米诺环素对口颌面部炎性疼痛及p38MAPK通路作用的研究
|
摘要
口颌面部疼痛发病机制十分复杂,近年的研究发现疼痛的形成和发展与信号转导的多条通路密切相关,其中p38MAPK信号转导通路已成为研究热点。大量的研究表明,p38MAPK通过对细胞转录、蛋白合成、受体表达等多方面的调节,在神经元可塑性变化及疼痛信号转导中起重要作用。因此深入分析p38MAPK在口颌面部病理性疼痛中的作用,将有助于我们更好的理解信号转导在口颌面部疼痛中的功能,并为发现更有效的疼痛治疗靶点提供依据。
米诺环素多年来作为一种抗生素药物已成功地应用于人类感染性疾病和炎症性疾病。最近在中枢神经系统疾病的研究中发现米诺环素具有神经保护作用,能够抑制神经病理性疼痛,那么,在口颌面部炎性疼痛中米诺环素是否起作用以及米诺环素的作用是否与p38MAPK通路有关成为值得研究的问题。
目的：通过建立福尔马林致口颌面部炎性疼痛模型,研究三叉神经脊束核尾侧亚核(Vc核)c-fos、GFAP和OX-42的变化时程,探讨口颌面部炎性疼痛的中枢致敏机制；观察Vc核中p38MAPK磷酸化水平(活性)的变化及其特异性抑制剂SB203580的镇痛疗效,探讨p38MAPK在口颌面部炎性疼痛中的作用；经中枢和外周给予米诺环素,观察米诺环素对福尔马林致口颌面部炎性疼痛的作用,并通过观察其对p38 MAPK活化的影响,探讨米诺环素在口颌面部病理性疼痛的作用机制。
材料和方法：采用雄性SD大鼠,在左上唇皮下注射2.5%福尔马林50μl建立口颌面部炎性疼痛模型。1.分别在造模后30、60、120、240、360min各时间点,通过免疫荧光染色观察各组大鼠Vc核c-fos、GFAP和OX-42表达的情况。2.在注射后10、20、30、40min各时间点用免疫蛋白印迹方法,检测各组大鼠Vc核p38活化(p-p38)的变化情况；大鼠小脑延髓池内置管后于造模前20min给予p38MAPK抑制剂SB20358 0,通过行为学和c-fos表达情况,观察其镇痛效果。3.各组大鼠在注射福尔马林前1h腹腔注射米诺环素(60 mg/kg,90mg/kg)或在注射福尔马林前2 0 min小脑延髓池注射米诺环素(60μg,120μg),每组动物测定痛行为反应后,用免疫荧光染色和免疫蛋白印迹法分析各组大鼠同侧Vc核c-fos、p-p38和OX-42表达的变化。
结果：
1.在左上唇皮下注射福尔马林后,免疫组化及免疫荧光染色结果显示fos阳性(fos-immunoreactivity, Fos-IR)神经元在注射后30min即可观察到,120min达到峰值,到360min观察结束仍有较高的表达。GFAP-IR在福尔马林注射后30min即有较高表达,60min达峰值后下降,240min即恢复到正常水平,二者分布区域相同。OX-42-IR 1d开始出现,3d后明显,7d达到峰值,14d后开始减弱。
2.在左上唇皮下注射福尔马林后,Western blot结果显示Vc核中总p38MAPK水平无明显变化,但是p-p38水平明显增加。p-p38在福尔马林注射后10min即可以检测到,20min达高峰,之后逐渐下降。预先经小脑延髓池注射p38MAPK抑制剂SB203580可以明显抑制福尔马林引发的第Ⅱ期疼痛行为反应,并且抑制疼痛引发的Vc核的c-fos表达。
3.大鼠左上唇注射福尔马林引起的痛行为反应包括两期,预先腹腔(i.p.)或经小脑延髓池(i.c.)注射米诺环素在较大剂量(i.p.90mg/kg, i.c.120μg)抑制福尔马林引起的第Ⅱ期痛行为反应,但对第Ⅰ期痛行为反应没有作用。预先腹腔或小脑延髓池内注射米诺环素可以抑制福尔马林注射后诱导的p-p38、c-fos和OX-42的表达,并呈现剂量依赖性。
结论：
1.在大鼠上唇皮下注射福尔马林可以引发典型的二期疼痛反应,是较好的口颌面部炎性疼痛模型。
2.在福尔马林致口颌面部炎性疼痛模型中Vc核内神经元和胶质细胞(星形胶质细胞、小胶质细胞)先后被激活,相互作用,共同参与中枢神经系统对炎性疼痛刺激的调节。
3.福尔马林致口颌面部炎性疼痛模型中p38MAPK活化水平增加,p38MAPK通路被激活,参与病理性疼痛的形成；p38MAPK抑制剂-SB203580可明显缓解疼痛,进一步证实了p38MAPK在口颌面部炎性疼痛中的作用。
4.米诺环素通过抑制小胶质细胞的激活和p38MAPK通路缓解福尔马林诱发的口颌面部炎性疼痛。
The orofacial region is one of the most densely innervated (by the trigeminal nerve) areas of the body, which focuses some of the most common pains. However, the mechanisms underlying these pains are still poorly understood, partly due to the relative scarcity of investigations devoted to the face and the mouth, compared to the rest of the body. P38MAPK represents a group of enzymes in the MAPK family that phosphorylated and activated by a variety of physical, chemical and biological stimuli. Accumulating evidences suggested that p38MPAK played an important role in neural plasticity through regulating cell transcription, protein synthesis and receptor expression. Recent work suggested that activation of p38 mitogen-activated protein kinase (p38) in dorsal root ganglia and spinal cord played a critical role in nerve injury and inflammation-induced spinal pain processing. Inhibition of this kinase prevents hypersensitivity induced by both peripheral inflammation and nerve injury. Minocycline is a semi-synthetic second-generation tetracycline that penetrates well into the central nervous system (CNS) via blood-brain barrier. In addition to its actions as an antibiotic, minocycline has neuroprotective and anti-inflammatory effects in the CNS. Recently, it has been demonstrated that the inhibition of microglial activation by minocycline attenuates the development of pain hypersensitivity in rat models of neuropathic pain. This finding raises the possibility that minocycline may behave as a potential analgesic for other pain model types. Using the orofacial formalin test, we evaluated the potential role of p38 mitogen-activated protein kinase (MAPK) in the spinal trigeminal nucleus in the orofacial inflammatory pain and investigated whether minocycline had effects on orofacial inflammatory pain.
Object:l.To investigate the changes of c-fos, GFAP and OX-42 expression in Vc in formalin-induced orofacial pain rat to explore the mechanism of central sensitization.2. To evaluate the potential role of p38 mitogen-activated protein kinase (MAPK) in the orofacial inflammatory pain. 3. To investigate the effects of minocycline on orofacial inflammatory pain and p38 MAPK path way.
Materials and methods:1. Male SD rats received subcutaneous injection of 2.5% formalin 50μl in the left vibrissa pad to establish the inflammatory pain model. The expressions of c-fos, GFAP and OX-42 were detected at specific time point by immunohistochemical and immunofluorescence staining.2. At each time point of 10,20,30,40 minutes after formalin injection, p38 MAPK activity in Vc were examined by means of western blot analysis; SB203580, a p38 MAPK inhibitor was inserted into the rat's cisterna magna 20 minutes prior to the formalin injection, then the behavioral changes and the expression of c-fos in Vc were tested.3.1 hour before formalin injection,60 mg/kg, 90mg/kg minocycline intraperitonially or 20 minutes before formalin injection,60μg,120μg minocycline intracisterna magna injected respectively, then the behavioral changes and the expression of p-p38,c-fos and OX-42 in Vc were tested.
Results:
1. Fos-immunoreactivity (Fos-IR) neurons were presented at 30 minutes, peaked at 120 minutes and remained at a higher level by 360 min after injection. Meanwhile, the expression of GFAP-IR was observed higher at 30 minutes, peaked at 60 minutes, then declined and returned to normal level by 240 minutes after injection. Fos-IR and GPAP-IR showed similar distribution. The expression of OX-42-IR started on day 1 and peaked at day 7, then declined at day 14 post-injection.
