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系統識別號 U0007-2505200908481800
論文名稱(中文) 手術後疼痛與脊髓背角內微小膠細胞衍生之p38絲裂原蛋白激活酶活化的關係之探討
論文名稱(英文) A Study on The Correlation of Spinal Microglia-derived p38 Mitogen-activated Protein Kinase (MAPK) Activation And Post-surgical Pain
校院名稱 臺北醫學大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Graduate Institute of Clinical Medicine
學年度 97
學期 2
出版年 98
研究生(中文) 溫永銳
研究生(英文) Yeong-Ray Wen
電子信箱 yr.wen@yahoo.com.tw
學號 D002089007
學位類別 博士
語文別 英文
口試日期 2009-05-04
論文頁數 116頁
口試委員 指導教授-葉健全
共同指導教授-孫維仁
委員-嚴震東
委員-何善台
委員-陳大樑
委員-李怡萱
委員-楊良友
中文關鍵字 手術後疼痛  微小膠細胞  絲裂原激活蛋白酶  針灸止痛  p38 
英文關鍵字 Postoperative pain  microglia  MAPK  electroacupuncture  p38 
學科別分類
中文摘要 越來越多新的研究,顛覆了傳統上認為疼痛只發生在神經元的觀念。它們發現,疼痛不僅侷限於神經元通路,還包括了背根神經節中的許旺細胞、衛星細胞,周邊神經的免疫系統,及脊髓中的神經膠細胞如微小膠細胞、星狀膠細胞等。其中,微小膠細胞最受到注意,且認為此細胞與神經元的交互反應,會強化疼痛的演化及維持。
絲裂原蛋白激活酶 (Mitogen-activated protein kinase, MAPK) 代表了細胞外刺激對細胞內反應的一個媒介,其活化過程需藉由磷酸化來完成。此家族的一個重要成員p38,逐漸被發現參與了許多神經病變性疼痛的敏感化。當神經損傷,活化了微小膠細胞中的p38後,會誘發一系列訊息傳遞,生成前發炎性細胞素 (proinflammatory cytokines) 及趨化激素 (chemokines)。但在手術後疼痛的機轉中,這一系列的變化並未被報告過。
手術後疼痛是一種可以預期並計畫性處理的疼痛。習慣上將此疼痛歸類於急性發炎性疼痛,但最新研究顯示,10-50% 的術後病患會發展成慢性疼痛,症狀類似神經病變性疼痛。雖然大部分的疼痛可經由嗎啡或消炎藥控制,但是藥物本身副作用卻增加病患的不適或危險性,所以有必要加入一些效果佳及低風險的止痛治療。
因此,本論文針對了手術後疼痛造成p38及與微小膠細胞的活化,探討這種機轉對術後止痛的治療;同時提出了非藥物的「電針止痛」,觀察是否可抑制p38活化,來減輕手術疼痛。
本論文分為三大部分,首先,將研究手術後疼痛是否誘發p38活化。利用大鼠後蹠部切口的手術模型,證明p38磷酸化會出現在脊髓背角的微小膠細胞中,而其活化(磷酸化)與術後疼痛反應有極密切關係。接著,第二部份則在手術前注射p38抑制劑,不但可抑制p38磷酸化,也明顯減輕手術後的疼痛,顯示p38參與了手術疼痛的敏感化。第三部份討論針刺止痛研究。因為針灸的機轉不明確,為此我們發展出一套可靠的動物針灸止痛模型,發現電針不只可提高疼痛閾值,減輕福馬林疼痛,也減少了脊髓背角Fos的表現。利用此針刺模型,進一步驗證電針刺激在手術疼痛的作用。結果發現,電針刺激不僅可明顯減輕手術後疼痛,且可降低脊髓背角Fos表現神經元的數量,及抑制微小膠細胞中的p38磷酸化;暗示針灸對於抑制手術後疼痛,具有多層面的機轉。
綜而言之,本論文的目的在探討微小膠細胞及訊息傳遞分子p38在手術後的反應,並藉由抑制此因子,調控疼痛的發展。由於p38活化後衍生出的發炎免疫反應,可能對疼痛記憶有更重要的影響,未來的發展將朝這一大方向,作更深入及廣泛的研究。
英文摘要 A growing body of evidence indicates, in contrast to traditional concept, the development of persistent pain involves not only neuronal pathways, but also Schwann cells, satellite cells in the dorsal root ganglia, components of the peripheral immune system, and microglia and astrocytes in the spinal cord. Among these cells, microglia play a pivot role in that release of immunological mediators from these cells affect the neuron-glial interactions and critically enhance the establishment and maintenance of pain sensitization.
Mitogen-activated protein kinase (MAPK), when activated via phosphorylation, can mediates many extracellular stimuli to trigger intracellular responses. p38, one member of this MAPK family, has been found to be important in pain sensitization, especially in various neuropathic pain types. After nerve injury, the activated (phosphorylated) p38 triggers a series of signal cascades and induces release of proinflammatory cytokines and chemokines. Nevertheless, the similar mechanistic changes have not been studied in postsurgical pain.
