核因子-κB对神经病理性疼痛及其脊髓免疫炎症因子表达的调节
摘要
目的1.观察鞘内注射核转录因子-κB(nuclear factor-kappaB,NF-κB)抑制剂吡咯烷二硫氨基甲酸(PDTC)对坐骨神经慢性挤压伤(chronic constriction injury,CCI)大鼠痛阈和脊髓NF-κBp-p65、小胶质细胞活性、CX3CR1、p-p38MAPK、TNFα表达的影响。2.观察NF-κB抑制剂吡咯烷二硫氨基甲酸(PDTC)对体外TNFα诱导的BV-2细胞CX3CR1基因和蛋白表达的影响。3.观察鞘内注射白藜芦醇(Resveratrol,Res)对坐骨神经慢性挤压伤(CCI)大鼠痛阈和脊髓NF-κB-p65、小胶质细胞活性、CX3CR1、TNFα表达的调节,并探讨其对临床疼痛治疗的机制。方法1.288只成年雄性SD大鼠,体质量250～300 g,鞘内置管成功后,随机分8组(n=36):正常对照组:实验大鼠不做任何处置;假手术组:仅暴露左侧坐骨神经不结扎;假手术+PDTC组:假手术处理大鼠并经鞘内置管注入PDTC1000pmol/d;CCI组:大鼠CCI手术处理;CCI+PDTC组1:CCI处理大鼠分为2个亚组,分别在CCI术前1天和CCI第3天开始经鞘内置管注入PDTC100pmol/d;CCI+PDTC组2:CCI处理大鼠分为2个亚组,分别在术前1天和CCI第3天开始鞘内注入PDTC1000pmol/d;假手术+盐水组:假手术处理大鼠并鞘内注入生理盐水;CCI+盐水组:CCI术处理大鼠并经鞘内注入生理盐水。鞘内置管5 d后按每组处理不同,开始鞘内输注生理盐水和不同剂量的PDTC,鞘内注射1 d后分别建立大鼠CCI神经病理性疼痛模型和假手术模型,测定大鼠的痛敏值,并在鞘内注射4d后取脊髓腰膨大部进行免疫组化测定NF-κBp-p65、OX42、TNFα表达、Western Blot检测CX3CR1、p-p38MAPK蛋白表达、RT-PCR检测CX3CR1mRNA的表达、并且进行脊髓切片HE染色。2.采用体外培养的永生态小胶质细胞BV-2细胞,设立对照组和实验组,实验组经TNFα(20ng/ml)、TNFα+PDTC、PDTC孵育,于10min,20min,40min,60min,2h,3h,4h,6h,8h采用MTT方法和倒置显微镜分别测定小胶质细胞的生长率及形态改变,免疫细胞化学测定NF-κBp-p65表达,Western blot和RT-PCR检测CX3CR1蛋白和mRNA表达情况。3.252只成年雄性SD大鼠,体质量250～300 g,鞘内置管成功后,随机分7组(n=36):正常对照组:实验大鼠不做任何处置;假手术组:仅暴露左侧坐骨神经不结扎;假手术+Res组:假手术处理大鼠经鞘内置管注入Res;CCI组;CCI+Res组:大鼠分为2个亚组,分别在CCI术前1天和CCI第3天开始经鞘内置管注入Res500ug/d;假手术+盐水组:假手术处理大鼠并鞘内注入生理盐水;CCI+盐水组:CCI术处理大鼠并经鞘内注入生理盐水。按各组处理,鞘内置管5d后开始分别鞘内输注生理盐水和Res,鞘内注射1d后分别建立大鼠CCI神经病理性疼痛模型和假手术模型,测定大鼠的痛敏值,并在鞘内注射4 d后取脊髓腰膨大部进行免疫组化测定NF-κBp-p65、OX42、TNFα表达、Western Blot检测CX3CR1蛋白表达、并进行脊髓切片HE染色。结果1.CCI组与sham组比较大鼠术后各时点痛敏阈值明显下降,并在术后第3日降至最低点(P＜0.05),脊髓CX3CR1、p-p38MAPK、p-p65、OX42、YNFα的表达明显升高(P＜0.05)。PDTC+CCI组与CCI组比较,术后各时点大鼠痛敏阈值增高,脊髓CX3CR1、p-p38MAPK、p-p65、OX42、TNFα的表达下降(P＜0.05)。HE染色假手术+PDTC组与假手术+盐水组比较,未见明显脊髓组织病理损伤。2.TNFα刺激后BV-2细胞形态突起增粗;刺激20 min内NF-κBp-p65核表达细胞显著增多(P＜0.05),1 h达高峰,TNFα诱导的CX3CR1蛋白和mRNA表达分别于4h和2h达到高峰,PDTC(100μmol/l)可抑制TNFα诱导的NF-κBp-p65核表达,明显降低了TNFα诱导的CX3CR1蛋白和mRNA表达。3.CCI组与sham组比较大鼠术后各时点痛敏阈值明显下降,并在术后第3日降至最低点(P＜0.05),脊髓CX3CR1、p-p65、OX42、TNFα的表达明显升高(P＜0.05)。Res+CCI组与CCI组比较,术后各时点大鼠痛敏阈值增高,脊髓CX3CR1、p-p65、OX42、TNFα的表达下降(P＜0.05)。HE染色假手术+Res组与假手术+盐水组比较,未见明显脊髓组织病理损伤。结论1.鞘内给予PDTC可剂量依赖性地减轻CCI大鼠的病理性疼痛,并抑制脊髓CX3CR1、p-p38MAPK、p-p65、TNFα的表达和小胶质细胞活性。活化NF-κB通路可能通过上调脊髓CX3CR1、p-p38MAPK、TNFα的表达和小胶质细胞活性而参与了神经病理性疼痛的发生。2.TNFα可激活BV-2细胞NF-κB通路,改变细胞形态,使细胞体积增大突起增粗,增加细胞CX3CR1蛋白和mRNA表达,其激活的细胞内机制可能与核因子-κB的活化有关。3.鞘内给予Res可减轻CCI大鼠的病理性疼痛,并抑制脊髓CX3CR1、p-p65、TNFα的表达和小胶质细胞活性,这可能成为Res止痛作用的机制之一。
Objectives:1.To examine the effects of intrathecal nuclear factor-kappaB(NF-κB) inhibitor,pyrrolidine dithiocarbamate(PDTC),on the development of neuropathic pain,spinal microglial activation and spinal NF-κBp-p65、CX3CR1、p-p38MAPK、tumor necrosis factor(TNF)αexpression induced by sciatic chronic constriction injury(CCI) in rats. 2.To examine the effects of NF-κB inhibitor PDTC on TNFα-induced CX3CR1 expression in BV-2 microglial cells.3.To examine the effects of intrathecal resveratrol(Res) on the development of neuropathic pain, spinal microglial activation and spinal NF-κBp-p65、CX3CR1、TNFαexpression induced by sciatic CCI in rats,and investigate the therapeutic potential of Res in neuropathic pain.Methods 1.288 male Sprague-Dawley(SD) rats(250～300 g) fitted with intrathecal(i.t.) catheters,underwent surgery.Randomly,rats were divided into 8 groups (n=36):normal control group:rats didn't undergo any surgery;sham group:rats underwent surgery of exposing sciatic nerve without ligation; sham+PDTC group:rats undergoing sham surgery were intrathecally administrated PDTC(1000pmol/d);CCI group:rats underwent sciatic CCI surgery;CCI+PDTC group 1:Rats were divided into 2 subgroups, and intrathecal PDTC(100pmol/d) was infused 1 day before and 3 days after sciatic CCI respectively;CCI+PDTC group 2:Rats were divided into 2 subgroups,and intrathecal PDTC(1000pmol/d) was infused 1 day before and 3 days after sciatic CCI respectively;sham+saline group: Intrathecal normal saline(NS) was infused 1 day before and 3 days after sham surgery respectively;CCI+saline group:Intrathecal NS was infused 1 day before and 3 days after sciatic CCI,respectively.5 days after intrathecal catheters implantation,rats were administrated various intrathecal medicine.And 1 day after administration,rats experiented CCI and sham surgery,respectively.The rat hind paw withdrawal threshold(WT) to mechanical stimuli and withdrawal latency(WL) to radiant heat were determined before surgery and from day 1 to 7 following CCI.4 days after administration,the spinal cord around lumbar enlargement was removed.Spinal microglial activation was evaluated with OX-42 immunoreactivity and spinal NF-κBp-p65、TNFαexpression were determined by immunohistochemisty,spinal CX3CR1、p-p38MAPK expression were assessed by western blotting,spinal CX3CR1 mRNA expression was assessed by reverse transcriptase polymerase chain reation(RT-PCR),and spinal cord sections were also stained with hematoxylin and eosin(HE).2.BV-2 microglial cells were cultured in vitro.For experiments,cells were treated with TNFα(20ng/ml) as the experimental group,TNFα(20ng/ml) and PDTC(100μmol/l) as TNFα+PDTC group,PDTC(100μmol/l) as PDTC group,and serum-free medium as the control group.At the time point of 10min,20min,40min, 60min,2h,3h,4h,6h,8h after treatment,we used MTT,the inverted microscope,RT-PCR,immunocytochemistry and western blotting to assess cell viability,morphology changes,NF-κBp-p65 protein expression、CX3CR1 protein and mRNA expression.3.252 male Sprague-Dawley(SD) rats(250～300 g) fitted with intrathecal catheters, underwent surgery.Randomly,rats were divided into 7 groups(n=36): normal control group:rats didn't undergo any surgery;sham group:rats underwent surgery of exposing sciatic nerve without ligation;sham+Res group:rats with sham surgery were intrathecally administrated Res (500ug/d);CCI group:rats underwent sciatic CCI surgery;CCI+Res group:Rats were divided into 2 subgroups and intrathecal Res(500ug/d) was infused 1 day before and 3 days after sciatic CCI respectively; sham+saline group:Intrathecal normal saline(NS) was infused 1 day before and 3 days after sham surgery,respectively;CCI+saline group: Rats were divided into 2 subgroups and intrathecal NS was infused 1 day before and 3 days after sciatic CCI respectively.5 days after intrathecal catheters implantation,rats were administrated various intrathecal medicine.And 1 day after administration,rats experiented sciatic CCI and sham surgery according to groups arrangement.The rat hind paw withdrawal threshold to mechanical stimuli and withdrawal latency to radiant heat were determined before surgery and from day 1 to 7 following CCI.4 days after administration,the spinal cord around lumbar enlargement was removed.Spinal microglial activation was evaluated with OX-42 immunoreactivity and spinal NF-κBp-p65、TNFαexpression were determined by immunohistochemisty,spinal CX3CR1 expression was assessed by western blotting and spinal cord sections were also stained with hematoxylin and eosin.Results 1.Compared with sham group,a significant decrease in WT and WL was observed after surgery in CCI group,and the lowest point was 3 days after surgery(P＜0.05), spinal CX3CR1、p-p38MAPK、p-p65、OX42、TNFαexpression were significantly increased(P＜0.05).The WTs and WLs of PDTC+CCI group were significantly increased compared with CCI group,spinal CX3CR1、p-p38MAPK、p-p65、OX42,TNFαexpression were significantly decreased(P＜0.05).HE staining didn't show obvious spinal histopathologic change in sham+Res group compard with sham+NS group.2.TNFα-stimulated BV-2 cells showed a thicker process,and a significant increase of NF-κBp-p65 expression in cell nuclear within 20 min(P＜0.05),peaked at 1 h.TNFα-induced CX3CR1 protein and mRNA expression increased significantly,peaked at 4h and 2h after treatment, and PDTC(100μmol/l) suppressed TNFα-induced NF-κBp-p65 expression,significantly downregulated TNFα-induced CX3CR1 protein and mRNA expression.3.Compared with sham group,a significant decrease in WT and WL was observed after surgery in CCI group,and the lowest point was 3 days after surgery(P＜0.05),spinal CX3CR1、p-p65、OX42、TNFαexpression were significantly increased(P＜0.05).The WTs and WLs of Res+CCI group were significantly increased compared with CCI group,spinal CX3CR1、p-p65、OX42、TNFαexpression were significantly decreased(P＜0.05).HE staining didn't show obvious spinal histopathologic change in sham+Res group compard with sham+NS group.Conclusions:1.Intrathecal PDTC attenuated the CCI-induced neuropathic pain in rats,and suppressed spinal CX3CR1、p-p38MAPK、p-p65、TNFαexpression and microglial activation.And the activation of NF-κB pathway may contribute to spinal CX3CR1、p-p38MAPK、TNFαupregulation and microglial activation in neuropathic pain.2.TNFαrapidly activated the NF-κB pathway,changed the morphology of cells and upregulated CX3CR1 protein and mRNA expression in BV-2 microglial cells.And the morphological changes and upregulation of CX3CR1 expression may be mediated by NF-κB pathway.3.Inthathecal Res attenuated the CCI-induced neuropathic pain in rats,and suppressed spinal CX3CR1、p-p65、TNFαexpression and microglial activation.The regulation of spinal neuroinflammation may contribute to therapeutic potential of Res in neuropathic pain.