2. P38 MAPK was constitutively expressed in Vc and p38 MAPK was activated following formalin injection. The level of phosphorylated p38 expression was increased 10 minutes after the formalin injection, peaked at 20 minutes, and declined at 30 minutes. Intracisterna magna pretreatment of p38 MAPK inhibitor-SB203580 resulted in potent attenuation of phase II of pain behavior but not phaseⅠ. Meanwhile, the expression of c-fos was also been inhibited.
3. Formalin induced orofacial pain behavioral responses included two Phases, and intraperitonial or intracisterna magna preadministration of minocycline significantly suppressed phase II with little effects on phase I. Intraperitonial or intracisterna magna preadministration of minocycline produced significant suppression on the activation of p38MAPK, c-fos and OX-42 in Vc.
Conclusion
1. Subcutaneous injection of formalin into the vibrissa pad could produced two phases nociceptive behavioral responses in rat, which is a suitable model for orofacial inflammatory pain research.
2. The results suggested that the neurons and glia (astrocytes and microglia) in the Vc might jointly participate in pain modulation in CNS and glia (astrocytes and microglia) and regulate neuron's function in formalin-induced orofacial pain model.
3. Activation of p38 mitogen-activated protein kinase played a major role in the development of orofacial inflammatory pain and it was verified by the experimental result that p38 MAPK inhibitor-SB203580 inhibited the fonnalin-induced orofacial pain.
4. Preadministration of minocycline produced a potent antinociception in formalin-induced orofacial pain model and this effect was mediated by inhibition of activation of p38MAPK and microgia in Vc.
米诺环素多年来作为一种抗生素药物已成功地应用于人类感染性疾病和炎症性疾病。最近在中枢神经系统疾病的研究中发现米诺环素具有神经保护作用,能够抑制神经病理性疼痛,那么,在口颌面部炎性疼痛中米诺环素是否起作用以及米诺环素的作用是否与p38MAPK通路有关成为值得研究的问题。
目的：通过建立福尔马林致口颌面部炎性疼痛模型,研究三叉神经脊束核尾侧亚核(Vc核)c-fos、GFAP和OX-42的变化时程,探讨口颌面部炎性疼痛的中枢致敏机制；观察Vc核中p38MAPK磷酸化水平(活性)的变化及其特异性抑制剂SB203580的镇痛疗效,探讨p38MAPK在口颌面部炎性疼痛中的作用；经中枢和外周给予米诺环素,观察米诺环素对福尔马林致口颌面部炎性疼痛的作用,并通过观察其对p38 MAPK活化的影响,探讨米诺环素在口颌面部病理性疼痛的作用机制。
材料和方法：采用雄性SD大鼠,在左上唇皮下注射2.5%福尔马林50μl建立口颌面部炎性疼痛模型。1.分别在造模后30、60、120、240、360min各时间点,通过免疫荧光染色观察各组大鼠Vc核c-fos、GFAP和OX-42表达的情况。2.在注射后10、20、30、40min各时间点用免疫蛋白印迹方法,检测各组大鼠Vc核p38活化(p-p38)的变化情况；大鼠小脑延髓池内置管后于造模前20min给予p38MAPK抑制剂SB20358 0,通过行为学和c-fos表达情况,观察其镇痛效果。3.各组大鼠在注射福尔马林前1h腹腔注射米诺环素(60 mg/kg,90mg/kg)或在注射福尔马林前2 0 min小脑延髓池注射米诺环素(60μg,120μg),每组动物测定痛行为反应后,用免疫荧光染色和免疫蛋白印迹法分析各组大鼠同侧Vc核c-fos、p-p38和OX-42表达的变化。
结果：
1.在左上唇皮下注射福尔马林后,免疫组化及免疫荧光染色结果显示fos阳性(fos-immunoreactivity, Fos-IR)神经元在注射后30min即可观察到,120min达到峰值,到360min观察结束仍有较高的表达。GFAP-IR在福尔马林注射后30min即有较高表达,60min达峰值后下降,240min即恢复到正常水平,二者分布区域相同。OX-42-IR 1d开始出现,3d后明显,7d达到峰值,14d后开始减弱。
2.在左上唇皮下注射福尔马林后,Western blot结果显示Vc核中总p38MAPK水平无明显变化,但是p-p38水平明显增加。p-p38在福尔马林注射后10min即可以检测到,20min达高峰,之后逐渐下降。预先经小脑延髓池注射p38MAPK抑制剂SB203580可以明显抑制福尔马林引发的第Ⅱ期疼痛行为反应,并且抑制疼痛引发的Vc核的c-fos表达。
3.大鼠左上唇注射福尔马林引起的痛行为反应包括两期,预先腹腔(i.p.)或经小脑延髓池(i.c.)注射米诺环素在较大剂量(i.p.90mg/kg, i.c.120μg)抑制福尔马林引起的第Ⅱ期痛行为反应,但对第Ⅰ期痛行为反应没有作用。预先腹腔或小脑延髓池内注射米诺环素可以抑制福尔马林注射后诱导的p-p38、c-fos和OX-42的表达,并呈现剂量依赖性。
结论：
1.在大鼠上唇皮下注射福尔马林可以引发典型的二期疼痛反应,是较好的口颌面部炎性疼痛模型。
2.在福尔马林致口颌面部炎性疼痛模型中Vc核内神经元和胶质细胞(星形胶质细胞、小胶质细胞)先后被激活,相互作用,共同参与中枢神经系统对炎性疼痛刺激的调节。
3.福尔马林致口颌面部炎性疼痛模型中p38MAPK活化水平增加,p38MAPK通路被激活,参与病理性疼痛的形成；p38MAPK抑制剂-SB203580可明显缓解疼痛,进一步证实了p38MAPK在口颌面部炎性疼痛中的作用。
4.米诺环素通过抑制小胶质细胞的激活和p38MAPK通路缓解福尔马林诱发的口颌面部炎性疼痛。
The orofacial region is one of the most densely innervated (by the trigeminal nerve) areas of the body, which focuses some of the most common pains. However, the mechanisms underlying these pains are still poorly understood, partly due to the relative scarcity of investigations devoted to the face and the mouth, compared to the rest of the body. P38MAPK represents a group of enzymes in the MAPK family that phosphorylated and activated by a variety of physical, chemical and biological stimuli. Accumulating evidences suggested that p38MPAK played an important role in neural plasticity through regulating cell transcription, protein synthesis and receptor expression. Recent work suggested that activation of p38 mitogen-activated protein kinase (p38) in dorsal root ganglia and spinal cord played a critical role in nerve injury and inflammation-induced spinal pain processing. Inhibition of this kinase prevents hypersensitivity induced by both peripheral inflammation and nerve injury. Minocycline is a semi-synthetic second-generation tetracycline that penetrates well into the central nervous system (CNS) via blood-brain barrier. In addition to its actions as an antibiotic, minocycline has neuroprotective and anti-inflammatory effects in the CNS. Recently, it has been demonstrated that the inhibition of microglial activation by minocycline attenuates the development of pain hypersensitivity in rat models of neuropathic pain. This finding raises the possibility that minocycline may behave as a potential analgesic for other pain model types. Using the orofacial formalin test, we evaluated the potential role of p38 mitogen-activated protein kinase (MAPK) in the spinal trigeminal nucleus in the orofacial inflammatory pain and investigated whether minocycline had effects on orofacial inflammatory pain.
Object:l.To investigate the changes of c-fos, GFAP and OX-42 expression in Vc in formalin-induced orofacial pain rat to explore the mechanism of central sensitization.2. To evaluate the potential role of p38 mitogen-activated protein kinase (MAPK) in the orofacial inflammatory pain. 3. To investigate the effects of minocycline on orofacial inflammatory pain and p38 MAPK path way.