Postoperative pain is an expectable pain and can be managed through the whole perioperative period. Though this type of pain is customarily categorized into acute inflammatory pain, the new studies revealed that there are 10-50% of postoperative patients suffering form chronic postoperative pain, with symptoms analog to neuropathic pain. Morphine or NSAID can control most of postoperative pain, however, their side effects result in patients’ discomfort and sometimes complications. Therefore, it is necessary to provide new low-risk and high efficacious therapeutic methods.
Accordingly, the current thesis is focusing on the surgery-induced p38 and microglial activation, and to explore the analgesic effect on postoperative pain by inhibiting the p-p38. I also present a novel electroacupuncture model in rats, and use this non-pharmacological treatment to reduce postoperative pain and to alter the p38 activation.
There are three major parts in this thesis. In the first part I will examine the p38 activation by surgical pain. Using a plantar incision pain model, we found the phospho-p38 expression showed a close correlation with postoperative pain behaviors. Immunohistochemistry showed a rapid p38 activation following surgery and a colocalization within microglia. Next, a preoperative intrathecal treatment with p38 inhibitor was shown not only to prevent p38 activation, but also significantly attenuate postoperative pain. These findings indicate p38 contributes to the development of postoperative pain and can be viewed as a new avenue for clinic use. In the third part, a study of electroacupuncture analgesia on surgical pain is conducted. Because acupuncture mechanism is still controversial, I developed a stable electroacupuncture (EA) model. Under low-concentration of gas anesthesia, EA stimulation showed an intensity-dependent analgesia, elevated pain threshold, attenuated formalin-induced hyperalgesia, and reduced Fos expression in the spinal dorsal horns. Then, we testify the EA effect on surgical pain. We found EA was effective in decreasing postoperative pain, reducing Fos expression and more importantly, inhibiting the p38 activation in microglia. This finding implicates that EA can regulate the sensitization of postoperative pain and provide a wide-range analgesic function.
In conclusion, the major issue in this thesis is to emphasize the importance of microglial and p38 activation in postoperative pain, and to regulate pain development through inhibition of this factor. Nevertheless, more lines of new evidence disclose that the neruoinflammatory and/or neuroimmunal reactions downstream to MAPK activation may have greater impact on pain memory, aiming at this horizon will be my future research efforts.
論文目次 中 文 摘 要 1
Abstract 3
Introduction 6
1. Pain sensitization and glial cell activation 6
2. Mitogen-activated protein kinase (MAPK) and pain 9
3. Surgical pain and its significance 12
4. Electroacupuncture analgesia: Models, Mechanisms,
and Glia 13
5. Three major aims 15
6. Aim 1: Surgical pain induced p38 MAPK activation in
spinal microglia 17
7. Aim 2: p38 inhibitor attenuated incisional pain and
spinal p38 activation 18
8. Aim 3: Electroacupuncture analgesia on postoperative
pain and p38 activation 19

