INTERLEUKIN-1-BETA AND CORTICOTROPIN-RELEASING FACTOR INHIBIT PAIN BY RELEASING OPIOIDS FROM IMMUNE CELLS IN INFLAMED TISSUE
INTERLEUKIN-1-BETA AND CORTICOTROPIN-RELEASING FACTOR INHIBIT PAIN BY RELEASING OPIOIDS FROM IMMUNE CELLS IN INFLAMED TISSUE
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DOI：
10.1073/pnas.91.10.4219
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发表时间：
1994-05-10
影响因子：
11.1
通讯作者：
STEIN, C
中科院分区：
文献类型：
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作者：
SCHAFER, M;CARTER, L;STEIN, C
外源性阿片激动剂的局部镇痛作用在疼痛性炎症条件下特别突出，并且由外周感觉神经上的阿片受体介导。这些受体的内源性配体，阿片肽，已被证明在动物和人类的发炎组织内的常驻免疫细胞。在这里，我们研究在体内和体外是否白细胞介素1 β（IL-1）或促肾上腺皮质激素释放因子（CRF）能够释放这些内源性阿片类药物和抑制疼痛。当注射到发炎的大鼠爪（但不是静脉注射）时，IL-1和CRF产生抗伤害感受，这分别被IL-1受体拮抗剂和α-螺旋CRF以及免疫抑制剂环孢素A逆转。体内施用抗阿片肽的抗体表明IL-1和CRF的作用分别由β-内啡肽介导，此外还由强啡肽A和[Met]脑啡肽介导。相应地，IL-1的作用被μ-、δ-和κ-阿片样物质拮抗剂抑制，而CRF的作用被除κ-拮抗剂之外的所有拮抗剂减弱。最后，IL-1和CRF在从发炎淋巴结新鲜制备的细胞悬液中产生免疫反应性β-内啡肽的急性释放。这种作用分别可被IL-1受体拮抗剂和α-螺旋CRF逆转。这些发现表明IL-1和CRF激活免疫细胞上的受体以释放阿片类物质，随后占据感觉神经上的多个阿片类受体并导致抗伤害感受。β-内啡肽、μ-和δ-阿片样物质受体起主要作用，但IL-1和CRF似乎差异性地释放额外的阿片样物质肽。
Local analgesic effects of exogenous opioid agonists are particularly prominent in painful inflammatory conditions and are mediated by opioid receptors on peripheral sensory nerves. The endogenous ligands of these receptors, opioid peptides, have been demonstrated in resident immune cells within inflamed tissue of animals and humans. Here we examine in vivo and in vitro whether interleukin 1 beta (IL-1) or corticotropin-releasing factor (CRF) is capable of releasing these endogenous opioids and inhibiting pain. When injected into inflamed rat paws (but not intravenously), IL-1 and CRF produce antinociception, which is reversible by IL-1 receptor antagonist and alpha-helical CRF, respectively, and by the immunosuppressant cyclosporine A. In vivo administration of antibodies against opioid peptides indicates that the effects of IL-1 and CRF are mediated by beta-endorphin and, in addition, by dynorphin A and [Met]enkephalin, respectively. Correspondingly, IL-1 effects are inhibited by mu-, delta-, and kappa-opioid antagonists, whereas CRF effects are attenuated by all except a kappa-antagonist. Finally, IL-1 and CRF produce acute release of immunoreactive beta-endorphin in cell suspensions freshly prepared from inflamed lymph nodes. This effect is reversible by IL-1 receptor antagonist and alpha-helical CRF, respectively. These findings suggest that IL-1 and CRF activate their receptors on immune cells to release opioids that subsequently occupy multiple opioid receptors on sensory nerves and result in antinociception. beta-Endorphin, mu- and delta-opioid receptors play a major role, but IL-1 and CRF appear to differentially release additional opioid peptides.