Materials and methods:1. Male SD rats received subcutaneous injection of 2.5% formalin 50μl in the left vibrissa pad to establish the inflammatory pain model. The expressions of c-fos, GFAP and OX-42 were detected at specific time point by immunohistochemical and immunofluorescence staining.2. At each time point of 10,20,30,40 minutes after formalin injection, p38 MAPK activity in Vc were examined by means of western blot analysis; SB203580, a p38 MAPK inhibitor was inserted into the rat's cisterna magna 20 minutes prior to the formalin injection, then the behavioral changes and the expression of c-fos in Vc were tested.3.1 hour before formalin injection,60 mg/kg, 90mg/kg minocycline intraperitonially or 20 minutes before formalin injection,60μg,120μg minocycline intracisterna magna injected respectively, then the behavioral changes and the expression of p-p38,c-fos and OX-42 in Vc were tested.
Results:
1. Fos-immunoreactivity (Fos-IR) neurons were presented at 30 minutes, peaked at 120 minutes and remained at a higher level by 360 min after injection. Meanwhile, the expression of GFAP-IR was observed higher at 30 minutes, peaked at 60 minutes, then declined and returned to normal level by 240 minutes after injection. Fos-IR and GPAP-IR showed similar distribution. The expression of OX-42-IR started on day 1 and peaked at day 7, then declined at day 14 post-injection.
2. P38 MAPK was constitutively expressed in Vc and p38 MAPK was activated following formalin injection. The level of phosphorylated p38 expression was increased 10 minutes after the formalin injection, peaked at 20 minutes, and declined at 30 minutes. Intracisterna magna pretreatment of p38 MAPK inhibitor-SB203580 resulted in potent attenuation of phase II of pain behavior but not phaseⅠ. Meanwhile, the expression of c-fos was also been inhibited.
3. Formalin induced orofacial pain behavioral responses included two Phases, and intraperitonial or intracisterna magna preadministration of minocycline significantly suppressed phase II with little effects on phase I. Intraperitonial or intracisterna magna preadministration of minocycline produced significant suppression on the activation of p38MAPK, c-fos and OX-42 in Vc.
Conclusion
1. Subcutaneous injection of formalin into the vibrissa pad could produced two phases nociceptive behavioral responses in rat, which is a suitable model for orofacial inflammatory pain research.
2. The results suggested that the neurons and glia (astrocytes and microglia) in the Vc might jointly participate in pain modulation in CNS and glia (astrocytes and microglia) and regulate neuron's function in formalin-induced orofacial pain model.
3. Activation of p38 mitogen-activated protein kinase played a major role in the development of orofacial inflammatory pain and it was verified by the experimental result that p38 MAPK inhibitor-SB203580 inhibited the fonnalin-induced orofacial pain.
4. Preadministration of minocycline produced a potent antinociception in formalin-induced orofacial pain model and this effect was mediated by inhibition of activation of p38MAPK and microgia in Vc.
引文
1. Watkins LR, Milligan ED, Maier SF, et al. Spinal cord glia:new players in pain. Pain.2001,93:201-205.
2. Jian Liu K,Rosenberg G A.Matrix matalloproteinases and free radicals in ceredral ischemia. Free Radic Biol Med.2005,399(10):71-80.
3. Dubuisson D, Dennis SG.The formalin test:a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain.1977,4(2):161-374.
4. Dickenson AH, Sullivan AF. Subcutaneous formalin-induced activity of dorsal horn neurones in the rat:differential response to an intrathecal opiate administered pre or post formalin. Pain.1987,30(3):349-60.
5. Ali Z, Meyer RA, Campbell JN. Secondary hyperalgesia to mechanical but not heat stimuli following a capsaicin injection in hairy skin.Pain.1996,68(2-3):401-11.
6. Simone DA, Nolano M, Johnson T,et al.Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers:correlation with sensory function. J eurosci.1998,18(21):8947-59.
7. Clavelou P, Pajot J, Dallel R, et al.Application of the formalin test to the study of orofacial pain in the rat. Neurosci Lett,1989,103:349-353.
8. Capone F, Aloisi AM.Refinement of pain evaluation techniques.The formalin test. Ann Ist Super Sanita,2004,40(2):223-229.
9. Rosland JH. The formalin test in mice:the influence of ambient temperature. Pain.1991,45:211-6.
10. Hole K, Tjolsen A. The tail-flick and formalin.tests in rodents:changes in skin temperature as a confounding factor. Pain.1993,53:247-54.
11. Wheeler-Aceto H, Cowan A. Standardization of the rat paw formalin test for the evaluation of analgesics. Psychopharmacol (Berl).1991, 104:35-44.
12. Pierre C, Radhouane D, Thierry O, et al.The orofacial formalin test in rats:effects of different formalin concentrations.Pain.1995,62: 295-301.
13. Eisenberg E, Vos BP, Strassman AM. The NMD A antagonist Memantine blocks pain behavior in a rat model of formalin-induced facial pain. Pain.1993,54:301-7.
14. Klein BG, Misra BR, White CF. Orofacial pain sensitivity in adult rats following neonatal infraorbital nerve transection. Behav Brain Res.1991 ,46:197-201.
15. Paula J, Seadi P, Fabiana N, et al Nociceptive and inflammatory responses induced by formalin in the orofacial region of rats:Effect of anti-TNFa strategies. International Immunopharmacology.2009,9, 80-85.
16. Sessle, B.J. Acute and chronic craniofacial pain:brainstem mechanisms of nociceptive transmission and neuroplasticity, and their clinical correlates. Crit. Rev. Oral Biol Med.2002,11,57-91.
17. Zhou Q,Imbe h, Dubner R, et al. Persistent Fos protein expression after
orofacial deep or cutaneous tissue inflammation in rats: implications for persistent orofacial pain. J Comp Neurl.1999,412(2): 276-291.
18. He YF, Ichikawa H, Sugimoto T. The effect of neonatal capsaicin on the c-Fos-like immunoreactivity induced in subnucleus oxalis neurons by noxious intraoral stimulation. Brain Res.2000,860(1-2):203-207.
19. 董研,刘洪臣,王新木等.咬合创伤对三叉神经脊束核敏化作用的研究.中华口腔医学杂志,2004,39(5)：418-420.
20. Takeshita S, Hirata H, Bereiter DA.Intensity coding by TMJ-responsive neurons in superficial laminae of caudal medullary dorsal horn of the rat. J Neurophysiol.2001,86:2393-404.
21. Jin Y. Ro, Norman F, JK Lee.Hypertonic saline-induced muscle nociception and c-fos activation are partially mediated by peripheral NMDA receptors. Eur J Pain.2007,11,398-405.
22. Bullit E. Expression of c-fos like protein as a marker for neuronal activity following noxious stimulation in the rat. J Comp Neurol, 1990,296:517-530.
23. Zheng G, Ik-Hyun C, Chul K P. Activation of glia and microglial p38 MAP-K in medullary dorsal horn contributes to tactile hypersensitivity following trigeminal sensory nerve injury. Pain.2006,121,219-231.
24. Iwata K, Takahashi 0, Tsuboi Y, et al. Fos protein induction in the medullary dorsal horn and first segment of the spinal cord by tooth-pulp stimulation in cats. Pain,1998,75(1):27-36.
25. 顾斌.脂多糖诱发急性牙髓炎致敏的三又神经节功能蛋白质组学研究.军医进修学院博士学位论文.2008,31-33.
26. Marfurt CF, Turner DF. The central projections of tooth pulp afferent neurons in the rat as determined by the transganglionic transport of horseradish peroxidase. J Comp Neurol.1984,223(4):535-47.
27. Watkins LR, Milligan ED, Maier SF, et al. Spinal cord glia:new players in pain. Pain,2001,93:201-205.
28. Jian LK, Rosenberg G A. Matrix matalloproteinases and free radicals in cerebral ischemia. Free Radic Biol Med.2005,39910:71-80.
29.兰莉,高蓓,饶志仁.脂多糖对大鼠中脑和桥脑内Fos、GFAP、OX42表达的影响.解剖学报.2005,36(1)：24-27.
30. Colbum RW, Rickman AJ, Deleo JA, et al. The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior. Exp Neuro.1999,157:289-304
31. Chen JW, Zhang J, Zhao YM, et al.. Hyperalgesia in response to traumatic occlusion and GFAP expression in rat parabranchial nucleus: modulation with fluorocitrate. Cell Tissue Res.2007,329:231-237.
