Schäfer M, Carter L, Stein C
Behavioral Pharmacology and Genetics Section, National Institute on Drug Abuse, Baltimore, MD 21224.
Proc Natl Acad Sci U S A. 1994 May 10;91(10):4219-23. doi: 10.1073/pnas.91.10.4219.
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.
外源性阿片类激动剂的局部镇痛作用在疼痛性炎症状态下尤为突出，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，已在动物和人类炎症组织中的驻留免疫细胞中得到证实。在此，我们在体内和体外研究白细胞介素1β（IL-1）或促肾上腺皮质激素释放因子（CRF）是否能够释放这些内源性阿片类物质并抑制疼痛。当注入发炎的大鼠爪子（而非静脉注射）时，IL-1和CRF产生抗伤害感受作用，分别可被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。体内给予抗阿片肽抗体表明，IL-1和CRF的作用分别由β-内啡肽介导，此外，还分别由强啡肽A和[甲硫氨酸]脑啡肽介导。相应地，IL-1的作用被μ-、δ-和κ-阿片受体拮抗剂抑制，而CRF的作用除κ-拮抗剂外均被减弱。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激活其在免疫细胞上的受体以释放阿片类物质，这些阿片类物质随后占据感觉神经上的多种阿片受体并导致抗伤害感受。β-内啡肽、μ-和δ-阿片受体起主要作用，但IL-1和CRF似乎以不同方式释放其他阿片肽。