Materials and Methods 22
1. Surgical pain induced p38 MAPK activation in spinal
microglia 22
2. p38 inhibitor attenuated incisional pain and spinal
p38 activation 27
3. Electroacupuncture analgesia on postoperative pain
and p38 activation 31

Results 39
1. Surgical pain induced p38 MAPK activation in spinal
microglia 39
2. p38 inhibitor attenuated incisional pain and spinal
p38 activation 42
3. Electroacupuncture analgesia on postoperative pain
and p38 activation 44

Discussions 51
1. Surgical pain induced p38 MAPK activation in spinal
microglia 51
2. p38 inhibitor attenuated incisional pain and spinal
p38 activation 54
3. Electroacupuncture analgesia on postoperative pain
and p38 activation 58

Conclusions and Perspectives 66

References 70

Figures and Legends 92
1. Surgical pain induced p38 MAPK activation in spinal
microglia 92
2. p38 inhibitor attenuated incisional pain and spinal
p38 activation 98
3. Electroacupuncture analgesia on postoperative pain
and p38 activation 101

Appendix 117

參考文獻 Acupuncture. NIH Consensus Statement 1997;15:1-34.
Aloisi AM, Ceccarelli I, Lupo C. Behavioral and hormonal effects of restraint stress and formalin test in male and female rats. Brain Res Bull 1998;47:57-62.
Araque A. Astrocyte-neuron signaling in the brain--implications for disease. Current Opinion in Investigational Drugs 2006;7:619-624.
Armario A, Martí O, Vallès A, Dal-Zotto S, Ons S. Long-term effects of a single exposure to immobilization on the hypothalamic-pituitary-adrenal axis: neurobiologic mechanisms. Ann NY Acad Sci 2004;1018:162-172.
Baek YH, Choi DY, Yang HI, Park DS. Analgesic effect of electroacupuncture on inflammatory pain in the rat model of collagen-induced arthritis: mediation by cholinergic and serotonergic receptors. Brain Res 2005;1057:181-185.
Baek YH, Huh JE, Lee JD, Choi do Y, Park DS. Antinociceptive effect and the mechanism of bee venom acupuncture (Apipuncture) on inflammatory pain in the rat model of collagen-induced arthritis: Mediation by alpha2-Adrenoceptors. Brain Res 2006;1073-1074:305-310.
Besson JM, Chaouch A. Peripheral and spinal mechanisms of nociception. Physiol Rev 1987;67:167-186.
Bing Z, Villanueva L, Le Bars D. Acupuncture-evoked response of subnucleus reticularis neurons in the rat medulla. Neuroscience 1991;44:693-703.
Boyle DL, Jones TL, Hammaker D, Svensson CI, Rosengren S, Albani S, Sorkin L, Firestein GS. Regulation of peripheral inflammation by spinal p38 MAP kinase in rats. PLoS Med 2006;3:e338.
Brennan TJ, Vandermeulen EP, Gebhart GF. Characterization of a rat model of incisional pain. Pain 1996;64:493-501.
Budai D, Fields HL. Endogenous opioid peptides acting at mu-opioid receptors in the dorsal horn contribute to midbrain modulation of spinal nociceptive neurons. J Neurophysiol 1998;79:677-687.
Bullitt E. Expression of c-fos like protein as a marker for neuronal activity following noxious stimulation in the rat. J Comparative Neurol 1990;296:517-530.
Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 2000;288:306-313.
Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997;389:816-824.
Chap 26 Acute and Postoperative Pain. In: Core Curriculum for Professional Education in Pain, edited by J. Edmond Charlton, IASP Press, Seattle; 2005.
Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Meth 1994;53:55-63.
Chapman CR, Benedetti C, Colpitts YH, Gerlach R. Naloxone fails to reverse pain thresholds elevated by acupuncture: acupuncture analgesia reconsidered. Pain 1983;16:13-31.