32. Kettenmann H,Ransom BR. Neuroglia. NewYork:Oxford University Press,1995.
33. Wakins LR, Milligan ED, Maiser SF. Glial proinflammatory cytokines mediate exaggerated pain states:implications for clinical pain. In: Immune mechanisms of pain & analgesia. Austin TX:Landes Biosciences,2001,199-213.
34. Vitkovic L, Konsman J, P, Bockaert J, et al. Cytokine signals propagate through the brain. Mol psychiatry.2000,5:604-615.
35. Qin M., Wang JJ, Cao R.The lumbar spinal cord glial cells actively modulate subcutaneous formalin induced hyperalgesia in the rat. Neurosci Res.2006,55:442-450.
36. Guo W, Wang H, Watanabe M, et al. Glial-cytokine neuronal interactions underlying the mechanisms of pensistent pain. Neurosci.2007,27(22):6006-8.
37. 贾静,刘洪臣,章捍东等。咬合创伤下大鼠三叉神经脊束核尾侧亚核星形胶质细胞的反应及其与细胞因子的关系.中华老年口腔医学杂志.2005,3(3)：132-134.
38. Steward O, Torre ER, Tomasulo R, et al.Neuronal activity up-regulates astroglial gene expression. Proc Natl Acad Sci USA.1991, 88(15):6819-23.
39. Bergles DE, Roberts JD, Somogyi P, et al. Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus. Nature. 2000,405(6783):187-191.
40. Guo LH, Traumann K, Schluesener J. Expression of P2X4 receptor by lesion activated microglia during formalin-induced inflammatory pain.Neuroimmu.2005,163:120-127.
1. Colburn, R.W., Rickman, A.J., DeLeo, J.A. The effect of site and type of Exp.Neurol.1999,157:289-304.
2. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science,2005, 308:(3)418.
3. Stolzing A,Wengner A,Grune T.Degredation of oxidized extracellular proteins by microglia.Arch Biochem Biophys.2002,400(2):171-179.
4. Kristin LS, Alvin JB, George LW,etal.Activation of spinal microglia in a murine model of peripheralinflammation-induced, long-lasting contralateral allodynia. Neuroscience Letters.2008,440:63-67.
5. 傅开元,Light AR, Maixner W.外周炎症性疼痛刺激诱发中枢神经系统小胶质细胞增殖活化.中国神经免疫学和神经病学杂志.2001,8(3)：179-183.
6. Watkins LR,Maier SF.The pain of being sick:implications of mmune-to-brain communication for understanding pain.AnnuRev Psychol.2000,51:29-57.
7. DeLeo JA,Colburn RW.Proinflammatory cytokines and glial cellsaheir role in neuropathic pain.In:Watkins LR,Maier SF eds.Cytokines and pain. Basel:Birkhauser verlag,1999,159-182.
8. Hashizume H, DeLeo JA,Colburn RW,etal.Spinalglialacti-Vation and cytokine expression after lumbar root injury in the rat. Spine,2000, 25:.1206-1217.
9. Milligan ED, Mehmert KK, Hinde GL, et al. Thermal hyperalgesia and mechanical allodynia produced by intiathecal administiation of the human im munodeficiency Viru 1(HIV-1) envelope glycoprotein, gp120.Brain Res,2000,861:105-116.
10. Piao ZG, Cho IH, Park CK, et al. Activation of glia and microglial p38 MAPK in medullary dorsal horn contributes to tactile hypersensitivity following trigeminal sensory nerve injury. Pain.2006,121 (3):219-31.
11. Lim EJ, Jeon HJ, Yang GY,et al.Intracisternal administration of mitogen-activated protein kinase inhibitors reduced mechanical allodynia following chronic constriction injury of infraorbital nerve in rats.Progress in Neuro-Psychophar & Biolo Psych 31 2007(31):1322-1329.
12. McMahon S B, Cafferty WB,Marchand F. Immune and glial cell factors as pain mediators and modulators. Exp Neurol.2005,192:444-462.
13. Aumeerally N, AllenG, Sawynok J.Glutamate-evoked release of adenosine and regulation of peripheral nociception. Neuroscience.2004,127:1-11.
14. Fu KY, Light AR, Maixner W. Relationship between nociceptor activity, peripheral edema, spinal microglial activation and long-term hyperalgesia induced by formalin. Neuroscience.2000,101:1127-35.
15. Honore P, Rogers SD, Schwei, MJ, et al. Murine models of inflammatory, neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons. Neuroscience.2000,98:585-598.
16. Zhang J, Hoffert C, Vu HK, et al.Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. Eur. J. Neurosci.2005.17:2750-54.
17. Hua XY, Svensson CI, Matsui T, et al. Intrathecalminocycline attenuates peripheral inflammation2induced hyperalgesia by inhibiting p38 MAPK in spinal microglia. Eur J Neurosci.2005,22(10):2431-40.
18. Svensson CI, Fitzsimmons B, Azizi S, et al. Spinal p38beta isoform mediates tissue injury2induced hyperalgesia and spinal sensitization. J Neurochem.2005,92(6):1508-19.
19. Chapman G, Moores K, Harrison D,etal.Fractalkine cleavage from neuronal membranes represents an acute event in the inflammatory response to exci to toxic brain damage.JNeu-rosci.2000,20(15):RC87.
1.吴立玲,细胞信号转导与疾病,金惠铭主编《病理生理学》人民卫生出版社.2000年10月第5版：163-177023(10)：4017-22.
2. Obata T, Brown GE, Yaffe MB. MAP kinase pathways activated by stress:the p38MAPKpathway. Crit Care Med,2000,28(4):67-77.
3. Brewster JL,De Valoir T,Dwyer N, et al. An osmosensing signal trans-duction pathway in yeast. Science.1993,259:1760-63.
4. Sheth K, Friel J,Nolan B, et al. Inhibition of p38 mitogen activated protein kinase increases LPS induced inhibition of apoptosis in neutrophils by activating extracellular signal regulated kinase. Surgery. 2001,130(2):242-248.
5. Svensson CI, MarsalaM, 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 Neurochem.2003,86(6): 1534-44.
6. Svensson CI, Fitzsimmons B, Azizi S, et al. Spinal p38beta isoform mediates tissue injury2induced hyperalgesia and spinal sensitization.J Neurochem.2005,92(6):1508-19.
7. Hiroki I, Keiichiro O, Fumiko A, Effects of peripheral inflammation on activation of p38 mitogen-activated protein kinase in the rostral ventromedial medull. Brain Res,2007,1134:131-139.
8. Sweitzer SM, Peters MC, Ma JY, et al. Peripheral and central p38MAPK mediates capsaicin-induced hyperalgesia. Pain.2004; 111:278-285.
9. Hua XY, Svensson CI, Matsui T, et al. Intrathecalminocycline attenuates peripheral inflammation2induced hyperalgesia by inhibiting p38 MAPK in spinal microglia. Eur J Neurosci,2005,22(10):2431-40.
10. Zhao P, Waxman SG, Hains BC. Extracellular signal-regulated kinase regulated microglia-neuron signaling by prostaglandin contributes to pain after spinal cord injury. J. Neurosci.2007,27,2357-68.
11. Tsuda M, Mizokoshi A, Shigemoto2Mogami 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(1):89-95.
12. Eric DC, Young SG, Ye ZM, et al. Activation of p38 MAP kinase is involved in central neuropathic pain following spinal cord injury.Exp Neuro 2008,213:257-267.
13. Ji RR. Peripheral and central mechanisms of inflammatory pain with emphasis on MAP kinases. Curr. Drug Targets Inflamm. Allergy 2004,3, 299-303.
1. Ahn DK, Kim YS. Intracisternal antidepressants suppressed the nociceptive jaw opening reflex in freely moving rats. Korean J. Physiol.Pharmacol.1998,2:301-305.
2. Ahn DK, Kim YS, Park JS.Central NO is involved in the antinociceptive action of intracisternal antidepressants in freely moving rats. Neurosci Lett.1998,243:105-108.
3. Lee M R,Dominguez C. MAP Kinase p38 inhibitors:Clinical results and an intimate look at their interactions with p38alpha protein. Curr Med Chem.2005,12(25):2979-94
4. Cirillo PF, Pargellis C, Regan J. The non-diaryl heterocycle classes of p38 MAP kinase inhibitors. Curr Top Med Chem.2002,2(9):1021-35.