Objectives:1.To examine the effects of intrathecal nuclear factor-kappaB(NF-κB) inhibitor,pyrrolidine dithiocarbamate(PDTC),on the development of neuropathic pain,spinal microglial activation and spinal NF-κBp-p65、CX3CR1、p-p38MAPK、tumor necrosis factor(TNF)αexpression induced by sciatic chronic constriction injury(CCI) in rats. 2.To examine the effects of NF-κB inhibitor PDTC on TNFα-induced CX3CR1 expression in BV-2 microglial cells.3.To examine the effects of intrathecal resveratrol(Res) on the development of neuropathic pain, spinal microglial activation and spinal NF-κBp-p65、CX3CR1、TNFαexpression induced by sciatic CCI in rats,and investigate the therapeutic potential of Res in neuropathic pain.Methods 1.288 male Sprague-Dawley(SD) rats(250～300 g) fitted with intrathecal(i.t.) catheters,underwent surgery.Randomly,rats were divided into 8 groups (n=36):normal control group:rats didn't undergo any surgery;sham group:rats underwent surgery of exposing sciatic nerve without ligation; sham+PDTC group:rats undergoing sham surgery were intrathecally administrated PDTC(1000pmol/d);CCI group:rats underwent sciatic CCI surgery;CCI+PDTC group 1:Rats were divided into 2 subgroups, and intrathecal PDTC(100pmol/d) was infused 1 day before and 3 days after sciatic CCI respectively;CCI+PDTC group 2:Rats were divided into 2 subgroups,and intrathecal PDTC(1000pmol/d) was infused 1 day before and 3 days after sciatic CCI respectively;sham+saline group: Intrathecal normal saline(NS) was infused 1 day before and 3 days after sham surgery respectively;CCI+saline group:Intrathecal NS was infused 1 day before and 3 days after sciatic CCI,respectively.5 days after intrathecal catheters implantation,rats were administrated various intrathecal medicine.And 1 day after administration,rats experiented CCI and sham surgery,respectively.The rat hind paw withdrawal threshold(WT) to mechanical stimuli and withdrawal latency(WL) to radiant heat were determined before surgery and from day 1 to 7 following CCI.4 days after administration,the spinal cord around lumbar enlargement was removed.Spinal microglial activation was evaluated with OX-42 immunoreactivity and spinal NF-κBp-p65、TNFαexpression were determined by immunohistochemisty,spinal CX3CR1、p-p38MAPK expression were assessed by western blotting,spinal CX3CR1 mRNA expression was assessed by reverse transcriptase polymerase chain reation(RT-PCR),and spinal cord sections were also stained with hematoxylin and eosin(HE).2.BV-2 microglial cells were cultured in vitro.For experiments,cells were treated with TNFα(20ng/ml) as the experimental group,TNFα(20ng/ml) and PDTC(100μmol/l) as TNFα+PDTC group,PDTC(100μmol/l) as PDTC group,and serum-free medium as the control group.At the time point of 10min,20min,40min, 60min,2h,3h,4h,6h,8h after treatment,we used MTT,the inverted microscope,RT-PCR,immunocytochemistry and western blotting to assess cell viability,morphology changes,NF-κBp-p65 protein expression、CX3CR1 protein and mRNA expression.3.252 male Sprague-Dawley(SD) rats(250～300 g) fitted with intrathecal catheters, underwent surgery.Randomly,rats were divided into 7 groups(n=36): normal control group:rats didn't undergo any surgery;sham group:rats underwent surgery of exposing sciatic nerve without ligation;sham+Res group:rats with sham surgery were intrathecally administrated Res (500ug/d);CCI group:rats underwent sciatic CCI surgery;CCI+Res group:Rats were divided into 2 subgroups and intrathecal Res(500ug/d) was infused 1 day before and 3 days after sciatic CCI respectively; sham+saline group:Intrathecal normal saline(NS) was infused 1 day before and 3 days after sham surgery,respectively;CCI+saline group: Rats were divided into 2 subgroups and intrathecal NS was infused 1 day before and 3 days after sciatic CCI respectively.5 days after intrathecal catheters implantation,rats were administrated various intrathecal medicine.And 1 day after administration,rats experiented sciatic CCI and sham surgery according to groups arrangement.The rat hind paw withdrawal threshold to mechanical stimuli and withdrawal latency to radiant heat were determined before surgery and from day 1 to 7 following CCI.4 days after administration,the spinal cord around lumbar enlargement was removed.Spinal microglial activation was evaluated with OX-42 immunoreactivity and spinal NF-κBp-p65、TNFαexpression were determined by immunohistochemisty,spinal CX3CR1 expression was assessed by western blotting and spinal cord sections were also stained with hematoxylin and eosin.Results 1.Compared with sham group,a significant decrease in WT and WL was observed after surgery in CCI group,and the lowest point was 3 days after surgery(P＜0.05), spinal CX3CR1、p-p38MAPK、p-p65、OX42、TNFαexpression were significantly increased(P＜0.05).The WTs and WLs of PDTC+CCI group were significantly increased compared with CCI group,spinal CX3CR1、p-p38MAPK、p-p65、OX42,TNFαexpression were significantly decreased(P＜0.05).HE staining didn't show obvious spinal histopathologic change in sham+Res group compard with sham+NS group.2.TNFα-stimulated BV-2 cells showed a thicker process,and a significant increase of NF-κBp-p65 expression in cell nuclear within 20 min(P＜0.05),peaked at 1 h.TNFα-induced CX3CR1 protein and mRNA expression increased significantly,peaked at 4h and 2h after treatment, and PDTC(100μmol/l) suppressed TNFα-induced NF-κBp-p65 expression,significantly downregulated TNFα-induced CX3CR1 protein and mRNA expression.3.Compared with sham group,a significant decrease in WT and WL was observed after surgery in CCI group,and the lowest point was 3 days after surgery(P＜0.05),spinal CX3CR1、p-p65、OX42、TNFαexpression were significantly increased(P＜0.05).The WTs and WLs of Res+CCI group were significantly increased compared with CCI group,spinal CX3CR1、p-p65、OX42、TNFαexpression were significantly decreased(P＜0.05).HE staining didn't show obvious spinal histopathologic change in sham+Res group compard with sham+NS group.Conclusions:1.Intrathecal PDTC attenuated the CCI-induced neuropathic pain in rats,and suppressed spinal CX3CR1、p-p38MAPK、p-p65、TNFαexpression and microglial activation.And the activation of NF-κB pathway may contribute to spinal CX3CR1、p-p38MAPK、TNFαupregulation and microglial activation in neuropathic pain.2.TNFαrapidly activated the NF-κB pathway,changed the morphology of cells and upregulated CX3CR1 protein and mRNA expression in BV-2 microglial cells.And the morphological changes and upregulation of CX3CR1 expression may be mediated by NF-κB pathway.3.Inthathecal Res attenuated the CCI-induced neuropathic pain in rats,and suppressed spinal CX3CR1、p-p65、TNFαexpression and microglial activation.The regulation of spinal neuroinflammation may contribute to therapeutic potential of Res in neuropathic pain.
引文
[1] DeLeo, JA, Sorkin LS, Watkins LR. (Eds.) Immune and glial regulation of pain. 2007 ;IASP Press, Seattle.
[2] Ledeboer A, Gamanos M, Lai W, et al.Involvement of spinal cord nuclear factor kB activation in rat models of proinflammatory cytokine-mediated pain facilitation. Eur J Neurosci 2005; 22:1977-1986.
[3] Wu LC, Goettl VM, Madiai F, et al.Reciprocal regulation of nuclear factor kappa B and its inhibitor ZAS3 after peripheral nerve injury. BMC Neurosci,2006,7:4.
[4] Laughlin TM, Bethea JR, Yezierski RP, et al. Cytokine involvement in dynorphin-induced allodynia. Pain 2000; 84:159-167.
[5] O'Rielly DD, Loomis CW. Spinal nerve ligation-induced activation of nuckear factor kappaB is facilitated by prostaglandins in the affected spinal cord and is a critical step in the development of mechanical allodynia. Neuroscience 2008;155: 902-913.
[6] Xiao HS, Huang QH, Zhang FX, et al. Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain. PNAS 2002; 99:8360-8365.
[7] Valder CR, Liu JJ, Song YH, et al. Coupling gene chip analyses and rat genetic variances in identifying potential target genes that may contribute to neuropathic allodynia development. J Neurochem 2003 ; 87:560-573.[8]
[8] Manning DC. New and emerging pharmacological targets for neuropathic pain. Curr Pain Headache Rep 2004 ; 8:192-198.
[9] Sommer C, Kress M. Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci Lett 2004 ; 361:184-187.
[10]Hiscott J, Marois J, Garoufalis J, et al. Characterization of a functional NF-kappa B site in the human interleukin 1 beta promoter: evidence for a positive autoregulatory loop. Mol Cell Biol 1993 ; 13:6231-6240.
[11] Libermann TA, Baltimore D. Activation of interleukin-6 gene expression through the NF-kappa B transcription factor. Mol Cell Biol 1990 ; 10:2327-2334.
[12]Shakhov AN, Collart MA, Vassalli P, et al. Kappa B-type enhancers are involved in lipopolysaccharidemediated transcriptional activation of the tumor necrosis factor alpha gene in primary macrophages. J Exp Med 1990 ; 171:35-47.
[13]Tegeder I, Niederberger E, Schmidt R, et al. Specific Inhibition of IkappaB kinase reduces hyperalgesia in inflammatory and neuropathic pain models in rats. J Neurosci 2004 ; 24:1637-1645.
[14]Sakaue G, Shimaoka M, Fukuoka T, et al. NF-kappa B decoy suppresses cytokine expression and thermal hyperalgesia in a rat neuropathic pain model. Neuroreport 2001 ; 12:2079-2084.
[15]Laughlin TM, Bethea JR, Yezierski RP, et al. Cytokine involvement in dynorphin-induced allodynia. Pain 2000 ; 84:159-167.
[16]Hanisch UK. Microglia as a source and target of cytokines. Glia 2002;40:140-155.
[17]Verge GM, Milligan ED, Maier SF, et al. Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions. Eur J Neurosci 2004;20:1150-1160
[18]Zhuang ZY, Yasuhiko Kawasaki, Tan PH, et al. Role of the CX3CRl/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine Brain Behav Immun. 2007; 21(5): 642-651.
[19] Sun S, Cao H, Han M, et al. New evidence for the involvement of spinal fractalkine receptor in pain facilitation and spinal glial activation in rat model of monoarthritis. Pain 2007; 129:64-75.
[20] Johnston IN, Milligan ED, Wieseler-Frank J, et al. A role for proinflammatory cytokines and fractalkine in analgesia, toletance, and subsequent pain facilitation induced by chronic intrathecal morphine. Journal of neuroscience 2004;24:7353-7365.
[21]Ignatowski TA, Covey WC, Knight PR, et al. Brain-derived TNFalpha mediates neuropathic pain. Brain Res. 1999; 841: 70-77.
[22] Sommer C, Schafers M, Marziniak M, et al. Etanercept reduces hyperalgesia in experimental painful neuropathy. J. Peripher. Nerv. Syst. 2001; 6: 67-72.
[23]Kolesnick R, Golde DW. The sphingomyclin pathway in tumor necrosis factor and interleukin-1 signaling.Cell 1994;77:325-328.
[24]Marchand F,Perretti M,McMahon SB. Role of the immune system in chronic pain. Nat Rev Neurosci 2005 ; 6:521-532.
[25]Bennet GJ, Xie YK. Peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988;33: 87-107.
[26] Lavon I ,et al. High susceptibility to bacterial infection , but no liver dysfunction in mice compromised for hepatocyte NF-kB activation. Nat Med 2000;6:573-577
[27]Egan LJ, Toruner M. NF-kappaB signaling: pros and cons of altering NF-kappaB as a therapeutic approach. Ann N YAcad Sci 2006;1072:114-122.
[28] Kumar A, Takada Y, Boriek AM. Nuclear factor-B: its role in health and disease. J. Mol. Med.2004;82:434-448.
