Role of lipocortin-1 in the anti-hyperalgesic actions of dexamethasone
Role of lipocortin-1 in the anti-hyperalgesic actions of dexamethasone
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DOI：
10.1038/sj.bjp.0701211
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发表时间：
1997-07-01
影响因子：
7.3
通讯作者：
Poole, S
中科院分区：
文献类型：
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作者：
Ferreira, SH;Cunha, FQ;Poole, S
1地塞米松、脂皮质素-1（2-26）和脂皮质素-1（2-26）抗血清（LCPS 1）对角叉菜胶、缓激肽、肿瘤坏死因子α对大鼠痛敏活性的影响（TNF α），白细胞介素-1（2），白细胞介素-6（IL-6），白细胞介素-8（IL-8），前列腺素E β（PGE（2））和多巴胺在机械性痛觉过敏模型中进行了研究。注射角叉菜胶（100 μ g）、缓激肽（500 ng）、TNF α（2.5 pg）、IL-1 β（0.5 pg）和IL-6（1.0 ng），但对IL-8（0.1 ng）、PGE（2）（100 ng）和多巴胺（10 μ g）的反应不受地塞米松（0.5 mg/kg，皮下，s.c.，或0.04-5.0 μ g/爪）。3对注射（i.pl.）地塞米松（0.5 mg kg（-1），皮下注射）产生缓激肽（500 ng）和IL-1 β（0.5 pg）LCPS1（0.5 ml/kg，s.c.，24小时和1小时前痛觉过敏物质）和注射（i.pl.）用脂皮质素-1（2-26）（100 μ g/爪）预处理可抑制缓激肽（500 ng）、TNF α（2.5 pg）和IL-1 β（0.5 pg）的释放，但不抑制对PGE（2）（100 ng）的反应。此外，脂皮质素-1（2-26）（30和100 μ g ml（-1））和地塞米松（10 μ g ml（-1））抑制LPS（3 μ g ml（-1））刺激的J774（鼠巨噬细胞样）细胞系细胞的TNF α释放，LCPS 1部分逆转地塞米松的抑制作用。这些数据与内源性脂皮质素-1（2-26）在介导地塞米松的抗痛觉过敏作用中的重要作用一致，脂皮质素-1（2 - 26）对TNF α产生的抑制部分地促成了该作用。4尽管花生四烯酸本身不是痛觉过敏的，但对IL-1 β（0.25 pg，i.pl.）花生四烯酸（50 μ g）可增强该反应，地塞米松（50 μ g，i.pl.）和脂皮质素-1（2-26）（100 μ g，i.pl.）。此外，脂皮质素-1（2-26）（30和100 μ g ml（-1））抑制/消除LPS（3 μ g ml（-1））刺激的J774细胞释放PGE（2）。这些数据表明，在炎性痛觉过敏中，地塞米松和脂皮质素1（2-26）抑制环加氧酶2（考克斯-2）而不是磷脂酶A（2）的诱导是这些药物的抗痛觉过敏作用的原因。5上述数据支持地塞米松诱导脂皮质素在地塞米松抑制角叉菜胶诱发的炎性痛觉过敏中起主要作用的观点，缓激肽和细胞因子TNF α、IL-1 β和IL-6，并提供了脂皮质素的生物活性存在于肽脂皮质素-1中的额外证据（2-26）。此外，数据表明，脂皮质素-1（2-26）通过考克斯-2抑制类花生酸产生也有助于脂皮质素-1的抗痛觉过敏作用。
1 The effect of dexamethasone, lipocorton-1(2-26) and an antiserum to lipocortin-1(2-26) (LCPS1) upon the hyperalgesic activities in rats of carrageenin, bradykinin, tumour necrosis factor alpha (TNF alpha), interleukin-1(2), interleukin-6 (IL-6), interleukin-8 (IL-8), prostaglandin E beta (PGE(2)) and dopamine were investigated in a model of mechanical hyperalgesia.2 Hyperalgesic responses to intraplantar (i.pl.) injections of carrageenin (100 mu g), bradykinin (500 ng), TNF alpha (2.5 pg), IL-1 beta (0.5 pg), and IL-6 (1.0 ng), but not responses to IL-8 (0.1 ng), PGE(2) (100 ng) and dopamine (10 mu g), were inhibited by pretreatment with dexamethasone (0.5 mg kg(-1), subcutaneously, s.c., or 0.04-5.0 mu g/paw).3 Inhibition of hyperalgesic responses to injections (i.pl.) of bradykinin (500 ng) and IL-1 beta (0.5 pg) by dexamethasone (0.5 mg kg(-1), s.c.) was reversed by LCPS1 (0.5 ml kg(-1), injected s.c., 24 h and 1 h before hyperalgesic substances) and hyperalgesic responses to injections (i.pl.) of bradykinin (500 ng), TNF alpha (2.5 pg) and IL-1 beta (0.5 pg), but not responses to PGE(2) (100 ng), were inhibited by pretreatment with lipocortin-1(2-26) (100 mu g/paw). Also, lipocortin-1(2-26) (30 and 100 mu g ml(-1)) and dexamethasone (10 mu g ml(-1)) inhibited TNF alpha release by cells of the J774 (murine macrophage-like) cell-line stimulated with LPS (3 mu g ml(-1)), and LCPS1 partially reversed the inhibition by dexamethasone. These data are consistent with an important role for endogenous lipocortin-1(2-26) in mediating the anti-hyperalgesic effect of dexamethasone, with inhibiton of TNF alpha production by lipocortin-1(2-26) contributing, in part, to this role.4 Although arachidonic acid by itself was not hyperalgesic, the hyperalgesic response to IL-1 beta (0.25 pg, i.pl.) was potentiated by arachidonic acid (50 mu g) and the potentiated response was inhibited by dexamethasone (50 mu g, i.pl.) and lipocortin-1(2-26) (100 mu g, i.pl.). Also, lipocortin-1(2-26) (30 and 100 mu g ml(-1)) inhibited/abolished PGE(2) release by J774 cells stimulated with LPS (3 mu g ml(-1)). These data suggest that, in inflammatory hyperalgesia, inhibition of the induction of cyclo-oxygenase 2 (COX-2), rather than phospholipase A(2), by dexamethasone and lipocortin1(2-26) accounts for the antihyperalgesic effects of these agents.5 The above data support the notion that induction of lipocortin by dexamethasone plays a major role in the inhibition by dexamethasone of inflammatory hyperalgesia evoked by carrageenin, bradykinin and the cytokines TNF alpha, IL-1 beta and IL-6, and provides additional evidence that the biological activity of lipocortin resides within the peptide lipocortin-1(2-26). Further, the data suggest that inhibition of lipocortin-1(2-26) of eicosanoid production by COX-2 also contributes to the anti-hyperalgesic effect of lipocortin-1.