Davis Randall L, Buck Daniel J, Saffarian Neda, Stevens Craig W
Department of Pharmacology/Physiology, Oklahoma State University Center for Health Sciences, 1111 W. 17th Street, Tulsa, Oklahoma 74107, USA.
J Neuroimmunol. 2007 May;186(1-2):141-9. doi: 10.1016/j.jneuroim.2007.03.021. Epub 2007 May 1.
Emerging evidence indicates that neuroinflammatory responses in astroglia, including chemokine expression, are altered by opioids. Astroglial chemokines, such as CXCL10, are instrumental in response to many neuropathological insults. Opioid mediated disruption of astroglial CXCL10 expression may be detrimental in opioid abusers or patients receiving acute opioid therapy. We have characterized the in vitro effects of opioids on CXCL10 protein expression in human astroglial (A172) cells. The proinflammatory cytokine, tumor necrosis factor (TNF)alpha induced CXCL10 expression in A172 cells. Using MG-132, helenalin and SN50 [inhibitors of the transcription factor, nuclear factor (NF)-kappaB], we determined that NF-kappaB activation is instrumental in TNFalpha-induced CXCL10 expression in A172 astroglia. Morphine exposure during the 24 h TNFalpha stimulation period did not alter CXCL10 expression. However, fentanyl, a more potent mu-opioid receptor (MOR) agonist, inhibited TNFalpha-induced CXCL10 expression. Interestingly, neither the non-selective opioid receptor antagonist, naltrexone nor beta-funaltrexamine (beta-FNA), a highly selective MOR antagonist, blocked fentanyl mediated inhibition of TNFalpha-induced CXCL10 expression. Rather, beta-FNA dose-dependently inhibited TNFalpha-induced CXCL10 expression with a greater potency than that observed for fentanyl. Immunoblot analysis indicated that morphine, fentanyl and beta-FNA each reduced TNFalpha-induced nuclear translocation of NF-kappaB p65. These data show that beta-FNA and fentanyl inhibit TNFalpha-induced CXCL10 expression via a MOR-independent mechanism. Data also suggest that inhibition of TNFalpha-induced CXCL10 expression by fentanyl and beta-FNA is not directly related to a reduction in NF-kappaB p65 nuclear translocation. Further investigation is necessary in order to fully elucidate the mechanism through which these two opioid compounds inhibit CXCL10 expression. Understanding the mechanism by which chemokine expression is suppressed, particularly by the opioid antagonist, beta-FNA, may provide insights into the development of safe and effective treatments for neuroinflammation.
新出现的证据表明，阿片类药物会改变星形胶质细胞中的神经炎症反应，包括趋化因子的表达。星形胶质细胞趋化因子，如CXCL10，在应对许多神经病理损伤中发挥作用。阿片类药物介导的星形胶质细胞CXCL10表达破坏，可能对阿片类药物滥用者或接受急性阿片类药物治疗的患者有害。我们已表征了阿片类药物对人星形胶质细胞（A172）中CXCL10蛋白表达的体外影响。促炎细胞因子肿瘤坏死因子（TNF）α诱导A172细胞中CXCL10表达。使用MG-132、海兔毒素和SN50[转录因子核因子（NF）-κB的抑制剂]，我们确定NF-κB激活在TNFα诱导的A172星形胶质细胞CXCL10表达中起作用。在24小时TNFα刺激期内暴露于吗啡不会改变CXCL10表达。然而，芬太尼，一种更强效的μ-阿片受体（MOR）激动剂，抑制TNFα诱导的CXCL10表达。有趣的是，非选择性阿片受体拮抗剂纳曲酮和β-氟纳曲胺（β-FNA），一种高选择性MOR拮抗剂，均未阻断芬太尼介导的对TNFα诱导的CXCL10表达的抑制。相反β-FNA剂量依赖性地抑制TNFα诱导的CXCL10表达，其效力比芬太尼观察到的更强。免疫印迹分析表明，吗啡、芬太尼和β-FNA均降低了TNFα诱导的NF-κB p65核转位。这些数据表明，β-FNA和芬太尼通过一种不依赖MOR的机制抑制TNFα诱导的CXCL10表达。数据还表明，芬太尼和β-FNA对TNFα诱导的CXCL10表达的抑制与NF-κB p65核转位减少没有直接关系。为了充分阐明这两种阿片类化合物抑制CXCL10表达的机制，有必要进行进一步研究。了解趋化因子表达被抑制的机制，特别是阿片受体拮抗剂β-FNA的抑制机制，可能为开发安全有效的神经炎症治疗方法提供见解。