[29] Sakaue G,Shimaoka M,Fukuoka T,et al.NF-kappa B decoy suppresses cytokine expression and thermal hyperalgesia in a rat neuropathic pain model.Neuroreport 2001;24:2079-84
[30] Pollock G,Pennypacker KR,Memet S,et al. Activation of NF-kappaB in the mouse spinal cord following sciatic nerve transection.Exp Brain Res 2005; 165:470-477
[31]Bethea JR,Castro M,Keane RW, et al. Traumatic spinal cord injury induces nuclear factor-kappaB activation.J Neurosci 1998; 18:3251-3260
[32] Ma W,Bisby MA.Increased activation of nuclear factor kappa B in rat lumbar dorsal root ganglion neurons following partial sciatic nerve injuries.Brain Res 1998;797:243-54
[33] Lee HL,Lee KM,Son SJ, et al. Temporal expression of cytokines and their receptors mRNAs in a neuropathic pain model.Neuroreport 2004; 15:2807-11
[34]Tegeder I,Niederberger E,Schmidt R,et al.Specific inhibition of IkappaB kinase reduces hyperalgesia in inflammatory and neuropathic pain models in rats.J Neurosci 2004;24: 1637-45
[35] Liu SF, Ye X, Malik AB. Pyrrolidine dithiocarbamate prevents Ⅰ-kappaB degradation and reduces micro vascular injury induced by lipopolysaccharide in multiple organs. Mol Pharmacol 1999;55:658-67.
[36] Sun T, Song WG, Fu ZJ, et al. Alleviation of neuropathic pain by intrathecal injection of antisense oligonucleotides to p65 subunit of NF-kB. Pain 2006;97:553-558.
[37]Watkins LR, Milligan ED, Maier SF. Glial activation: a driving force for pathological pain. Trends Neurosci 2001;24:450-455.
[38] Watkins LR, Milligan ED, Maier SF. Spinal cord glia: new players in pain. Pain 2001;93:201-205.
[39]Marchand F, Perretti M, McMahon SB. Role of the immune system in chronic pain. Nat Rev Neurosci 2005;6:521-532.
[40] Zhang FX, Vadakkan KI, Kim SS, et al. Selective activation of microglia in spinal cord but not higher cortical regions following nerve injury in adult mouse.Molecular Pain 2008;4:15.
[41]Ladeby R, Wirenfeldt M, Garcia-Ovejero D, et al. Microglial cell population dynamics in the injuried adult central nervous system. Brain Res Brain Res Rev 2005;48:196-206.
[42]Kajander KC, Benett GJ. Onset of a painful peripheral neuropathy in rat: a partial and differential deafferentation and spontaneous discharge in A beta and A delta primary afferent neurons.J Neurophysiol 1992;68:734-744.
[43]Gehrmann J, Banati RB. Microglial turnover in the injured CNS: activated microglia undergo delayed DNA fragmentation following peripheral nerve injury. J Neuropathol Exp Neurol 1995,54:680-688.
[44] Clark AK, Yip PK, Grist J, et al. Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc.Natl.Acad.Sci.2007;104:10655-10660.
[45] Jin SX, Woolf CJ, Ji RR. Activation of p38 MAP kinase in the dorsal root ganglion and spinal cord after spinal nerve ligation. Soc. Neurosci.Abstr.2002;28:13.
[46] Jin SX, Zhuang ZY, Woolf CJ, et al. p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. J Neurosci. 2003;23:4017-4022.
[47] Kim SY, Bae JC, Lee HL, et al. Activation of p38 MAP kinase in the rat dorsal root ganglia and spinal cord following peripheral inflammation and nerve injury. Neuroreport 2002;13:2483-2486.
[48] Schafers M, Svensson CI, Sommer C, et al. Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J. Neurosci.2003;23:2517-2521.
[49]Tsuda M, Mizokoshi A, Shigemoto-Mogami Y, et al. Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury. Glia 2004; 45: 89-95.
[50]Hua XY, Svensson CI, Matsui T, et al. Intrathecal minocycline attenuates peripheral inflammation-induced hyperalgesia by inhibiting p38 MAPK in spinal microglia. Eur.J.Neurosci.2005;22:2431 -2440.
[51] Sung CS, Wen ZH, Chang WK, et al. Inhibition of p38 mitogen-activated protein kinase attenuates interleukin-1 beta-induced thermal hyperalgesia and inducible nitric oxide synthase expression in the spinal cord. J Neurochem 2005;94:742-752.
[52]Svensson CI, Marsala M, Westerlund A, et al. Activation of p38 mitogen-activated protein kinase in spinal microglia is a critical link in inflammation-induced spinal pain processing. J Neurochem2003;86:1534-1544.
[53] Svensson CI, Schafers M, Jones TL, et al. Spinal blockade of TNF blocks spinal nerveligation-induced increases in spinal P-p38. Neurosci Lett 2005;379:209-213.
[54] George A, Schmidt C, Weishaupt A, et al. Serial determination of tumor necrosis factor-alpha content in rat sciatic nerve after chronic constriction injury. Exp. Neurol.1999; 160 :124-132.
[55] George A, Buehl A, Sommer C. Tumor necrosis factor receptor 1 and 2 proteins are differentially regulated during Wallerian degeneration of mouse sciatic nerve. Exp. Neurol. 2005 ; 192 : 163-166.
[56] Yang L, Lindholm K, Konishi Y, et al. Target depletion of distinct tumor necrosis factor receptor subtypes reveals hippocampal neuron death and survival through different signal transduction pathways. J Neurosci.2002;22:3025-3032.
[57]Marchetti L, Klein M, Schlett K, et al. Tumor necrosis factor (TNF)-mediated neuroprotection against glutamate-induced excitotoxicity is enhanced by N-methyl-D-aspartate receptor activation. Essential role of a TNF receptor 2 mediated phosphatidylinositol 3-kinase -dependent NF-kappaB pathway.J.Biol.Chem.2004;279:32869-32881.
[58]Junger H, Sorkin LS. Nociceptive and inflammatory effects of subcutaneous TNFalpha. Pain 2000;85,145-151.
[59] Sorkin LS, Xiao WH, Wagner R, et al. Tumour necrosis factor-alpha induces ectopic activity in nociceptive primary afferent fibres. Neuroscience 1997;81,255-262.
[1] Winkelstein BA, Rutkowski MD, Sweitzer SM, et al. Nerve injury proximal or distal to the DRG induces similar spinal glial activation and selective cytokine expression but differential behavioral responses to pharmacologic treatment. J Comp Neurol 2001 ;439:127-139.
[2] Raghavendra V, Tanga F, Deleo JA. Inhibition of microglial activation attenuates the development but not existing hyperaensitivity in a rat model of neuropathy. J Pharmacol Exp Therapy 2003;306:624-630.
[3] Ledeboer A, Sloane EM, Milligan ED, et al. Minocycline attenuates mechamical allodynia and proinfiammatory cytokine expression in rat model of pain facilitation. Pain 2005;115:71-83
[4] Hao S, Mata M, Glorioso JC, et al. Gene transfer to interfere with TNFa signaling in neuropathic pain. Gene Theraphy 2007; 14:1010-1016.
[5] Verge GM, Milligan ED, Maier SF, et al. Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions. Eur J Neurosci 2004;20:1150-1160
[6] Egan LJ, Toruner M. NF-kappaB signaling: pros and cons of altering NF-kappaB as a therapeutic approach. Ann N Y Acad Sci 2006;1072:114-122.
[7] Marchand F,Perretti M,McMahon SB. Role of the immune system in chronic pain.Nat Rev Neurosci 2005; 6:521-532.
[8] Ledeboer A, Gamanos M, Lai W, et al.Involvement of spinal cord nuclear factor kB activation in rat models of proinfiammatory cytokine-mediated pain facilitation. Eur J Neurosci 2005; 22:1977-1986.
[9] Wu LC, Goettl VM, Madiai F, et al.Reciprocal regulation of nuclear factor kappa B and its inhibitor ZAS3 after peripheral nerve injury. BMC Neurosci 2006; 7:4.
[10] Sun S, Cao H, Han M, et al. New evidence for the involvement of spinal fractalkine receptor in pain facilitation and spinal glial activation in rat model of monoarthritis. Pain 2007; 129:64-75.
[1 l]Zhuang ZY, Kavasaki Y, Tan PH, et al. Role of the CX3CRl/p38MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine. Brain,Behavior,and Immunity 2007;21:642-651.
[12]Milligan E, Zapata V, Schoeniger D, et al. An initial investigation of spinal mechanisms underlying pain enhancement induced by fractalkine, a neuronally released chemokine. European Journal of Neuroscience 2005;22:2775-2782
[13] Moon SO, Kim W, Sung MJ, et al. Resveratrol suppresses tumor necrosis factor-a-induced fractalkine expression in endothelial cells. Mol Pharmacol. 2006; 70: 112-119.
[14]Kaltschmidt B, Widera D, Kaltschmidt C. Signaling via NF-Kb in the nerous system. Biochim. Biophys. Acta 2005; 1745:287-299.
[15] Kumar A, Takada Y, Boriek AM. Nuclear factor-KB: its role in health and disease. J. Mol. Med.2004;82:434-448.
[16] Herrmann O, Baumann B, de Lorenzi R, et al. IKK mediates ischemia-induced neuronal death. Nat. Med. 2005; 11:1322-1329.
[17] Liu SF, Ye X, Malik AB. Pyrrolidine dithiocarbamate prevents Ⅰ-kappaB degradation and reduces microvascular injury induced by lipopolysaccharide in multiple organs. Mol Pharmacol 1999;55:658-67.
[18]Schreck R, Meier B, Mannel DN, et al. Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. J Exp Med 1992; 175:1181-94.
[19]Cardona AE, et al. Control of microglial neurotoxicity by the fractalkine receptor. Nat.Neurosci. 2006;9:917-924.
[20] Liu YL, Zhou LJ, Hu NW, et al. Tumor necrosis factor-a induces long-term potentiation of C-fiber evoked field potentials in spinal dorsal horn in rats with nerve injury: the role of NF-kappa B, JNK and p38 MAPK. 2007;52:708-715.
[21]Cui YH, Le Y, Gong W, et al. Bacterial lipopolysaccharide selectively up-regulates the function of the chemotactic peptide receptor formy1 peptide receptor 2 in murine microglial cells. J Immunol 2002; 168:434-42.
[22] Hu S, Peterson PK, Chao CC. Cytokine-mediated neuronal apoptosis. Neurochem Int1997;30:427-31.
[1] Jorge E TL, Mario 10, Gilberto CH, et al. Comparison of the antinociceptive effect of celecoxib, diclofenac and resveratrol in the formalin test. Life Sciences 2002; 0:1669-1676.
[2] Marc G, Jean XM, Herve B, et al. Resveratrol decreases hyperalgesia induced by carrageenan in the rat hind paw. Life sciences 2001 ;68:1317-1321.
[3] Bi XL, Yang JY, Dong YX, et al. Resveratrol inhibits nitric oxide and TNF-alpha production by lipopolysaccharide-activated microglia. 2005;5:185-193.
[4] Arner S, Meyerson BA. Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain. Pain 1998;33:11-23.
[5] Soleas GJ, Diamandis EP, Goldberg DM. Resveratrol: a molecule whose time has come? And gone? Clin Biochem 1997;30:91-113.
[6] Fremont L. Biological effects of resveratrol. Life Sci 2000;66:663-673.
[7] Gao X, Deeb D, Media J, et al. Immunomodulatory activity of resveratrol : discrepant in vitro and in vivo immunological effects. Biochem Pharmacol 2003;66:2427-2435.
[8] Wang Q, Yu S, Simonyi A, et al. Resveratrol protects against neurotoxicity induced by kainic acid. Neurochem Res 2004;29:2105-2112.
[9] Ates O, Cayli SR, Yucel N, et al. Central nervous system protection by resveratrol in streptozotocin-induced diabetic rats. J Clin Neurosci 2007; 14:256-260.
[10]Zhuang H, Kim YS, Koehler RC, et al. Potential mechanism by which resveratrol, a red wine constituent, protects neurons. Ann N Y Acad Sci 2003;993:276-296.
[11]Aggarwal BB, Bharadwaj A, Aggarwal RS, et al. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Research 2004;24:2783-2840.
[12]Deysi YB, Monica AT, Francisca PS, et al. Pharmacological evidence for the participation of NO-cyclic GMP-PKG-K channel pathway in the antiallodynic actionof resveratrol.Pharmacology, Biochemistry and Behavior 2006;84:535-542.
[13] Sameer S, Kanwaljit C, Shrinivas KK. Effect of insulin and its combination with resveratrol or curcumin in attenuation of diabetic neuropathic pain: participation of nitric oxide and TNF-alpha. Phytother. Res. 2007;21:278-283.
[14]Hao S, Mata M, Glorioso JC, et al. Gene transfer to interfere with TNFα signaling in neuropathic pain. Gene Theraphy 2007,14:1010-1016.
[15]Ohtori S, Takahashi K, Moriya H, et al. TNF-alpha and TNF-alpha receptor type 1 upregulation in glia and neurons after peripheral nerve injury: studies in murine DRG and spinal cord. Spine 2004;29:1082-1088.
