not inhibit IL-18-evoked hypernociception (40 ng paw(-1)), whereas dexamethasone (2 mg kg(-1)) inhibited the process. IL-18-evoked hypernociception was not inhibited by pretreatment with antiserum to rat tumor necrosis factor-alpha (50 mul paw(-1)) or IL-1 receptor antagonist (300 pg paw(-1)). Pretreatment with N-cys-2,6 dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D-1-methoxycarboyl-D-norleucine (BQ788) (ETB receptor antagonist; 3-30 nmol paw(-1)), but not with cyclo[(D)Trp-(D)Asp-Pro-(D)Val-Leu] (BQ123) (ETA receptor antagonist; 30 nmol paw(-1)), dose dependently inhibited the IL-18-induced hypernociception. Pretreatment with morphine (3-12 mug paw(-1)) also dose-dependently inhibited the IL-18-induced hypernociception. Moreover, endothelin-1-induced mechanical hypernociception also was inhibited by BQ788, but not by BQ123, indomethacin, or atenolol. In conclusion, we demonstrated for the first time that IL-18 is a prohypernociceptive cytokine that induces mechanical hypernociception mediated by endothelin, via ETB receptor. Therefore, inhibition of the endothelin ETB receptor could be beneficial on controlling inflammatory hypernociception of diseases in which IL-18 plays a role in their pathogenesis.