Role of opioids for the microglial activation

许多证据表明中枢神经系统(CNS)与免疫系统之间存在相互作用。小胶质细胞在中枢神经系统中发挥着重要的免疫功能，是阐明其功能及其与星形胶质细胞相互作用的重要途径。我们研究了不同的阿片类药物和其他化合物对内毒素诱导的小胶质细胞和星形胶质细胞产生NO的影响。阿片类药物的作用因细胞制剂的不同而不同，提示内源性阿片类药物可释放到培养基中，其程度因细胞培养条件的不同而不同。我们观察了阿片类拮抗剂纳洛酮的作用。纳洛酮呈剂量依赖性抑制小胶质细胞NO的生成，但不抑制星形胶质细胞的NO生成。甲硫氨酸脑啡肽和β-内啡肽均能显著逆转这种抑制作用。在所考察的其他化合物中，膜通透性类似物二丁酰环磷酸腺苷和黄嘌呤类似物普罗托菲林具有非常有趣的作用。它们对内毒素诱导的NO和IL-6的产生几乎没有影响，但对内毒素诱导的肿瘤坏死因子-α和IL-1β的产生有强烈的抑制作用。对细胞因子产生的不同抑制表明，对小胶质细胞激活的控制可能保护神经元损伤。进一步的研究可能会为治疗神经退行性中枢性疾病提供有益的工具。

There are many evidences indicating the interaction between central nervous system (CNS) and immune system. Microglia play major roles of immunological function in CNS and it is a very important approaches to elucidate their function including the interaction to astrocytes. We examined the effects of various opioids and the other compounds on the LPS-induced NO production from cultured microglia and astrocytes. The effect of opioids varied from cell preparations to preparations suggesting that endogenous opioids may be released into culture media and its extent varies under cell culture conditions. We examined the effect of naloxone, an opioid antagonist. Naloxone inhibited dose-dependently NO production from microglia but not from astrocytes. The inhibition was reversed by Met-enkephalin remarkably and β-endorphin slightly.Among the other compounds examined, very interesting effects were observed in dibutyryl-cAMP, a membrane permeable analog, and propentofilline, a xanthine analoge. They showed almost no effect on LPS-induced production of NO and IL-6 ; however, they strongly inhibited LPS-induced production of TNF-α and IL-1β. The differential inhibition of cytokines production suggests that a possible control of microglial activation protects neuronal damage. Further investigation may provide a beneficial tool against neurodegenerative central diseases.