[16]Schafers M, Svensson CI, Sommer C, et al. Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38MAPK in primary sensory neurons. J Neurosci 2003 ;23:2517-2521.
[17] Svensson CI, Schafers M, Jones TL, et al. Spinal blockade of TNF blocks spinal nerve ligation-induced increases in spinal p-p38. Neurosci Lett 2005;379:209-213.
[18] Justin JH, Waylon MW, Lucy AH, et al. Substituted trans-Stilbenes, including analogues of the natural product resveratrol, inhibit the human tumor necrosis factor alpha-induced activation of transcription factor nuclear factor kappaB. J.Med.Chem 2006;49:7182-7189.
[19]KangG,KongPJ, Yuh YJ, et al. Curcumin suppresses lipopolysaccharide-induced cyclooxygenase-2 expression by inhibiting activator protein-1 and nuclear factor kappab bindings in BV2 microglial cells. J Pharmacol. Sci. 2004;94: 325-328.
[20] Moon SO, Kim W, Sung MJ, et al. Resveratrol suppresses tumor necrosis factor-a-induced fractalkine expression in endothelial cells. Mol Pharmacol. 2006; 70: 112-119.
[21] Sun S, Cao H, Han M, et al. New evidence for the involvement of spinal fractalkine receptor in pain facilitation and spinal glial activation in rat model of monoarthritis. Pain 2007;129:64-75.
[22]Zhuang ZY, Kavasaki Y, Tan PH, et al. Role of the CX3CRl/p38MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine. Brain,Behavior,and Immunity 2007;21:642-651.
[23]Milligan E, Zapata V, Schoeniger D, et al. An initial investigation of spinal mechanisms underlying pain enhancement induced by fractalkine, a neuronally released chemokine. European Journal of Neuroscience 2005;22:2775-2782.
[24] Johnston BD, DeMaster EG. Suppression of nitric oxide oxidation to nitrite by curcumin is due to the sequestration of the reaction intermediate nitrogen dioxide,not nitric oxide. Nitric Oxide.2003;8:231-234.
[25]Mann SK, Mukhopadhyay A, Aggarwal BB. et al. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kB , activator rotein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J. Immunol.2000;164:6509-6519.
[26] Chen Jennifer, Zhou Yungui, Mueller-Steiner S, et al. SIRT1 protects against microglia-dependent amyloid-p toxicity through inhibiting NF-kB signaling Journal of biological chemistry 2005;280:40364-40374.
[27] Verge GM, Milligan ED, Maier SF, et al. Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions. Eur J Neurosci 2004;20:l 150-1160
[28] Kim HI, Kim TH, Song JH. Resveratrol inhibit Na currents in rat dorsal root ganglion neurons. Brain Research 2005; 1045:134-141.
[1]鞠躬,吕国蔚,王百忍.神经生物学.北京:人民卫生出版社2004,343-370.
[2]Millan MJ The induction of pain:an integrative review.Prog.Neurobiol.1999;57:1-164.
[3]DeLeo JA,Sorkin LS,Watkins LR.(Eds.).Immune and Glial Regulation of Pain.IASP Press 2007;Seattle.
[4]Raivich G.Like cops on the beat:the active role of resting microglia.Trends Neurosci.2005;28:571-573.
[5]Perry VH,Hume DA,Gordon S.Immunohistochemical localisation of macrophages and microglia in the adult and developing mouse brain.Neurosci.1985;15:313-326.
[6]Aldskogius H,Kozlova EN.Central neuron-glial and glial-glial interations following axon injury.Prog.Neurobiol.1998;55:1-26.
[7]Lee JC,Mayer-Proschel M,Rao MS.Gliogenesis in the central nervous system Glia 2000;30:105-121.
[8]Haydon PG,Carmignoto G.Astrocyte control of synaptic transmission and neurovascular coupling.Physiol.Rev.2006;86:1009-1031.
[9]Pasti L,Zonata.M,Pozzan T,et al.Cytosolic calcium oscillations in astrocytes may regulate exocytotic release of glutamate.J.Neurosci.2001;21:477-484.
[10]Tsacopoulos M.Metabolic signaling between neurons and glial cells:a short review.J.Physiol.2002;96:283-288.
[11]Haydon PG.GLIA:listening and talking to the synapse.Nat.Rev.Neurosci.2001;2:185-193.
[12]McMahon SB,Cafferty WBJ,Marchand F.Immune and glial cell factors as pain mediators and modulators.Exp.Neurol.2005;192:444-462.
[13]Rostene W,Kitabgi P,Parsadaniantz SM.Chemokines:a new class of neuromodulator.Nat.Rev.Neurosci.2007;8:895-903.
[14]Fellin T,Sul J-Y,D'ascenzo M,et al.Bidirectional astrocyte-neuron communication:the many roles of glutamate and ATP.Novartis Foundation Symposium.2006;Wiley,Chichester.New York.
[15]Porter JT,Mccarthy KD.Astrocytic neurotransmitter receptors in situ and in vivo.Prog.Neurobiol.1997;51:439-455.
[16] Schipke CG, Ohlemeyer C, Matyash M, et al. Astrocytes of the mouse neocortex express functional N-methyl-D-aspartate receptors. FASEB J. 2001;15:1270-1272.
[17] Pocock JM, Kettenmann H. Neurotransmitter receptors on microglia. Trends Neurosci. 2007;30:527-535.
[18] Scholz J, Woolf CJ. The neuropathic pain triad: neurons, immune cells, and glia. Nat. Neurosci. 2007; 10:1361-1368.
[19] Hanisch U-K. Microglia as a source and target of cytokines. Glia 2002; 40:140-155.
[20] Keane RW, Hickey WF. Immunology of the Nervous System. Oxford University Press, New York. 1997.
[21] Aimar P, Pasti L, Carmignoto G, et al. Nitric oxide-producing islet cells modulate the release of sensory neuropeptides in the rat substantia gelatinosa. J.Neurosci. 1998; 18:10375-10388.
[22] Guo L-H, Schluesener HJ. The innate immunity of the central nervous system in chronic pain: the role of Toll-like receptors. Cell. Mol. Life Sci. 2007;64:1128-1136.
[23] Inoue A, Ikoma K, Morioka N,et al. Interleukin-1beta induces substance P release from primary afferent neurons through the cyclooxygenase-2 system.J.Neurochem. 1999; 73: 2206-2213.
[24] Malcangio M, Bowery NG, Flower RJ, et al. Effect of interleukin-lbeta on the release of substance P from rat isolated spinal cord. Eur. J. Pharmacol. 1996; 299:113-118.
[25] Southall MD, Michael RL, Vasko MR. Intrathecal NSAIDS attenuate inflammation-induced neuropeptide release from rat spinal cord slices. Pain 1998; 78:39-48.
[26] Halassa MM, Fellin T, Haydon PG. The tripartite synapse: roles for gliotransmission in health and disease. Trends Mol. Med. 2007; 13: 54-63.
[27] Nguyen MD, Julien J-P, Rivest S. Innate immunity: the missing link in neuroprotection and neurodegeneration? Nat. Rev. Neurosci. 2002; 3: 216-227.
[28] Burgher KL, Heroux JA, Ringheim GE. Cyclic AMP potentiation of cytokine-induced nitric oxide synthetase activity in a murine astrocyte cell line.Neurochem. Int. 1997; 30: 483-489.
[29] Murphy S, Grzybycki D. Glial NO. normal and pathological roles. Neurosci. 1996;2:90-99.
[30] Samad TA, Moore KA, Sapirstein A, et al. Interleukin-1b-mediated induction of COX-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 2001;410:471-475.
[31] Wolf G, Yirmiya R, Goshen I, et al. Impairment of interleukin-1 (IL-1) signaling reduces basal pain sensitivity in mice: genetic, pharmacological and developmental aspects. Pain 2003; 104: 471-480.
[32] Dantzer R. Cytokine-induced sickness behaviour: a neuroimmune response to activation of innate immunity. Eur. J. Pharmacol. 2004;500:399-411.
[33] Watkins LR, Maier SF. The pain of being sick: implications of immune-to-brain communication for understanding pain. Annu. Rev.Psychol. 2000; 51: 29-57.
[34] Zimmermann M. Pathobiology of neuropathic pain. Eur. J. Pharmacol. 2001 ;429: 23-37.
[35] Bennett GJ, Xie KY. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988;33: 87-107.
[36] Garrison CJ, Dougherty PM, Kajander KC, et al. Staining of glial fibrillary acidic protein (GFAP) in lumbar spinal cord increases following a sciatic nerve constriction injury. Brain Res. 1991; 565:1-7
[37] Watkins LR, Milligan ED, Maier SF. Glial activation: a driving force for pathological pain. Trends Neurosci. 2001; 24: 450-455.
[38] Pocock JM, Kettenmann H. Neurotransmitter receptors on microglia. Trends Neurosci. 2007; 30: 527-535.
[39] Garrison CJ, Dougherty PM, Carlton SM. GFAP expression in lumbar spinal cord of naive and neuropathic rats treated with MK-801. Exp. Neurol. 1994; 129:237-243
[40] Fonnum F, Johnsen A, Hassel B. Use of fluorocitrate and fluoroacetate in the study of brain metabolism. Glia 1997;21: 106-113.
[41] Ledeboer A, Sloane EM, Milligan ED, et al. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain 2005;115: 71-83.
[42] Obata K, Katsura H, Miyoshi K, et al. Activation of Toll-like receptor 3 in spinal microglia is required for tactile allodynia after nerve injury. Society for Neuroscience Conference Proceedings. San Diego, CA. 2007.
[43] Milligan ED, O'connor KA, Nguyen KT, et al. Intrathecal HIV-1 envelope glycoprotein gp 120 enhanced pain states mediated by spinal cord proinflammatory cytokines. J. Neurosci. 2001; 21:2808-2819.
[44] Holguin A, O'connor KA, Biedenkapp J, et al. HIV-1 gp120 stimulates proinflammatory cytokine-mediated pain facilitation via activation of nitric oxide synthase-Ⅰ (nNOS). Pain 2004; 110: 517-530.
[45] Ledeboer A, Jekich BM, Sloane EM,et al. Intrathecal interleukin-10 gene therapy attenuates paclitaxel-induced mechanical allodynia and proinflammatory cytokine expression in dorsal root ganglia in rats. Brain Behav. Immun. 2007;21:686-698.
[46] Abraham KE, Mcmillen D, Brewer KL. The effects of endogenous interleukin-10 on gray matter damage and pain behaviors following excitotoxic spinal cord injury in the mouse. Neuroscience 2004;124: 922-945.
[47] Johnston IN, Milligan ED, Wieseler-Frank J, et al. A role for pro-inflammatory cytokines and fractalkine in analgesia, tolerance and subsequent pain facilitation induced by chronic intrathecal morphine. J. Neurosci. 2004;24: 7353-7365.
[48] Milligan ED, Sloane EM, Langer SJ, et al. Controlling neuropathic pain by adeno-associated virus driven production of the antiinflammatory cytokine,interleukin-10. Mol. Pain 2005; 1:9-22.
[49] Moore KW, De Waal Malefyt R, Coffman RL, et al. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 2001 ; 19:683-765.
[50] Tikka TM, Koistinaho JE. Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia. J.Immunol. 2001;166, 7527-7533.
[51] Inoue K. The function of microglia through purinergic receptors: neuropathic pain and cytokine release. Pharmacol. Ther. 2006; 109: 210-226.
[52] Tsuda M, Shigemoto-Mogami Y, Koizumi S, et al. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 2003;424:778-783.
[53] Holguin A, Biedenkapp J, Campisi J, et al. HIV-1 gp120 stimulates proinXammatory cytokine-mediated pathological pain via activation of nitric oxide synthase-I (nNOS). Pain 2004; 110:517-530.
[54] Svensson CI, Hua XY, Powell HC, et al. Prostaglandin E2 release evoked by intrathecal dynorphin is dependent on spinal p38 mitogen activated protein kinase. Neuropeptides 2005;39: 485-494.
[55] Costigan M, Mannion RJ, Kendall G, et al. Heat shock protein 27:developmental regulation and expression after peripheral nerve injury. J.Neurosci. 1998; 18: 5891-5900.
[56] Vargas ME, Singh SJ, Barres BA. Why is Wallerian degeneration so slow in the CNS? Glia in Health and Disease, Cold Spring Harbor Laboratories, Cold Spring Harbor Laboratories. 2006.
[57] Scholz J, Broom DC, Youn DH, et al. Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina Ⅱ of the dorsal horn after peripheral nerve injury. J. Neurosci. 2005; 25: 7317-7323.