5. Ozdemir C,Akdis CA. Discontinued drugs in 2006: pulmonary-allergy,dermatological,gastrointestinal and arthritis drugs. Expert Opin Investig Drugs.2007,16(9):1327-44.
6. Tsuda M, Mizokoshi A, Shigemoto MY, et al. Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury. Glia.2004,45(1): 89-95.
7. Sweitzer SM, Peters MC, Ma JY, et al. Peripheral and central p38MAPK mediates capsaicin-induced hyperalgesia. Pain.2004;111:278-285.
8. Hua XY, Svensson CI, Matsui T, et al. Intrathecalminocycline attenuates peripheral inflammation2induced hyperalgesia by inhibiting p38 MAPK in spinal microglia. Eur J Neurosci.2005,22(10):2431-40.
9. Svensson CI, Fitzsimmons B, Azizi S, et al. Spinal p38beta isoform mediates tissue injury2induced hyperalgesia and spinal sensitization. J Neurochem,2005,92(6):1508-19.
10. Schafers M, Svensson CI, Sommer C, Sorkin LS. Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons.J Neurosci. 2003,23(7):2517-2521.
11. Ji RR. Peripheraland central mechanisms of inflammatory pain with emphasis on MAP kinases. Curr. Drug Targets Inflamm. Allergy.2004,3, 299-303.
12. Zhuang ZY, Gerner P, Woolf CJ, et al. ERK is sequentially activated in neurons, microglia,and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain 2005; 114(1-2):149-159.
13. Norcini M, Vivoli E, Galeotti N.Supraspinal role of protein kinase C in oxaliplatin-induced neuropathy in rat.Pain.2009,146:141-147
14. Huang WJ, Wang BR, Yao LB, et al. Activity of p44/42 MAP kinase in the caudal subnucleus of trigeminal spinal nucleus is increased following perioral noxious stimulation in the mouse. Brain Res.2000; 861:181-185.
1. Ledebore A,Sloane EM,Milligan ED,et al.Minocycline attenuates mechanical allodyia and proinflammatory cytokin expression in rat models of pain facilitation.Pain,2005,115(1-2):71-83.
2. Taey Y, Jeey L, Gily J, et al.Minocycline alleviates death of oligodendrocytes by inhibiting pro-nerve growth factor production in microglia after spinal cord injury. J Neurosci.2007,27,7751-7761.
3. Raghavendra, V., Tanga, F., DeLeo, J.A.. Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J. Pharmacol. Exp Ther.2003,306:624-630.
4. I nnemarie L, Evan M. Sloane,D. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation.Pain.2005,115:71-83.
5. Samuel A. Owolabi, Carl Y. Fractalkine and minocycline alter neuronal activity in the spinal cord dorsal horn FEBS Letters.2006,06:87-91.
6. Lee SM, Yune TY, Kim SJ, et al. Minocycline inhibits apoptotic cell death via attenuation of TNF-alpha expression following iNOS/NO induction by lipopolysac charide in neuron/glia co-cultures. J Neurochem,2004,91 (3):568-578.
7. Schuetz E, Thanos S. Microglia targeted pharmacotherapy in retinal neurodegenerative diseases.Current Drug Targets.2004; 5 (7):619-627.
8. Lai AY, Todd KG. Hypoxia-activated microglial mediators of neuronal survival are differentially regulated by tetracyclins. Glia.2006; 53 (8) 809-816.
9. Kremlev SG, Roberts RL, Palmer C.Differential expression of chemokines and chemokine receptors during microglial activation and inhibition. J Neuroimmunol,2004,149 (1-2):1-9.
10. Lee SM, Yune TY, Kim SJ, et al.Minocycline reduces cell death and imp roves functional recovery after traumatic spinal cord injury in the rat.J Neurotrauma.2003,20 (10):1017-1027.
11. Ambrosini E, Aloisi F.Chemokines and glial cells:a complex network in the central nervous system.N eurochem Res.2004,29 (5):1017-1038.
12. Song Y, Wei EQ, Zhang WP, et al.Minocycline protects PC12 cells from ischemic-like injury and inhibits 5-lipoxygenase activation. Neuroreport. 2004,15(14):2181-2184.
13. HainsBC, Waxman SG. Activated microglia contribute to the maintenance of chronic pain after spinal cord injury. J Neurosci.2006, 26(16):4308-17.
14. Piao ZG, Cho IH, Park CK, et al. Activation of glia and microglia] p38 MAPK in medullary dorsal horn contributes to tactile hypersensitivity following trigeminal sensory nerve injury. Pain.2006,121 (3):219-31.
15. Hua XY, Svensson CI, Matsui T,et al. Intrathecal minocycline attenuates peripheral inflammation induced hyperalgesia by inhibiting p38 MAPK in spinal microglia. Euro J Neurosci.2005,22:2431-2440.
16. Lebrun P,Manil J,Colin F.Formalin-induced central sensitization in the rat: somatosensory evoked potential data. Neurosci Lett.2000,283 (2):113-6.
17. Coderre TJ, Melzack R. The contribution of excitatory amino acids to central sensitization and persistent nociception after formalin-induced tissue injury. J Neurosci.1992,12(9):3665-70.
18. Dallel R,Raboisson P,Clavelou P,et al. Evidence for a peripheral origin of the tonic nociceptive response to subcutaneous formalin. Pain.l995,61(1):11-6.
19. Kingery WS, Guo TZ, Davies MF, et al. The alpha(2A)adrenoceptor and the sympathetic postganglionic neuron contribute to the development of neuropathic heat hyperalgesia in mice.Pain.2000,85(3):345-58.
20. Holanda SA, Pintoa LMS, Guedes MA.Antinoceptive effect of triterpenoid a,b-amyrin in rats on orofacial pain induced by formalin and capsaicin. Phytomed.2008,15:630-634
21.董研,刘洪臣,王新木等.咬合创伤对三叉神经脊束核敏化作用的研究.中华口腔医学杂志.2004,39(5)：418-420.
22. Takeshita S, Hirata H, Bereiter DA. Intensity coding by TMJ-responsive neurons in superficial laminae of caudal medullary dorsal horn of the rat. J Neurophysiol.2001,86:2393-404.
1. Cao H, Zhang YQ. Spinal glial activation contributes to pathological pain states. Neurosci Biobehav Rev.2008,32 (5):972-83.
2. Campbell JN, Meyer RA. Mechanisms of neuropathic pain. Neuron. 2006,52(1):77-92.
3. Abbadie C. Chemokines, chemokine receptors and pain. Trends Immunol.2005,26 (10):529-34.
4. Laing KJ, Secombes CJ. Chemokines. Dev Comp Immunol.2004,28 (5): 443-60.
5. Savarin-Vuaillat C, Ransohoff RM. Chemokines and chemokine receptors in neurological disease:raise, retain, or reduce? Neurotherapeutics.2007,4 (4):590-601.
6. Ransohoff RM. Chemokines and chemokine receptors:standing at the crossroads of immunobiology and neurobiology. Immunity.2009,31 (5): 711-21.
7. Ribeiro S, Horuk R. The clinical potential of chemokine receptor antagonists. Pharmacol Ther.2005,107 (1):44-58.
8. Biber K, Vinet J, Boddeke HW. Neuron-microglia signaling:chemokines as versatile messengers. J Neuroimmunol.2008,198 (1-2):69-74.
9. Boddeke EW. Involvement of chemokines in pain. Eur J Pharmacol.2001,429 (1-3):115-9.
10. Onuffer JJ, Horuk R. Chemokines, chemokine receptors and small-molecule antagonists:recent developments. Trends Pharmacol Sci.2002,23 (10):459-67.
11. 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 U S A.1998,95 (18): 10896-901.
12. Hughes PM, Botham MS, Frentzel S, et al. Expression of fractalkine (CX3CL1) and its receptor, CX3CR1, during acute and chronic inflammation in the rodent CNS. Glia.2002,37 (4):314-27.
13. de Haas AH, van Weering HR, de Jong EK, et al. Neuronal chemokines: versatile messengers in central nervous system cell interaction. Mol Neurobiol.2007,36 (2):137-51.
