Stefano G B, Kushnerik V, Rodriquez M, Bilfinger T V
Multidisciplinary Center for the Study of Aging, State University of New York College at Old Westbury, NY 11568.
Int J Immunopharmacol. 1994 Apr;16(4):329-34. doi: 10.1016/0192-0561(94)90008-6.
We demonstrate that morphine, at higher concentrations than that effective in the inhibition of spontaneously active cells, can antagonize stimulation of human granulocytes by tumor necrosis factor (TNF) or substance P. The antagonistic effect appears to occur indirectly by way of downregulation of the cells' responsiveness to these stimulatory substances. We have previously shown that neutral endopeptidase 24.11 (NEP) is an important enzyme in neuro- and autoimmunoregulation of both vertebrates and invertebrates, and that activation of human granulocytes by monokines and neuropeptides results in regulation of NEP. Exposure of intact human granulocytes to morphine increases NEP by a naloxone-sensitive mechanism. The increased expression of NEP downregulates the stimulatory effect of substance P and TNF. In the case of substance P, we demonstrate the significance of NEP in modulating the process of downregulation by use of a specific NEP inhibitor, phosphoramidon. These results indicate that morphine is a significant factor in downregulating immunocyte responsiveness to NEP substrates and also to those signal molecules (i.e. cytokines) not metabolized by it. In summary, we infer that opiates may be endogenous signal molecules, a status that appears to be amply supported by their immunosuppressive actions.
我们证明，吗啡在高于抑制自发活动细胞的有效浓度时，能够拮抗肿瘤坏死因子（TNF）或P物质对人粒细胞的刺激作用。这种拮抗作用似乎是通过下调细胞对这些刺激物质的反应性间接发生的。我们先前已表明，中性内肽酶24.11（NEP）是脊椎动物和无脊椎动物神经及自身免疫调节中的一种重要酶，并且单因子和神经肽对人粒细胞的激活会导致NEP的调节。完整的人粒细胞暴露于吗啡会通过一种对纳洛酮敏感的机制增加NEP。NEP表达的增加会下调P物质和TNF的刺激作用。对于P物质，我们通过使用特异性NEP抑制剂磷酰胺脒证明了NEP在调节下调过程中的重要性。这些结果表明，吗啡是下调免疫细胞对NEP底物以及对那些不由其代谢的信号分子（即细胞因子）反应性的一个重要因素。总之，我们推断阿片类药物可能是内源性信号分子，它们的免疫抑制作用似乎充分支持了这一地位。