[58] Lehnardt S, Lachance C, Patrizi S, et al. The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J.Neurosci. 2002; 22:2478-2486.
[59] Tanga FY, Raghavendra V, DeLeo JA. Quantitative real-time RTPCR assessment of spinal microglial and astrocytic activation markers in a rat model of neuropathic pain. Neurochem. Int. 2004 ;45: 397-407.
[60] Laing KJ, Secombes CJ. 2004. Chemokines. Dev. Comp. Immunol. 28, 443-460.
[61] Murphy PM. International Union of Pharmacology. XXX. Update on chemokine receptor nomenclature. Pharmacol. Rev. 2002;54, 227-229.
[62] Mackay CR. Chemokines: immunology's high impact factors. Nat.Immunol. 2001; 2: 95-101.
[63] Mellado M, Rodriquez-Frade JM, Vila-Coro AJ, et al. Chemokine receptor homo- or heterodimerization activates distinct signaling pathways. EMBO J. 2001; 20: 2497-2507.
[64] Laudanna C, Alon R. Right on the spot. Chemokine triggering of integrinmediated arrest of rolling leukocytes. Thromb. Haemost. 2006; 95: 5-11.
[65] Rittner HL, Brack A. Chemokines and pain. Curr. Opin. Investig. Drugs 2006;7:643-646.
[66] Harrison JK, Jiang Y, Chen S, et al. Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia.Proc. Natl. Acad. Sci. 1998;95: 10896-10901.
[67] Lindia JA, Mcgowan E, Jochnowitz N, et al. Induction of CX3CL1 expression in astrocytes and CX3CR1 in microglia in the spinal cord of a rat model of neuropathic pain. J. Pain 2005;6: 434-438.
[68] Verge GM, Milligan ED, Maier SF, et al. Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions. Eur. J. Neurosci. 2004. 20,1150-1160.
[69] Meucci O, Fratatis A, Simen AA, et al. Expression of CX3CR1 chemokine receptors on neurons and their role in neuronal survival. Proc. Natl. Acad. Sci. 2000; 97: 8075-8080.
[70] Clark AK, Yip PK, Grist J, et al. Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc. Natl. Acad. Sci. 2007; 104:10655-10660.
[71] Zhuang Z-Y, Kawasaki Y, Tan P-H, et al. Role of the CX3CRl/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine. Brain Behav. Immun. 2007;21: 642-651.
[72] Milligan ED, Zapata V, Schoeniger D, et al. An initial investigation of spinal mechanisms underlying pain enhancement induced by fractalkine, a neuronally released chemokine. Eur. J. Neurosci. 2005;22:2775-2782.
[73] Langer SJ, Busha D, Milligan ED, et al. In vivo over-expression of fractalkine, a putative neuron-to-glia signal, to characterize underlying mechanisms of neuropathic pain. In: Therapy, A.S.O.G. (Ed.), American Society of Gene Therapy 9th Annual Meeting. MD, Elsevier Inc., Baltimore. 2006.
[74] Owolabi SA, Saab CY. Fractalkine and minocycline alter neuronal activity in the spinal cord dorsal horn. FEBS Lett. 2006; 580: 4306-4310.
[75] Hundhausen C, Schulte A, Schulz B, et al. Regulated shedding of transmembrane chemokines by the disintegrin and metalloproteinase 10 facilitates detachment of adherent leukocytes. J. Immunol. 2007; 178,8064-8072.
[76] Chapman GA, Moores K, Harrison D. Fractalkine cleavage from neuronal membranes represents an acute event in the inflammatory response to excitotoxic brain damage. J. Neurosci. 2000; 20: 1-5.
[77] Ludwig A, Hundhausen C, Lambert MH,et al. Metalloproteinase inhibitors for the disintegrin-like metalloproteinases ADAM 10 and ADAM 17 that differentially block constitutive and phorbol ester-inducible shedding of cell surface molecules. Comb. Chem. High Throughput Screen. 2005;8: 161-171.
[78] Hundhausen C, Misztela D, Berkhout TA,et al. The disintegrin-like metalloproteinase ADAM 10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1 -mediated cell-cell adhesion. Blood 2003;102:1186-1195.
[79] Cross AK, Woodroofe MN. Chemokine modulation of matrix metalloproteinase and TIMP production in adult rat brain microglia and a human microglial cell line in vitro. Glia 1999; 28,183-189.
[80] Biber K, Dijkstra I, Trebst C,et al. Functional expression of CXCR3 in cultured mouse and human astrocytes and microglia. Neuroscience 2002; 112: 487-497.
[81] Rappert A, Bechmann I, Pivneva T, et al. CXCR3-dependent microglial recruitment is essential for dendrite loss after brain lesion. J. Neurosci. 2004;24:8500-85009.
[82] Zhang J, De Koninck Y. Spatial and temporal relationship between monocyte chemoattractant protein-1 expression and spinal glial activation following peripheral nerve injury. J. Neurochem. 2006;97:772-783.
[83] Abbadie C, Lindia JA, Cumiskey AM,et al. Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2. Proc. Natl. Acad. Sci. USA 2003;100:7947-7952.
[84] Cao L, Deleo JA. CNS-infiltrating CD4+ T lymphocytes contribute to murine spinal nerve transection-induced neuropathic pain. Eur. J. Immunol. 2008;38: 448-458.
[85] Aravalli RN, Peterson PK, Lokensgard JR. Toll-like receptors in defense and damage of the central nervous system. J. Neuroimmune.Pharmacol. 2007; 2:297-312.
[86] Jack CS, Arbour N, Manusow J, et al. TLR signaling tailors innate immune responses in human microglia and astrocytes. J. Immunol. 2005; 175:4320-4330.
[87] Kigerl KA, Lai W, Rivest S,et al. Toll-like receptor (TLR)-2 TLR-4 regulate inflammation, gliosis, myelin sparing after spinal cord injury. J. Neurochem. 2007;102: 37-50.
[88] White FA, Bhangoo SK, Miller RD. Chemokines: integrators of pain and inflammation. Nature Rev. 2005; 4: 834-844.
[89] van Rossum D, Hanisch UK. Microglia. Metab. Brain Dis. 2004; 19: 393-411.
[90] Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005; 308: 1314-1318.
[91] Davalos D, Grutaendler J, Yang G, et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 2005;8: 752-758.
[92] Haynes SE, Hollopeter G, Kurpius D, et al. The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat. Neurosci. 2006; 9: 1512-1519.
[93] Boillee S, Yamanaka K, Lobsiger CS, et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science 2006;312: 1389-1392.
[94] Streit WJ. Microglial senescence: does the brain's immune system have an expiration date? Trends Neurosci. 2006;29: 506-510.
[95] Neumann H, Takahashi K. Essential role of the microglial triggering receptor expressed on myeloid cells-2 (TREM2) for central nervous tissue immune homeostasis. J. Neuroimmunol. 2007; 184:92-99.
[96] Biber K, Neumann H, Inoue K, et al. Neuronal On and Off signals control microglia. Trends Neurosci. 2007;30: 596-602.
[97] Pocock JM, Kettenmann HK. Neurotransmitter receptor on microglia. Trends Neurosci. 2007; 30: 527.
[98] Loredo GA, Benton HP. ATP and UTP activate calcium-moblizing P2U-like receptors and act synergistically with interleukin-1 to stimulate prostaglandin E2 release from human rheumatoid synovial cells. Arthritis Rheum. 1998;41: 246-255.
[99] Ledeboer A, Sloane EM, Milligan ED, et al. Minocycline attenuates mechanical allodynia and proinXammatory cytokine expression in rat models of pain facilitation. Pain 2005;l 15:71-83.
[100]Schafers M, Sommer C. Anticytokine therapy in neuropathic pain management. Expert Rev. Neurotherapeutics 2007;7:1613-1627.
[101]Milligan ED, Sloane EM, Langer SJ, et al. Repeated intrathecal injections of plasmid DNA encoding interleukin-10 produce prolonged reversal of neuropathic pain. Pain 2006; 126:294-308.
[102] Song P, Zhao ZQ. The involvement of glial cells in the development of morphine tolerance. Neurosci. Res. 2001; 39:281-286.
[103] Johnston IN, Milligan ED, Wieseler-Frank J,et al. A role for proinXammatory cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine. J. Neurosci. 2004;24: 7353-7365.
[104]Raghavendra V, Rutkowski MD, DeLeo JA. The role of spinal neuroimmune activation in morphine tolerance/hyperalgesia in neuropathic and sham-operated rats. J. Neurosci. 2002;22:9980-9989.
[105]Shavit Y, Wolf G, Goshen I, et al. Interleukin-1 antagonizes morphine analgesia and underlies morphine tolerance. Pain 2005;l 15: 50-59.
[106]Mao J, Sung B, Ji RR, et al. Chronic morphine induces downregulation of spinal glutamate transporters: implications in morphine tolerance and abnormal pain sensitivity. J. Neurosci. 2002;22: 8312-8323.
[107]Hutchinson MR, Somogyi AA. Relationship between 4,5-epoxymorphinan structure and in vitro modulation of cell proliferation. Eur. J. Pharmacol. 2004; 494:251-262.
[108]Hutchinson MR, Somogyi AA. (S)-(+)-methadone is more immunosuppressive than the potent analgesic (R)-(-)-methadone. Intlmmunopharmacol. 2004; 4: 1525-1530.
[109]Hutchinson MR, Somogyi AA. Characterisation of the in vitro modulation of splenocyte proliferation by non-4,5-epoxymorphinan opioids. Int. Immunopharmacol. 2005;5: 1713-1722.
[110] Coats BD, Hutchinson MR, Watkins LR. Opioid inactive (+)-naloxone potentiates morphine analgesia: further evidence that opioid analgesia is opposed by opioid induced glial activation. Neuroscience Meeting Planner.Atlanta, GA: Society for Neuroscience. 2006.
[111]Zhang N, Rogers TJ, Caterina M, et al. ProinXammatory chemokines, such as C-C chemokine ligand 3, desensitize mu-opioid receptors on dorsal root ganglia neurons. J. Immunol. 2004; 173:594-599.
[112]Adler MW, Geller EB, Chen X,et al. Viewing chemokines as a third major ystem of communication in the brain. Aaps J. 2006; 7: E865-E870.
[2] Ledeboer A, Gamanos M, Lai W, et al.Involvement of spinal cord nuclear factor kB activation in rat models of proinflammatory cytokine-mediated pain facilitation. Eur J Neurosci 2005; 22:1977-1986.
[3] Wu LC, Goettl VM, Madiai F, et al.Reciprocal regulation of nuclear factor kappa B and its inhibitor ZAS3 after peripheral nerve injury. BMC Neurosci,2006,7:4.
[4] Laughlin TM, Bethea JR, Yezierski RP, et al. Cytokine involvement in dynorphin-induced allodynia. Pain 2000; 84:159-167.
[5] O'Rielly DD, Loomis CW. Spinal nerve ligation-induced activation of nuckear factor kappaB is facilitated by prostaglandins in the affected spinal cord and is a critical step in the development of mechanical allodynia. Neuroscience 2008;155: 902-913.
[6] Xiao HS, Huang QH, Zhang FX, et al. Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain. PNAS 2002; 99:8360-8365.
[7] Valder CR, Liu JJ, Song YH, et al. Coupling gene chip analyses and rat genetic variances in identifying potential target genes that may contribute to neuropathic allodynia development. J Neurochem 2003 ; 87:560-573.[8]
[8] Manning DC. New and emerging pharmacological targets for neuropathic pain. Curr Pain Headache Rep 2004 ; 8:192-198.
[9] Sommer C, Kress M. Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci Lett 2004 ; 361:184-187.
[10]Hiscott J, Marois J, Garoufalis J, et al. Characterization of a functional NF-kappa B site in the human interleukin 1 beta promoter: evidence for a positive autoregulatory loop. Mol Cell Biol 1993 ; 13:6231-6240.
[11] Libermann TA, Baltimore D. Activation of interleukin-6 gene expression through the NF-kappa B transcription factor. Mol Cell Biol 1990 ; 10:2327-2334.
[12]Shakhov AN, Collart MA, Vassalli P, et al. Kappa B-type enhancers are involved in lipopolysaccharidemediated transcriptional activation of the tumor necrosis factor alpha gene in primary macrophages. J Exp Med 1990 ; 171:35-47.
[13]Tegeder I, Niederberger E, Schmidt R, et al. Specific Inhibition of IkappaB kinase reduces hyperalgesia in inflammatory and neuropathic pain models in rats. J Neurosci 2004 ; 24:1637-1645.
[14]Sakaue G, Shimaoka M, Fukuoka T, et al. NF-kappa B decoy suppresses cytokine expression and thermal hyperalgesia in a rat neuropathic pain model. Neuroreport 2001 ; 12:2079-2084.