14. Cardona AE, Pioro EP, Sasse ME, et al. Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci.2006,9 (7):917-24.
15. Clark AK, Yip PK, Grist J, et al. Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc Natl Acad Sci U S A,2007,104 (25):10655-60.
16. Zhuang ZY, Kawasaki Y, Tan PH, et al. Role of the CX3CR1/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):642-51.
17. Abbadie C, Bhangoo S, De Koninck Y, et al. Chemokines and pain mechanis-ms. Brain Res Rev.2009,60 (1):125-34.
18. Dansereau MA, Gosselin RD, Pohl M, et al. Spinal CCL2 pronociceptive action is no longer effective in CCR2 receptor antagonist-treated rats. J Neuro-chem.2008,106 (2):757-69.
19. Zhang J, Shi XQ, Echeverry S, et al. Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain. J Neuro-sci.2007,27 (45):12396-406.
20. Zhao P, Waxman SG, Hains BC. Modulation of thalamic nociceptive proces-sing after spinal cord injury through remote activation of thalamic microglia by cysteine cysteine chemokine ligand 21. J Neurosci.2007,27 (33):8893-902.
21. Hulsebosch CE, Hains BC, Crown ED, et al. Mechanisms of chronic central neuropathic pain after spinal cord injury. Brain Res Rev.2009,60 (1): 202-13.
2. Jian Liu K,Rosenberg G A.Matrix matalloproteinases and free radicals in ceredral ischemia. Free Radic Biol Med.2005,399(10):71-80.
3. Dubuisson D, Dennis SG.The formalin test:a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain.1977,4(2):161-374.
4. Dickenson AH, Sullivan AF. Subcutaneous formalin-induced activity of dorsal horn neurones in the rat:differential response to an intrathecal opiate administered pre or post formalin. Pain.1987,30(3):349-60.
5. Ali Z, Meyer RA, Campbell JN. Secondary hyperalgesia to mechanical but not heat stimuli following a capsaicin injection in hairy skin.Pain.1996,68(2-3):401-11.
6. Simone DA, Nolano M, Johnson T,et al.Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers:correlation with sensory function. J eurosci.1998,18(21):8947-59.
7. Clavelou P, Pajot J, Dallel R, et al.Application of the formalin test to the study of orofacial pain in the rat. Neurosci Lett,1989,103:349-353.
8. Capone F, Aloisi AM.Refinement of pain evaluation techniques.The formalin test. Ann Ist Super Sanita,2004,40(2):223-229.
9. Rosland JH. The formalin test in mice:the influence of ambient temperature. Pain.1991,45:211-6.
10. Hole K, Tjolsen A. The tail-flick and formalin.tests in rodents:changes in skin temperature as a confounding factor. Pain.1993,53:247-54.
11. Wheeler-Aceto H, Cowan A. Standardization of the rat paw formalin test for the evaluation of analgesics. Psychopharmacol (Berl).1991, 104:35-44.
12. Pierre C, Radhouane D, Thierry O, et al.The orofacial formalin test in rats:effects of different formalin concentrations.Pain.1995,62: 295-301.
13. Eisenberg E, Vos BP, Strassman AM. The NMD A antagonist Memantine blocks pain behavior in a rat model of formalin-induced facial pain. Pain.1993,54:301-7.
14. Klein BG, Misra BR, White CF. Orofacial pain sensitivity in adult rats following neonatal infraorbital nerve transection. Behav Brain Res.1991 ,46:197-201.
15. Paula J, Seadi P, Fabiana N, et al Nociceptive and inflammatory responses induced by formalin in the orofacial region of rats:Effect of anti-TNFa strategies. International Immunopharmacology.2009,9, 80-85.
16. Sessle, B.J. Acute and chronic craniofacial pain:brainstem mechanisms of nociceptive transmission and neuroplasticity, and their clinical correlates. Crit. Rev. Oral Biol Med.2002,11,57-91.
17. Zhou Q,Imbe h, Dubner R, et al. Persistent Fos protein expression after
orofacial deep or cutaneous tissue inflammation in rats: implications for persistent orofacial pain. J Comp Neurl.1999,412(2): 276-291.
18. He YF, Ichikawa H, Sugimoto T. The effect of neonatal capsaicin on the c-Fos-like immunoreactivity induced in subnucleus oxalis neurons by noxious intraoral stimulation. Brain Res.2000,860(1-2):203-207.
19. 董研,刘洪臣,王新木等.咬合创伤对三叉神经脊束核敏化作用的研究.中华口腔医学杂志,2004,39(5)：418-420.
20. Takeshita S, Hirata H, Bereiter DA.Intensity coding by TMJ-responsive neurons in superficial laminae of caudal medullary dorsal horn of the rat. J Neurophysiol.2001,86:2393-404.
21. Jin Y. Ro, Norman F, JK Lee.Hypertonic saline-induced muscle nociception and c-fos activation are partially mediated by peripheral NMDA receptors. Eur J Pain.2007,11,398-405.
22. Bullit E. Expression of c-fos like protein as a marker for neuronal activity following noxious stimulation in the rat. J Comp Neurol, 1990,296:517-530.
23. Zheng G, Ik-Hyun C, Chul K P. Activation of glia and microglial p38 MAP-K in medullary dorsal horn contributes to tactile hypersensitivity following trigeminal sensory nerve injury. Pain.2006,121,219-231.
24. Iwata K, Takahashi 0, Tsuboi Y, et al. Fos protein induction in the medullary dorsal horn and first segment of the spinal cord by tooth-pulp stimulation in cats. Pain,1998,75(1):27-36.
25. 顾斌.脂多糖诱发急性牙髓炎致敏的三又神经节功能蛋白质组学研究.军医进修学院博士学位论文.2008,31-33.
26. Marfurt CF, Turner DF. The central projections of tooth pulp afferent neurons in the rat as determined by the transganglionic transport of horseradish peroxidase. J Comp Neurol.1984,223(4):535-47.
27. Watkins LR, Milligan ED, Maier SF, et al. Spinal cord glia:new players in pain. Pain,2001,93:201-205.
28. Jian LK, Rosenberg G A. Matrix matalloproteinases and free radicals in cerebral ischemia. Free Radic Biol Med.2005,39910:71-80.
29.兰莉,高蓓,饶志仁.脂多糖对大鼠中脑和桥脑内Fos、GFAP、OX42表达的影响.解剖学报.2005,36(1)：24-27.
30. Colbum RW, Rickman AJ, Deleo JA, et al. The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior. Exp Neuro.1999,157:289-304
31. Chen JW, Zhang J, Zhao YM, et al.. Hyperalgesia in response to traumatic occlusion and GFAP expression in rat parabranchial nucleus: modulation with fluorocitrate. Cell Tissue Res.2007,329:231-237.
32. Kettenmann H,Ransom BR. Neuroglia. NewYork:Oxford University Press,1995.
33. Wakins LR, Milligan ED, Maiser SF. Glial proinflammatory cytokines mediate exaggerated pain states:implications for clinical pain. In: Immune mechanisms of pain & analgesia. Austin TX:Landes Biosciences,2001,199-213.
34. Vitkovic L, Konsman J, P, Bockaert J, et al. Cytokine signals propagate through the brain. Mol psychiatry.2000,5:604-615.
35. Qin M., Wang JJ, Cao R.The lumbar spinal cord glial cells actively modulate subcutaneous formalin induced hyperalgesia in the rat. Neurosci Res.2006,55:442-450.
36. Guo W, Wang H, Watanabe M, et al. Glial-cytokine neuronal interactions underlying the mechanisms of pensistent pain. Neurosci.2007,27(22):6006-8.
37. 贾静,刘洪臣,章捍东等。咬合创伤下大鼠三叉神经脊束核尾侧亚核星形胶质细胞的反应及其与细胞因子的关系.中华老年口腔医学杂志.2005,3(3)：132-134.
38. Steward O, Torre ER, Tomasulo R, et al.Neuronal activity up-regulates astroglial gene expression. Proc Natl Acad Sci USA.1991, 88(15):6819-23.
39. Bergles DE, Roberts JD, Somogyi P, et al. Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus. Nature. 2000,405(6783):187-191.