[15]Laughlin TM, Bethea JR, Yezierski RP, et al. Cytokine involvement in dynorphin-induced allodynia. Pain 2000 ; 84:159-167.
[16]Hanisch UK. Microglia as a source and target of cytokines. Glia 2002;40:140-155.
[17]Verge GM, Milligan ED, Maier SF, et al. Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions. Eur J Neurosci 2004;20:1150-1160
[18]Zhuang ZY, Yasuhiko Kawasaki, Tan PH, et al. Role of the CX3CRl/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine Brain Behav Immun. 2007; 21(5): 642-651.
[19] Sun S, Cao H, Han M, et al. New evidence for the involvement of spinal fractalkine receptor in pain facilitation and spinal glial activation in rat model of monoarthritis. Pain 2007; 129:64-75.
[20] Johnston IN, Milligan ED, Wieseler-Frank J, et al. A role for proinflammatory cytokines and fractalkine in analgesia, toletance, and subsequent pain facilitation induced by chronic intrathecal morphine. Journal of neuroscience 2004;24:7353-7365.
[21]Ignatowski TA, Covey WC, Knight PR, et al. Brain-derived TNFalpha mediates neuropathic pain. Brain Res. 1999; 841: 70-77.
[22] Sommer C, Schafers M, Marziniak M, et al. Etanercept reduces hyperalgesia in experimental painful neuropathy. J. Peripher. Nerv. Syst. 2001; 6: 67-72.
[23]Kolesnick R, Golde DW. The sphingomyclin pathway in tumor necrosis factor and interleukin-1 signaling.Cell 1994;77:325-328.
[24]Marchand F,Perretti M,McMahon SB. Role of the immune system in chronic pain. Nat Rev Neurosci 2005 ; 6:521-532.
[25]Bennet GJ, Xie YK. Peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988;33: 87-107.
[26] Lavon I ,et al. High susceptibility to bacterial infection , but no liver dysfunction in mice compromised for hepatocyte NF-kB activation. Nat Med 2000;6:573-577
[27]Egan LJ, Toruner M. NF-kappaB signaling: pros and cons of altering NF-kappaB as a therapeutic approach. Ann N YAcad Sci 2006;1072:114-122.
[28] Kumar A, Takada Y, Boriek AM. Nuclear factor-B: its role in health and disease. J. Mol. Med.2004;82:434-448.
[29] Sakaue G,Shimaoka M,Fukuoka T,et al.NF-kappa B decoy suppresses cytokine expression and thermal hyperalgesia in a rat neuropathic pain model.Neuroreport 2001;24:2079-84
[30] Pollock G,Pennypacker KR,Memet S,et al. Activation of NF-kappaB in the mouse spinal cord following sciatic nerve transection.Exp Brain Res 2005; 165:470-477
[31]Bethea JR,Castro M,Keane RW, et al. Traumatic spinal cord injury induces nuclear factor-kappaB activation.J Neurosci 1998; 18:3251-3260
[32] Ma W,Bisby MA.Increased activation of nuclear factor kappa B in rat lumbar dorsal root ganglion neurons following partial sciatic nerve injuries.Brain Res 1998;797:243-54
[33] Lee HL,Lee KM,Son SJ, et al. Temporal expression of cytokines and their receptors mRNAs in a neuropathic pain model.Neuroreport 2004; 15:2807-11
[34]Tegeder I,Niederberger E,Schmidt R,et al.Specific inhibition of IkappaB kinase reduces hyperalgesia in inflammatory and neuropathic pain models in rats.J Neurosci 2004;24: 1637-45
[35] Liu SF, Ye X, Malik AB. Pyrrolidine dithiocarbamate prevents Ⅰ-kappaB degradation and reduces micro vascular injury induced by lipopolysaccharide in multiple organs. Mol Pharmacol 1999;55:658-67.
[36] Sun T, Song WG, Fu ZJ, et al. Alleviation of neuropathic pain by intrathecal injection of antisense oligonucleotides to p65 subunit of NF-kB. Pain 2006;97:553-558.
[37]Watkins LR, Milligan ED, Maier SF. Glial activation: a driving force for pathological pain. Trends Neurosci 2001;24:450-455.
[38] Watkins LR, Milligan ED, Maier SF. Spinal cord glia: new players in pain. Pain 2001;93:201-205.
[39]Marchand F, Perretti M, McMahon SB. Role of the immune system in chronic pain. Nat Rev Neurosci 2005;6:521-532.
[40] Zhang FX, Vadakkan KI, Kim SS, et al. Selective activation of microglia in spinal cord but not higher cortical regions following nerve injury in adult mouse.Molecular Pain 2008;4:15.
[41]Ladeby R, Wirenfeldt M, Garcia-Ovejero D, et al. Microglial cell population dynamics in the injuried adult central nervous system. Brain Res Brain Res Rev 2005;48:196-206.
[42]Kajander KC, Benett GJ. Onset of a painful peripheral neuropathy in rat: a partial and differential deafferentation and spontaneous discharge in A beta and A delta primary afferent neurons.J Neurophysiol 1992;68:734-744.
[43]Gehrmann J, Banati RB. Microglial turnover in the injured CNS: activated microglia undergo delayed DNA fragmentation following peripheral nerve injury. J Neuropathol Exp Neurol 1995,54:680-688.
[44] Clark AK, Yip PK, Grist J, et al. Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc.Natl.Acad.Sci.2007;104:10655-10660.
[45] Jin SX, Woolf CJ, Ji RR. Activation of p38 MAP kinase in the dorsal root ganglion and spinal cord after spinal nerve ligation. Soc. Neurosci.Abstr.2002;28:13.
[46] Jin SX, Zhuang ZY, Woolf CJ, et al. p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. J Neurosci. 2003;23:4017-4022.
[47] Kim SY, Bae JC, Lee HL, et al. Activation of p38 MAP kinase in the rat dorsal root ganglia and spinal cord following peripheral inflammation and nerve injury. Neuroreport 2002;13:2483-2486.
[48] Schafers M, Svensson CI, Sommer C, et al. Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J. Neurosci.2003;23:2517-2521.
[49]Tsuda M, Mizokoshi A, Shigemoto-Mogami Y, et al. Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury. Glia 2004; 45: 89-95.
[50]Hua XY, Svensson CI, Matsui T, et al. Intrathecal minocycline attenuates peripheral inflammation-induced hyperalgesia by inhibiting p38 MAPK in spinal microglia. Eur.J.Neurosci.2005;22:2431 -2440.
[51] Sung CS, Wen ZH, Chang WK, et al. Inhibition of p38 mitogen-activated protein kinase attenuates interleukin-1 beta-induced thermal hyperalgesia and inducible nitric oxide synthase expression in the spinal cord. J Neurochem 2005;94:742-752.
[52]Svensson CI, Marsala M, Westerlund A, et al. Activation of p38 mitogen-activated protein kinase in spinal microglia is a critical link in inflammation-induced spinal pain processing. J Neurochem2003;86:1534-1544.
[53] Svensson CI, Schafers M, Jones TL, et al. Spinal blockade of TNF blocks spinal nerveligation-induced increases in spinal P-p38. Neurosci Lett 2005;379:209-213.
[54] George A, Schmidt C, Weishaupt A, et al. Serial determination of tumor necrosis factor-alpha content in rat sciatic nerve after chronic constriction injury. Exp. Neurol.1999; 160 :124-132.
[55] George A, Buehl A, Sommer C. Tumor necrosis factor receptor 1 and 2 proteins are differentially regulated during Wallerian degeneration of mouse sciatic nerve. Exp. Neurol. 2005 ; 192 : 163-166.
[56] Yang L, Lindholm K, Konishi Y, et al. Target depletion of distinct tumor necrosis factor receptor subtypes reveals hippocampal neuron death and survival through different signal transduction pathways. J Neurosci.2002;22:3025-3032.
[57]Marchetti L, Klein M, Schlett K, et al. Tumor necrosis factor (TNF)-mediated neuroprotection against glutamate-induced excitotoxicity is enhanced by N-methyl-D-aspartate receptor activation. Essential role of a TNF receptor 2 mediated phosphatidylinositol 3-kinase -dependent NF-kappaB pathway.J.Biol.Chem.2004;279:32869-32881.
[58]Junger H, Sorkin LS. Nociceptive and inflammatory effects of subcutaneous TNFalpha. Pain 2000;85,145-151.
[59] Sorkin LS, Xiao WH, Wagner R, et al. Tumour necrosis factor-alpha induces ectopic activity in nociceptive primary afferent fibres. Neuroscience 1997;81,255-262.
[1] Winkelstein BA, Rutkowski MD, Sweitzer SM, et al. Nerve injury proximal or distal to the DRG induces similar spinal glial activation and selective cytokine expression but differential behavioral responses to pharmacologic treatment. J Comp Neurol 2001 ;439:127-139.
[2] Raghavendra V, Tanga F, Deleo JA. Inhibition of microglial activation attenuates the development but not existing hyperaensitivity in a rat model of neuropathy. J Pharmacol Exp Therapy 2003;306:624-630.
[3] Ledeboer A, Sloane EM, Milligan ED, et al. Minocycline attenuates mechamical allodynia and proinfiammatory cytokine expression in rat model of pain facilitation. Pain 2005;115:71-83
[4] Hao S, Mata M, Glorioso JC, et al. Gene transfer to interfere with TNFa signaling in neuropathic pain. Gene Theraphy 2007; 14:1010-1016.
[5] Verge GM, Milligan ED, Maier SF, et al. Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions. Eur J Neurosci 2004;20:1150-1160
[6] Egan LJ, Toruner M. NF-kappaB signaling: pros and cons of altering NF-kappaB as a therapeutic approach. Ann N Y Acad Sci 2006;1072:114-122.
[7] Marchand F,Perretti M,McMahon SB. Role of the immune system in chronic pain.Nat Rev Neurosci 2005; 6:521-532.
[8] Ledeboer A, Gamanos M, Lai W, et al.Involvement of spinal cord nuclear factor kB activation in rat models of proinfiammatory cytokine-mediated pain facilitation. Eur J Neurosci 2005; 22:1977-1986.
[9] Wu LC, Goettl VM, Madiai F, et al.Reciprocal regulation of nuclear factor kappa B and its inhibitor ZAS3 after peripheral nerve injury. BMC Neurosci 2006; 7:4.
[10] Sun S, Cao H, Han M, et al. New evidence for the involvement of spinal fractalkine receptor in pain facilitation and spinal glial activation in rat model of monoarthritis. Pain 2007; 129:64-75.
[1 l]Zhuang ZY, Kavasaki Y, Tan PH, et al. Role of the CX3CRl/p38MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine. Brain,Behavior,and Immunity 2007;21:642-651.
[12]Milligan E, Zapata V, Schoeniger D, et al. An initial investigation of spinal mechanisms underlying pain enhancement induced by fractalkine, a neuronally released chemokine. European Journal of Neuroscience 2005;22:2775-2782
[13] Moon SO, Kim W, Sung MJ, et al. Resveratrol suppresses tumor necrosis factor-a-induced fractalkine expression in endothelial cells. Mol Pharmacol. 2006; 70: 112-119.
[14]Kaltschmidt B, Widera D, Kaltschmidt C. Signaling via NF-Kb in the nerous system. Biochim. Biophys. Acta 2005; 1745:287-299.
[15] Kumar A, Takada Y, Boriek AM. Nuclear factor-KB: its role in health and disease. J. Mol. Med.2004;82:434-448.
[16] Herrmann O, Baumann B, de Lorenzi R, et al. IKK mediates ischemia-induced neuronal death. Nat. Med. 2005; 11:1322-1329.
[17] Liu SF, Ye X, Malik AB. Pyrrolidine dithiocarbamate prevents Ⅰ-kappaB degradation and reduces microvascular injury induced by lipopolysaccharide in multiple organs. Mol Pharmacol 1999;55:658-67.
[18]Schreck R, Meier B, Mannel DN, et al. Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. J Exp Med 1992; 175:1181-94.
[19]Cardona AE, et al. Control of microglial neurotoxicity by the fractalkine receptor. Nat.Neurosci. 2006;9:917-924.
[20] Liu YL, Zhou LJ, Hu NW, et al. Tumor necrosis factor-a induces long-term potentiation of C-fiber evoked field potentials in spinal dorsal horn in rats with nerve injury: the role of NF-kappa B, JNK and p38 MAPK. 2007;52:708-715.
[21]Cui YH, Le Y, Gong W, et al. Bacterial lipopolysaccharide selectively up-regulates the function of the chemotactic peptide receptor formy1 peptide receptor 2 in murine microglial cells. J Immunol 2002; 168:434-42.
[22] Hu S, Peterson PK, Chao CC. Cytokine-mediated neuronal apoptosis. Neurochem Int1997;30:427-31.