40. Guo LH, Traumann K, Schluesener J. Expression of P2X4 receptor by lesion activated microglia during formalin-induced inflammatory pain.Neuroimmu.2005,163:120-127.
1. Colburn, R.W., Rickman, A.J., DeLeo, J.A. The effect of site and type of Exp.Neurol.1999,157:289-304.
2. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science,2005, 308:(3)418.
3. Stolzing A,Wengner A,Grune T.Degredation of oxidized extracellular proteins by microglia.Arch Biochem Biophys.2002,400(2):171-179.
4. Kristin LS, Alvin JB, George LW,etal.Activation of spinal microglia in a murine model of peripheralinflammation-induced, long-lasting contralateral allodynia. Neuroscience Letters.2008,440:63-67.
5. 傅开元,Light AR, Maixner W.外周炎症性疼痛刺激诱发中枢神经系统小胶质细胞增殖活化.中国神经免疫学和神经病学杂志.2001,8(3)：179-183.
6. Watkins LR,Maier SF.The pain of being sick:implications of mmune-to-brain communication for understanding pain.AnnuRev Psychol.2000,51:29-57.
7. DeLeo JA,Colburn RW.Proinflammatory cytokines and glial cellsaheir role in neuropathic pain.In:Watkins LR,Maier SF eds.Cytokines and pain. Basel:Birkhauser verlag,1999,159-182.
8. Hashizume H, DeLeo JA,Colburn RW,etal.Spinalglialacti-Vation and cytokine expression after lumbar root injury in the rat. Spine,2000, 25:.1206-1217.
9. Milligan ED, Mehmert KK, Hinde GL, et al. Thermal hyperalgesia and mechanical allodynia produced by intiathecal administiation of the human im munodeficiency Viru 1(HIV-1) envelope glycoprotein, gp120.Brain Res,2000,861:105-116.
10. Piao ZG, Cho IH, Park CK, et al. Activation of glia and microglial p38 MAPK in medullary dorsal horn contributes to tactile hypersensitivity following trigeminal sensory nerve injury. Pain.2006,121 (3):219-31.
11. Lim EJ, Jeon HJ, Yang GY,et al.Intracisternal administration of mitogen-activated protein kinase inhibitors reduced mechanical allodynia following chronic constriction injury of infraorbital nerve in rats.Progress in Neuro-Psychophar & Biolo Psych 31 2007(31):1322-1329.
12. McMahon S B, Cafferty WB,Marchand F. Immune and glial cell factors as pain mediators and modulators. Exp Neurol.2005,192:444-462.
13. Aumeerally N, AllenG, Sawynok J.Glutamate-evoked release of adenosine and regulation of peripheral nociception. Neuroscience.2004,127:1-11.
14. Fu KY, Light AR, Maixner W. Relationship between nociceptor activity, peripheral edema, spinal microglial activation and long-term hyperalgesia induced by formalin. Neuroscience.2000,101:1127-35.
15. Honore P, Rogers SD, Schwei, MJ, et al. Murine models of inflammatory, neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons. Neuroscience.2000,98:585-598.
16. Zhang J, Hoffert C, Vu HK, et al.Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. Eur. J. Neurosci.2005.17:2750-54.
17. Hua XY, Svensson CI, Matsui T, et al. Intrathecalminocycline attenuates peripheral inflammation2induced hyperalgesia by inhibiting p38 MAPK in spinal microglia. Eur J Neurosci.2005,22(10):2431-40.
18. Svensson CI, Fitzsimmons B, Azizi S, et al. Spinal p38beta isoform mediates tissue injury2induced hyperalgesia and spinal sensitization. J Neurochem.2005,92(6):1508-19.
19. Chapman G, Moores K, Harrison D,etal.Fractalkine cleavage from neuronal membranes represents an acute event in the inflammatory response to exci to toxic brain damage.JNeu-rosci.2000,20(15):RC87.
1.吴立玲,细胞信号转导与疾病,金惠铭主编《病理生理学》人民卫生出版社.2000年10月第5版：163-177023(10)：4017-22.
2. Obata T, Brown GE, Yaffe MB. MAP kinase pathways activated by stress:the p38MAPKpathway. Crit Care Med,2000,28(4):67-77.
3. Brewster JL,De Valoir T,Dwyer N, et al. An osmosensing signal trans-duction pathway in yeast. Science.1993,259:1760-63.
4. Sheth K, Friel J,Nolan B, et al. Inhibition of p38 mitogen activated protein kinase increases LPS induced inhibition of apoptosis in neutrophils by activating extracellular signal regulated kinase. Surgery. 2001,130(2):242-248.
5. Svensson CI, MarsalaM, 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 Neurochem.2003,86(6): 1534-44.
6. Svensson CI, Fitzsimmons B, Azizi S, et al. Spinal p38beta isoform mediates tissue injury2induced hyperalgesia and spinal sensitization.J Neurochem.2005,92(6):1508-19.
7. Hiroki I, Keiichiro O, Fumiko A, Effects of peripheral inflammation on activation of p38 mitogen-activated protein kinase in the rostral ventromedial medull. Brain Res,2007,1134:131-139.
8. Sweitzer SM, Peters MC, Ma JY, et al. Peripheral and central p38MAPK mediates capsaicin-induced hyperalgesia. Pain.2004; 111:278-285.
9. Hua XY, Svensson CI, Matsui T, et al. Intrathecalminocycline attenuates peripheral inflammation2induced hyperalgesia by inhibiting p38 MAPK in spinal microglia. Eur J Neurosci,2005,22(10):2431-40.
10. Zhao P, Waxman SG, Hains BC. Extracellular signal-regulated kinase regulated microglia-neuron signaling by prostaglandin contributes to pain after spinal cord injury. J. Neurosci.2007,27,2357-68.
11. Tsuda M, Mizokoshi A, Shigemoto2Mogami 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(1):89-95.
12. Eric DC, Young SG, Ye ZM, et al. Activation of p38 MAP kinase is involved in central neuropathic pain following spinal cord injury.Exp Neuro 2008,213:257-267.
13. Ji RR. Peripheral and central mechanisms of inflammatory pain with emphasis on MAP kinases. Curr. Drug Targets Inflamm. Allergy 2004,3, 299-303.
1. Ahn DK, Kim YS. Intracisternal antidepressants suppressed the nociceptive jaw opening reflex in freely moving rats. Korean J. Physiol.Pharmacol.1998,2:301-305.
2. Ahn DK, Kim YS, Park JS.Central NO is involved in the antinociceptive action of intracisternal antidepressants in freely moving rats. Neurosci Lett.1998,243:105-108.
3. Lee M R,Dominguez C. MAP Kinase p38 inhibitors:Clinical results and an intimate look at their interactions with p38alpha protein. Curr Med Chem.2005,12(25):2979-94
4. Cirillo PF, Pargellis C, Regan J. The non-diaryl heterocycle classes of p38 MAP kinase inhibitors. Curr Top Med Chem.2002,2(9):1021-35.
5. Ozdemir C,Akdis CA. Discontinued drugs in 2006: pulmonary-allergy,dermatological,gastrointestinal and arthritis drugs. Expert Opin Investig Drugs.2007,16(9):1327-44.
6. Tsuda M, Mizokoshi A, Shigemoto MY, et al. Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury. Glia.2004,45(1): 89-95.
7. Sweitzer SM, Peters MC, Ma JY, et al. Peripheral and central p38MAPK mediates capsaicin-induced hyperalgesia. Pain.2004;111:278-285.
8. Hua XY, Svensson CI, Matsui T, et al. Intrathecalminocycline attenuates peripheral inflammation2induced hyperalgesia by inhibiting p38 MAPK in spinal microglia. Eur J Neurosci.2005,22(10):2431-40.
9. Svensson CI, Fitzsimmons B, Azizi S, et al. Spinal p38beta isoform mediates tissue injury2induced hyperalgesia and spinal sensitization. J Neurochem,2005,92(6):1508-19.
10. Schafers M, Svensson CI, Sommer C, Sorkin LS. Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons.J Neurosci. 2003,23(7):2517-2521.
11. Ji RR. Peripheraland central mechanisms of inflammatory pain with emphasis on MAP kinases. Curr. Drug Targets Inflamm. Allergy.2004,3, 299-303.
12. Zhuang ZY, Gerner P, Woolf CJ, et al. ERK is sequentially activated in neurons, microglia,and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain 2005; 114(1-2):149-159.
13. Norcini M, Vivoli E, Galeotti N.Supraspinal role of protein kinase C in oxaliplatin-induced neuropathy in rat.Pain.2009,146:141-147
14. Huang WJ, Wang BR, Yao LB, et al. Activity of p44/42 MAP kinase in the caudal subnucleus of trigeminal spinal nucleus is increased following perioral noxious stimulation in the mouse. Brain Res.2000; 861:181-185.
1. Ledebore A,Sloane EM,Milligan ED,et al.Minocycline attenuates mechanical allodyia and proinflammatory cytokin expression in rat models of pain facilitation.Pain,2005,115(1-2):71-83.
2. Taey Y, Jeey L, Gily J, et al.Minocycline alleviates death of oligodendrocytes by inhibiting pro-nerve growth factor production in microglia after spinal cord injury. J Neurosci.2007,27,7751-7761.
3. Raghavendra, V., Tanga, F., DeLeo, J.A.. Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J. Pharmacol. Exp Ther.2003,306:624-630.
4. I nnemarie L, Evan M. Sloane,D. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation.Pain.2005,115:71-83.
5. Samuel A. Owolabi, Carl Y. Fractalkine and minocycline alter neuronal activity in the spinal cord dorsal horn FEBS Letters.2006,06:87-91.
6. Lee SM, Yune TY, Kim SJ, et al. Minocycline inhibits apoptotic cell death via attenuation of TNF-alpha expression following iNOS/NO induction by lipopolysac charide in neuron/glia co-cultures. J Neurochem,2004,91 (3):568-578.
7. Schuetz E, Thanos S. Microglia targeted pharmacotherapy in retinal neurodegenerative diseases.Current Drug Targets.2004; 5 (7):619-627.
8. Lai AY, Todd KG. Hypoxia-activated microglial mediators of neuronal survival are differentially regulated by tetracyclins. Glia.2006; 53 (8) 809-816.
9. Kremlev SG, Roberts RL, Palmer C.Differential expression of chemokines and chemokine receptors during microglial activation and inhibition. J Neuroimmunol,2004,149 (1-2):1-9.
10. Lee SM, Yune TY, Kim SJ, et al.Minocycline reduces cell death and imp roves functional recovery after traumatic spinal cord injury in the rat.J Neurotrauma.2003,20 (10):1017-1027.
11. Ambrosini E, Aloisi F.Chemokines and glial cells:a complex network in the central nervous system.N eurochem Res.2004,29 (5):1017-1038.
12. Song Y, Wei EQ, Zhang WP, et al.Minocycline protects PC12 cells from ischemic-like injury and inhibits 5-lipoxygenase activation. Neuroreport. 2004,15(14):2181-2184.
13. HainsBC, Waxman SG. Activated microglia contribute to the maintenance of chronic pain after spinal cord injury. J Neurosci.2006, 26(16):4308-17.
14. Piao ZG, Cho IH, Park CK, et al. Activation of glia and microglia] p38 MAPK in medullary dorsal horn contributes to tactile hypersensitivity following trigeminal sensory nerve injury. Pain.2006,121 (3):219-31.
15. Hua XY, Svensson CI, Matsui T,et al. Intrathecal minocycline attenuates peripheral inflammation induced hyperalgesia by inhibiting p38 MAPK in spinal microglia. Euro J Neurosci.2005,22:2431-2440.
16. Lebrun P,Manil J,Colin F.Formalin-induced central sensitization in the rat: somatosensory evoked potential data. Neurosci Lett.2000,283 (2):113-6.
17. Coderre TJ, Melzack R. The contribution of excitatory amino acids to central sensitization and persistent nociception after formalin-induced tissue injury. J Neurosci.1992,12(9):3665-70.
18. Dallel R,Raboisson P,Clavelou P,et al. Evidence for a peripheral origin of the tonic nociceptive response to subcutaneous formalin. Pain.l995,61(1):11-6.
19. Kingery WS, Guo TZ, Davies MF, et al. The alpha(2A)adrenoceptor and the sympathetic postganglionic neuron contribute to the development of neuropathic heat hyperalgesia in mice.Pain.2000,85(3):345-58.
20. Holanda SA, Pintoa LMS, Guedes MA.Antinoceptive effect of triterpenoid a,b-amyrin in rats on orofacial pain induced by formalin and capsaicin. Phytomed.2008,15:630-634
21.董研,刘洪臣,王新木等.咬合创伤对三叉神经脊束核敏化作用的研究.中华口腔医学杂志.2004,39(5)：418-420.
22. Takeshita S, Hirata H, Bereiter DA. Intensity coding by TMJ-responsive neurons in superficial laminae of caudal medullary dorsal horn of the rat. J Neurophysiol.2001,86:2393-404.
1. Cao H, Zhang YQ. Spinal glial activation contributes to pathological pain states. Neurosci Biobehav Rev.2008,32 (5):972-83.
2. Campbell JN, Meyer RA. Mechanisms of neuropathic pain. Neuron. 2006,52(1):77-92.
3. Abbadie C. Chemokines, chemokine receptors and pain. Trends Immunol.2005,26 (10):529-34.
4. Laing KJ, Secombes CJ. Chemokines. Dev Comp Immunol.2004,28 (5): 443-60.
5. Savarin-Vuaillat C, Ransohoff RM. Chemokines and chemokine receptors in neurological disease:raise, retain, or reduce? Neurotherapeutics.2007,4 (4):590-601.
6. Ransohoff RM. Chemokines and chemokine receptors:standing at the crossroads of immunobiology and neurobiology. Immunity.2009,31 (5): 711-21.
7. Ribeiro S, Horuk R. The clinical potential of chemokine receptor antagonists. Pharmacol Ther.2005,107 (1):44-58.
8. Biber K, Vinet J, Boddeke HW. Neuron-microglia signaling:chemokines as versatile messengers. J Neuroimmunol.2008,198 (1-2):69-74.
9. Boddeke EW. Involvement of chemokines in pain. Eur J Pharmacol.2001,429 (1-3):115-9.
10. Onuffer JJ, Horuk R. Chemokines, chemokine receptors and small-molecule antagonists:recent developments. Trends Pharmacol Sci.2002,23 (10):459-67.
11. 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 U S A.1998,95 (18): 10896-901.
12. Hughes PM, Botham MS, Frentzel S, et al. Expression of fractalkine (CX3CL1) and its receptor, CX3CR1, during acute and chronic inflammation in the rodent CNS. Glia.2002,37 (4):314-27.
13. de Haas AH, van Weering HR, de Jong EK, et al. Neuronal chemokines: versatile messengers in central nervous system cell interaction. Mol Neurobiol.2007,36 (2):137-51.
14. Cardona AE, Pioro EP, Sasse ME, et al. Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci.2006,9 (7):917-24.
15. Clark AK, Yip PK, Grist J, et al. Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc Natl Acad Sci U S A,2007,104 (25):10655-60.
16. Zhuang ZY, Kawasaki Y, Tan PH, et al. Role of the CX3CR1/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):642-51.
17. Abbadie C, Bhangoo S, De Koninck Y, et al. Chemokines and pain mechanis-ms. Brain Res Rev.2009,60 (1):125-34.
18. Dansereau MA, Gosselin RD, Pohl M, et al. Spinal CCL2 pronociceptive action is no longer effective in CCR2 receptor antagonist-treated rats. J Neuro-chem.2008,106 (2):757-69.
19. Zhang J, Shi XQ, Echeverry S, et al. Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain. J Neuro-sci.2007,27 (45):12396-406.
20. Zhao P, Waxman SG, Hains BC. Modulation of thalamic nociceptive proces-sing after spinal cord injury through remote activation of thalamic microglia by cysteine cysteine chemokine ligand 21. J Neurosci.2007,27 (33):8893-902.
21. Hulsebosch CE, Hains BC, Crown ED, et al. Mechanisms of chronic central neuropathic pain after spinal cord injury. Brain Res Rev.2009,60 (1): 202-13.