[1] Jorge E TL, Mario 10, Gilberto CH, et al. Comparison of the antinociceptive effect of celecoxib, diclofenac and resveratrol in the formalin test. Life Sciences 2002; 0:1669-1676.
[2] Marc G, Jean XM, Herve B, et al. Resveratrol decreases hyperalgesia induced by carrageenan in the rat hind paw. Life sciences 2001 ;68:1317-1321.
[3] Bi XL, Yang JY, Dong YX, et al. Resveratrol inhibits nitric oxide and TNF-alpha production by lipopolysaccharide-activated microglia. 2005;5:185-193.
[4] Arner S, Meyerson BA. Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain. Pain 1998;33:11-23.
[5] Soleas GJ, Diamandis EP, Goldberg DM. Resveratrol: a molecule whose time has come? And gone? Clin Biochem 1997;30:91-113.
[6] Fremont L. Biological effects of resveratrol. Life Sci 2000;66:663-673.
[7] Gao X, Deeb D, Media J, et al. Immunomodulatory activity of resveratrol : discrepant in vitro and in vivo immunological effects. Biochem Pharmacol 2003;66:2427-2435.
[8] Wang Q, Yu S, Simonyi A, et al. Resveratrol protects against neurotoxicity induced by kainic acid. Neurochem Res 2004;29:2105-2112.
[9] Ates O, Cayli SR, Yucel N, et al. Central nervous system protection by resveratrol in streptozotocin-induced diabetic rats. J Clin Neurosci 2007; 14:256-260.
[10]Zhuang H, Kim YS, Koehler RC, et al. Potential mechanism by which resveratrol, a red wine constituent, protects neurons. Ann N Y Acad Sci 2003;993:276-296.
[11]Aggarwal BB, Bharadwaj A, Aggarwal RS, et al. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Research 2004;24:2783-2840.
[12]Deysi YB, Monica AT, Francisca PS, et al. Pharmacological evidence for the participation of NO-cyclic GMP-PKG-K channel pathway in the antiallodynic actionof resveratrol.Pharmacology, Biochemistry and Behavior 2006;84:535-542.
[13] Sameer S, Kanwaljit C, Shrinivas KK. Effect of insulin and its combination with resveratrol or curcumin in attenuation of diabetic neuropathic pain: participation of nitric oxide and TNF-alpha. Phytother. Res. 2007;21:278-283.
[14]Hao S, Mata M, Glorioso JC, et al. Gene transfer to interfere with TNFα signaling in neuropathic pain. Gene Theraphy 2007,14:1010-1016.
[15]Ohtori S, Takahashi K, Moriya H, et al. TNF-alpha and TNF-alpha receptor type 1 upregulation in glia and neurons after peripheral nerve injury: studies in murine DRG and spinal cord. Spine 2004;29:1082-1088.
[16]Schafers M, Svensson CI, Sommer C, et al. Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38MAPK in primary sensory neurons. J Neurosci 2003 ;23:2517-2521.
[17] Svensson CI, Schafers M, Jones TL, et al. Spinal blockade of TNF blocks spinal nerve ligation-induced increases in spinal p-p38. Neurosci Lett 2005;379:209-213.
[18] Justin JH, Waylon MW, Lucy AH, et al. Substituted trans-Stilbenes, including analogues of the natural product resveratrol, inhibit the human tumor necrosis factor alpha-induced activation of transcription factor nuclear factor kappaB. J.Med.Chem 2006;49:7182-7189.
[19]KangG,KongPJ, Yuh YJ, et al. Curcumin suppresses lipopolysaccharide-induced cyclooxygenase-2 expression by inhibiting activator protein-1 and nuclear factor kappab bindings in BV2 microglial cells. J Pharmacol. Sci. 2004;94: 325-328.
[20] Moon SO, Kim W, Sung MJ, et al. Resveratrol suppresses tumor necrosis factor-a-induced fractalkine expression in endothelial cells. Mol Pharmacol. 2006; 70: 112-119.
[21] Sun S, Cao H, Han M, et al. New evidence for the involvement of spinal fractalkine receptor in pain facilitation and spinal glial activation in rat model of monoarthritis. Pain 2007;129:64-75.
[22]Zhuang ZY, Kavasaki Y, Tan PH, et al. Role of the CX3CRl/p38MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine. Brain,Behavior,and Immunity 2007;21:642-651.
[23]Milligan E, Zapata V, Schoeniger D, et al. An initial investigation of spinal mechanisms underlying pain enhancement induced by fractalkine, a neuronally released chemokine. European Journal of Neuroscience 2005;22:2775-2782.
[24] Johnston BD, DeMaster EG. Suppression of nitric oxide oxidation to nitrite by curcumin is due to the sequestration of the reaction intermediate nitrogen dioxide,not nitric oxide. Nitric Oxide.2003;8:231-234.
[25]Mann SK, Mukhopadhyay A, Aggarwal BB. et al. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kB , activator rotein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J. Immunol.2000;164:6509-6519.
[26] Chen Jennifer, Zhou Yungui, Mueller-Steiner S, et al. SIRT1 protects against microglia-dependent amyloid-p toxicity through inhibiting NF-kB signaling Journal of biological chemistry 2005;280:40364-40374.
[27] Verge GM, Milligan ED, Maier SF, et al. Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions. Eur J Neurosci 2004;20:l 150-1160
[28] Kim HI, Kim TH, Song JH. Resveratrol inhibit Na currents in rat dorsal root ganglion neurons. Brain Research 2005; 1045:134-141.
[1]鞠躬,吕国蔚,王百忍.神经生物学.北京:人民卫生出版社2004,343-370.
[2]Millan MJ The induction of pain:an integrative review.Prog.Neurobiol.1999;57:1-164.
[3]DeLeo JA,Sorkin LS,Watkins LR.(Eds.).Immune and Glial Regulation of Pain.IASP Press 2007;Seattle.
[4]Raivich G.Like cops on the beat:the active role of resting microglia.Trends Neurosci.2005;28:571-573.
[5]Perry VH,Hume DA,Gordon S.Immunohistochemical localisation of macrophages and microglia in the adult and developing mouse brain.Neurosci.1985;15:313-326.
[6]Aldskogius H,Kozlova EN.Central neuron-glial and glial-glial interations following axon injury.Prog.Neurobiol.1998;55:1-26.
[7]Lee JC,Mayer-Proschel M,Rao MS.Gliogenesis in the central nervous system Glia 2000;30:105-121.
[8]Haydon PG,Carmignoto G.Astrocyte control of synaptic transmission and neurovascular coupling.Physiol.Rev.2006;86:1009-1031.
[9]Pasti L,Zonata.M,Pozzan T,et al.Cytosolic calcium oscillations in astrocytes may regulate exocytotic release of glutamate.J.Neurosci.2001;21:477-484.
[10]Tsacopoulos M.Metabolic signaling between neurons and glial cells:a short review.J.Physiol.2002;96:283-288.
[11]Haydon PG.GLIA:listening and talking to the synapse.Nat.Rev.Neurosci.2001;2:185-193.
[12]McMahon SB,Cafferty WBJ,Marchand F.Immune and glial cell factors as pain mediators and modulators.Exp.Neurol.2005;192:444-462.
[13]Rostene W,Kitabgi P,Parsadaniantz SM.Chemokines:a new class of neuromodulator.Nat.Rev.Neurosci.2007;8:895-903.
[14]Fellin T,Sul J-Y,D'ascenzo M,et al.Bidirectional astrocyte-neuron communication:the many roles of glutamate and ATP.Novartis Foundation Symposium.2006;Wiley,Chichester.New York.
[15]Porter JT,Mccarthy KD.Astrocytic neurotransmitter receptors in situ and in vivo.Prog.Neurobiol.1997;51:439-455.
[16] Schipke CG, Ohlemeyer C, Matyash M, et al. Astrocytes of the mouse neocortex express functional N-methyl-D-aspartate receptors. FASEB J. 2001;15:1270-1272.
[17] Pocock JM, Kettenmann H. Neurotransmitter receptors on microglia. Trends Neurosci. 2007;30:527-535.
[18] Scholz J, Woolf CJ. The neuropathic pain triad: neurons, immune cells, and glia. Nat. Neurosci. 2007; 10:1361-1368.
[19] Hanisch U-K. Microglia as a source and target of cytokines. Glia 2002; 40:140-155.
[20] Keane RW, Hickey WF. Immunology of the Nervous System. Oxford University Press, New York. 1997.
[21] Aimar P, Pasti L, Carmignoto G, et al. Nitric oxide-producing islet cells modulate the release of sensory neuropeptides in the rat substantia gelatinosa. J.Neurosci. 1998; 18:10375-10388.
[22] Guo L-H, Schluesener HJ. The innate immunity of the central nervous system in chronic pain: the role of Toll-like receptors. Cell. Mol. Life Sci. 2007;64:1128-1136.
[23] Inoue A, Ikoma K, Morioka N,et al. Interleukin-1beta induces substance P release from primary afferent neurons through the cyclooxygenase-2 system.J.Neurochem. 1999; 73: 2206-2213.
[24] Malcangio M, Bowery NG, Flower RJ, et al. Effect of interleukin-lbeta on the release of substance P from rat isolated spinal cord. Eur. J. Pharmacol. 1996; 299:113-118.
[25] Southall MD, Michael RL, Vasko MR. Intrathecal NSAIDS attenuate inflammation-induced neuropeptide release from rat spinal cord slices. Pain 1998; 78:39-48.
[26] Halassa MM, Fellin T, Haydon PG. The tripartite synapse: roles for gliotransmission in health and disease. Trends Mol. Med. 2007; 13: 54-63.
[27] Nguyen MD, Julien J-P, Rivest S. Innate immunity: the missing link in neuroprotection and neurodegeneration? Nat. Rev. Neurosci. 2002; 3: 216-227.
[28] Burgher KL, Heroux JA, Ringheim GE. Cyclic AMP potentiation of cytokine-induced nitric oxide synthetase activity in a murine astrocyte cell line.Neurochem. Int. 1997; 30: 483-489.
[29] Murphy S, Grzybycki D. Glial NO. normal and pathological roles. Neurosci. 1996;2:90-99.
[30] Samad TA, Moore KA, Sapirstein A, et al. Interleukin-1b-mediated induction of COX-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 2001;410:471-475.
[31] Wolf G, Yirmiya R, Goshen I, et al. Impairment of interleukin-1 (IL-1) signaling reduces basal pain sensitivity in mice: genetic, pharmacological and developmental aspects. Pain 2003; 104: 471-480.
[32] Dantzer R. Cytokine-induced sickness behaviour: a neuroimmune response to activation of innate immunity. Eur. J. Pharmacol. 2004;500:399-411.
[33] Watkins LR, Maier SF. The pain of being sick: implications of immune-to-brain communication for understanding pain. Annu. Rev.Psychol. 2000; 51: 29-57.
[34] Zimmermann M. Pathobiology of neuropathic pain. Eur. J. Pharmacol. 2001 ;429: 23-37.
[35] Bennett GJ, Xie KY. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988;33: 87-107.
[36] Garrison CJ, Dougherty PM, Kajander KC, et al. Staining of glial fibrillary acidic protein (GFAP) in lumbar spinal cord increases following a sciatic nerve constriction injury. Brain Res. 1991; 565:1-7
[37] Watkins LR, Milligan ED, Maier SF. Glial activation: a driving force for pathological pain. Trends Neurosci. 2001; 24: 450-455.
[38] Pocock JM, Kettenmann H. Neurotransmitter receptors on microglia. Trends Neurosci. 2007; 30: 527-535.
[39] Garrison CJ, Dougherty PM, Carlton SM. GFAP expression in lumbar spinal cord of naive and neuropathic rats treated with MK-801. Exp. Neurol. 1994; 129:237-243
[40] Fonnum F, Johnsen A, Hassel B. Use of fluorocitrate and fluoroacetate in the study of brain metabolism. Glia 1997;21: 106-113.
[41] Ledeboer A, Sloane EM, Milligan ED, et al. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain 2005;115: 71-83.
[42] Obata K, Katsura H, Miyoshi K, et al. Activation of Toll-like receptor 3 in spinal microglia is required for tactile allodynia after nerve injury. Society for Neuroscience Conference Proceedings. San Diego, CA. 2007.
[43] Milligan ED, O'connor KA, Nguyen KT, et al. Intrathecal HIV-1 envelope glycoprotein gp 120 enhanced pain states mediated by spinal cord proinflammatory cytokines. J. Neurosci. 2001; 21:2808-2819.
[44] Holguin A, O'connor KA, Biedenkapp J, et al. HIV-1 gp120 stimulates proinflammatory cytokine-mediated pain facilitation via activation of nitric oxide synthase-Ⅰ (nNOS). Pain 2004; 110: 517-530.
[45] Ledeboer A, Jekich BM, Sloane EM,et al. Intrathecal interleukin-10 gene therapy attenuates paclitaxel-induced mechanical allodynia and proinflammatory cytokine expression in dorsal root ganglia in rats. Brain Behav. Immun. 2007;21:686-698.
[46] Abraham KE, Mcmillen D, Brewer KL. The effects of endogenous interleukin-10 on gray matter damage and pain behaviors following excitotoxic spinal cord injury in the mouse. Neuroscience 2004;124: 922-945.
[47] Johnston IN, Milligan ED, Wieseler-Frank J, et al. A role for pro-inflammatory cytokines and fractalkine in analgesia, tolerance and subsequent pain facilitation induced by chronic intrathecal morphine. J. Neurosci. 2004;24: 7353-7365.
[48] Milligan ED, Sloane EM, Langer SJ, et al. Controlling neuropathic pain by adeno-associated virus driven production of the antiinflammatory cytokine,interleukin-10. Mol. Pain 2005; 1:9-22.
[49] Moore KW, De Waal Malefyt R, Coffman RL, et al. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 2001 ; 19:683-765.
[50] Tikka TM, Koistinaho JE. Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia. J.Immunol. 2001;166, 7527-7533.
[51] Inoue K. The function of microglia through purinergic receptors: neuropathic pain and cytokine release. Pharmacol. Ther. 2006; 109: 210-226.
[52] Tsuda M, Shigemoto-Mogami Y, Koizumi S, et al. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 2003;424:778-783.
[53] Holguin A, Biedenkapp J, Campisi J, et al. HIV-1 gp120 stimulates proinXammatory cytokine-mediated pathological pain via activation of nitric oxide synthase-I (nNOS). Pain 2004; 110:517-530.
[54] Svensson CI, Hua XY, Powell HC, et al. Prostaglandin E2 release evoked by intrathecal dynorphin is dependent on spinal p38 mitogen activated protein kinase. Neuropeptides 2005;39: 485-494.
[55] Costigan M, Mannion RJ, Kendall G, et al. Heat shock protein 27:developmental regulation and expression after peripheral nerve injury. J.Neurosci. 1998; 18: 5891-5900.
[56] Vargas ME, Singh SJ, Barres BA. Why is Wallerian degeneration so slow in the CNS? Glia in Health and Disease, Cold Spring Harbor Laboratories, Cold Spring Harbor Laboratories. 2006.
[57] Scholz J, Broom DC, Youn DH, et al. Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina Ⅱ of the dorsal horn after peripheral nerve injury. J. Neurosci. 2005; 25: 7317-7323.
[58] Lehnardt S, Lachance C, Patrizi S, et al. The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J.Neurosci. 2002; 22:2478-2486.
[59] Tanga FY, Raghavendra V, DeLeo JA. Quantitative real-time RTPCR assessment of spinal microglial and astrocytic activation markers in a rat model of neuropathic pain. Neurochem. Int. 2004 ;45: 397-407.
[60] Laing KJ, Secombes CJ. 2004. Chemokines. Dev. Comp. Immunol. 28, 443-460.
[61] Murphy PM. International Union of Pharmacology. XXX. Update on chemokine receptor nomenclature. Pharmacol. Rev. 2002;54, 227-229.
[62] Mackay CR. Chemokines: immunology's high impact factors. Nat.Immunol. 2001; 2: 95-101.
[63] Mellado M, Rodriquez-Frade JM, Vila-Coro AJ, et al. Chemokine receptor homo- or heterodimerization activates distinct signaling pathways. EMBO J. 2001; 20: 2497-2507.
[64] Laudanna C, Alon R. Right on the spot. Chemokine triggering of integrinmediated arrest of rolling leukocytes. Thromb. Haemost. 2006; 95: 5-11.
[65] Rittner HL, Brack A. Chemokines and pain. Curr. Opin. Investig. Drugs 2006;7:643-646.
[66] Harrison JK, Jiang Y, Chen S, et al. Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia.Proc. Natl. Acad. Sci. 1998;95: 10896-10901.
[67] Lindia JA, Mcgowan E, Jochnowitz N, et al. Induction of CX3CL1 expression in astrocytes and CX3CR1 in microglia in the spinal cord of a rat model of neuropathic pain. J. Pain 2005;6: 434-438.
[68] Verge GM, Milligan ED, Maier SF, et al. Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions. Eur. J. Neurosci. 2004. 20,1150-1160.
[69] Meucci O, Fratatis A, Simen AA, et al. Expression of CX3CR1 chemokine receptors on neurons and their role in neuronal survival. Proc. Natl. Acad. Sci. 2000; 97: 8075-8080.
[70] Clark AK, Yip PK, Grist J, et al. Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc. Natl. Acad. Sci. 2007; 104:10655-10660.
[71] Zhuang Z-Y, Kawasaki Y, Tan P-H, et al. Role of the CX3CRl/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine. Brain Behav. Immun. 2007;21: 642-651.
[72] Milligan ED, Zapata V, Schoeniger D, et al. An initial investigation of spinal mechanisms underlying pain enhancement induced by fractalkine, a neuronally released chemokine. Eur. J. Neurosci. 2005;22:2775-2782.
[73] Langer SJ, Busha D, Milligan ED, et al. In vivo over-expression of fractalkine, a putative neuron-to-glia signal, to characterize underlying mechanisms of neuropathic pain. In: Therapy, A.S.O.G. (Ed.), American Society of Gene Therapy 9th Annual Meeting. MD, Elsevier Inc., Baltimore. 2006.
[74] Owolabi SA, Saab CY. Fractalkine and minocycline alter neuronal activity in the spinal cord dorsal horn. FEBS Lett. 2006; 580: 4306-4310.
[75] Hundhausen C, Schulte A, Schulz B, et al. Regulated shedding of transmembrane chemokines by the disintegrin and metalloproteinase 10 facilitates detachment of adherent leukocytes. J. Immunol. 2007; 178,8064-8072.
[76] Chapman GA, Moores K, Harrison D. Fractalkine cleavage from neuronal membranes represents an acute event in the inflammatory response to excitotoxic brain damage. J. Neurosci. 2000; 20: 1-5.
[77] Ludwig A, Hundhausen C, Lambert MH,et al. Metalloproteinase inhibitors for the disintegrin-like metalloproteinases ADAM 10 and ADAM 17 that differentially block constitutive and phorbol ester-inducible shedding of cell surface molecules. Comb. Chem. High Throughput Screen. 2005;8: 161-171.
[78] Hundhausen C, Misztela D, Berkhout TA,et al. The disintegrin-like metalloproteinase ADAM 10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1 -mediated cell-cell adhesion. Blood 2003;102:1186-1195.
[79] Cross AK, Woodroofe MN. Chemokine modulation of matrix metalloproteinase and TIMP production in adult rat brain microglia and a human microglial cell line in vitro. Glia 1999; 28,183-189.
[80] Biber K, Dijkstra I, Trebst C,et al. Functional expression of CXCR3 in cultured mouse and human astrocytes and microglia. Neuroscience 2002; 112: 487-497.
[81] Rappert A, Bechmann I, Pivneva T, et al. CXCR3-dependent microglial recruitment is essential for dendrite loss after brain lesion. J. Neurosci. 2004;24:8500-85009.
[82] Zhang J, De Koninck Y. Spatial and temporal relationship between monocyte chemoattractant protein-1 expression and spinal glial activation following peripheral nerve injury. J. Neurochem. 2006;97:772-783.
[83] Abbadie C, Lindia JA, Cumiskey AM,et al. Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2. Proc. Natl. Acad. Sci. USA 2003;100:7947-7952.
[84] Cao L, Deleo JA. CNS-infiltrating CD4+ T lymphocytes contribute to murine spinal nerve transection-induced neuropathic pain. Eur. J. Immunol. 2008;38: 448-458.
[85] Aravalli RN, Peterson PK, Lokensgard JR. Toll-like receptors in defense and damage of the central nervous system. J. Neuroimmune.Pharmacol. 2007; 2:297-312.
[86] Jack CS, Arbour N, Manusow J, et al. TLR signaling tailors innate immune responses in human microglia and astrocytes. J. Immunol. 2005; 175:4320-4330.
[87] Kigerl KA, Lai W, Rivest S,et al. Toll-like receptor (TLR)-2 TLR-4 regulate inflammation, gliosis, myelin sparing after spinal cord injury. J. Neurochem. 2007;102: 37-50.
[88] White FA, Bhangoo SK, Miller RD. Chemokines: integrators of pain and inflammation. Nature Rev. 2005; 4: 834-844.
[89] van Rossum D, Hanisch UK. Microglia. Metab. Brain Dis. 2004; 19: 393-411.
[90] Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005; 308: 1314-1318.
[91] Davalos D, Grutaendler J, Yang G, et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 2005;8: 752-758.
[92] Haynes SE, Hollopeter G, Kurpius D, et al. The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat. Neurosci. 2006; 9: 1512-1519.
[93] Boillee S, Yamanaka K, Lobsiger CS, et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science 2006;312: 1389-1392.
[94] Streit WJ. Microglial senescence: does the brain's immune system have an expiration date? Trends Neurosci. 2006;29: 506-510.
[95] Neumann H, Takahashi K. Essential role of the microglial triggering receptor expressed on myeloid cells-2 (TREM2) for central nervous tissue immune homeostasis. J. Neuroimmunol. 2007; 184:92-99.
[96] Biber K, Neumann H, Inoue K, et al. Neuronal On and Off signals control microglia. Trends Neurosci. 2007;30: 596-602.
[97] Pocock JM, Kettenmann HK. Neurotransmitter receptor on microglia. Trends Neurosci. 2007; 30: 527.
[98] Loredo GA, Benton HP. ATP and UTP activate calcium-moblizing P2U-like receptors and act synergistically with interleukin-1 to stimulate prostaglandin E2 release from human rheumatoid synovial cells. Arthritis Rheum. 1998;41: 246-255.
[99] Ledeboer A, Sloane EM, Milligan ED, et al. Minocycline attenuates mechanical allodynia and proinXammatory cytokine expression in rat models of pain facilitation. Pain 2005;l 15:71-83.
[100]Schafers M, Sommer C. Anticytokine therapy in neuropathic pain management. Expert Rev. Neurotherapeutics 2007;7:1613-1627.
[101]Milligan ED, Sloane EM, Langer SJ, et al. Repeated intrathecal injections of plasmid DNA encoding interleukin-10 produce prolonged reversal of neuropathic pain. Pain 2006; 126:294-308.
[102] Song P, Zhao ZQ. The involvement of glial cells in the development of morphine tolerance. Neurosci. Res. 2001; 39:281-286.
[103] Johnston IN, Milligan ED, Wieseler-Frank J,et al. A role for proinXammatory cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine. J. Neurosci. 2004;24: 7353-7365.
[104]Raghavendra V, Rutkowski MD, DeLeo JA. The role of spinal neuroimmune activation in morphine tolerance/hyperalgesia in neuropathic and sham-operated rats. J. Neurosci. 2002;22:9980-9989.
[105]Shavit Y, Wolf G, Goshen I, et al. Interleukin-1 antagonizes morphine analgesia and underlies morphine tolerance. Pain 2005;l 15: 50-59.
[106]Mao J, Sung B, Ji RR, et al. Chronic morphine induces downregulation of spinal glutamate transporters: implications in morphine tolerance and abnormal pain sensitivity. J. Neurosci. 2002;22: 8312-8323.
[107]Hutchinson MR, Somogyi AA. Relationship between 4,5-epoxymorphinan structure and in vitro modulation of cell proliferation. Eur. J. Pharmacol. 2004; 494:251-262.
[108]Hutchinson MR, Somogyi AA. (S)-(+)-methadone is more immunosuppressive than the potent analgesic (R)-(-)-methadone. Intlmmunopharmacol. 2004; 4: 1525-1530.
[109]Hutchinson MR, Somogyi AA. Characterisation of the in vitro modulation of splenocyte proliferation by non-4,5-epoxymorphinan opioids. Int. Immunopharmacol. 2005;5: 1713-1722.
[110] Coats BD, Hutchinson MR, Watkins LR. Opioid inactive (+)-naloxone potentiates morphine analgesia: further evidence that opioid analgesia is opposed by opioid induced glial activation. Neuroscience Meeting Planner.Atlanta, GA: Society for Neuroscience. 2006.
[111]Zhang N, Rogers TJ, Caterina M, et al. ProinXammatory chemokines, such as C-C chemokine ligand 3, desensitize mu-opioid receptors on dorsal root ganglia neurons. J. Immunol. 2004; 173:594-599.
[112]Adler MW, Geller EB, Chen X,et al. Viewing chemokines as a third major ystem of communication in the brain. Aaps J. 2006; 7: E865-E870.