Chiang C-Y, Wang J, Xie Y-F, Zhang S, Hu JW, Dostrovsky JO, Sessle BJ. Astroglial glutamate-glutamine shuttle is involved in central sensitization of nociceptive neurons in rat medullary dorsal horn. Journal of Neuroscience 2007;27:9068-9076.
Chung JM, Fang ZR, Hori Y, Lee KH, Willis WD. Prolonged inhibition of primate spinothalamic tract cells by peripheral nerve stimulation. Pain 1984a;19:259-275.
Chung JM, Lee KH, Hori Y, Endo K, Willis WD. Factors influencing peripheral nerve stimulation produced inhibition of primate spinothalamic tract cells. Pain 1984b;19:277-293.
Clark AK, Yip PK, Grist J, Gentry C, Staniland AA, Marchand F, Dehvari M, Wotherspoon G, Winter J, Ullah J, Bevan S, Malcangio M. Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc Natl Acad Sci U S A 2007;104:10655-10660.
Colburn RW, DeLeo JA, Rickman AJ, Yeager MP, Kwon P, Hickey WF. Dissociation of microglial activation and neuropathic pain behaviors following peripheral nerve injury in the rat. J Neuroimmunol 1997;79:163-175.
Crown ED, Ye Z, Johnson KM, Xu GY, McAdoo DJ, Hulsebosch CE. Increases in the activated forms of ERK 1/2, p38 MAPK, and CREB are correlated with the expression of at-level mechanical allodynia following spinal cord injury. Exp Neurol 2006;199:397-407.
Cuellar JM, Antognini JF, Eger Second EI, Carstens E. Halothane depress C-fiber-evoked windup of deep dorsal horn neuron. Neurosci Lett 2004;363:207-211.
Cui XY, Dai Y, Wang SL, Yamanaka H, Kobayashi K, Obata K, Chen J, Noguchi K. Differential activation of p38 and extracellular signal-regulated kinase in spinal cord in a model of bee venom-induced inflammation and hyperalgesia. Mol Pain 2008;4:17.
Dai Y, Kondo E, Fukuoka T, Tokunaga A, Miki K, Noguchi K. The effect of electroacupuncture on pain behaviors and noxious stimulus-evoked Fos expression in a rat model of neuropathic pain. J Pain 2001;2:151-159.
Daulhac L, Mallet C, Courteix C, Etienne M, Duroux E, Privat AM, Eschalier A, Fialip J. Diabetes-induced mechanical hyperalgesia involves spinal mitogen-activated protein kinase activation in neurons and microglia via N-methyl-D-aspartate-dependent mechanisms. Mol Pharmacol 2006;70:1246-1254.
Davis JB, Gray J, Gunthorpe MJ, Hatcher JP, Davey PT, Overend P, Harries MH, Latcham J, Clapham C, Atkinson K, Hughes SA, Rance K, Grau E, Harper AJ, Pugh PL, Rogers DC, Bingham S, Randall A, Sheardown SA. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 2000;405:183-187.
De Leo JA, Tawfik VL, LaCroix-Fralish ML. The tetrapartite synapse: path to CNS sensitization and chronic pain. Pain 2006;122:17-21.
de Medeiros MA, Canteras NS, Suchecki D, Mello LE. Analgesia and c-fos expression in the periaqueductal gray induced electroacupuncture at the Zusanli point in rats. Brain Res 2003;973:196-204.
Deng G, Rusch V, Vickers A, Malhotra V, Ginex P, Downey R, Bains M, Park B, Rizk N, Flores R, Yeung S, Cassiletha B. Randomized controlled trial of a special acupuncture technique for pain after thoracotomy. J Thorac Cardiovasc Surg 2008;136:1464-1469.
Dixon WJ. Efficient analysis of experimental observations. Annu Rev Pharmacol Toxicol 1980;20:441-462.
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 1997;4:161-174.
Echeverry S, Shi XQ, Zhang J. Characterization of cell proliferation in rat spinal cord following peripheral nerve injury and the relationship with neuropathic pain. Pain 2008;135:37-47.
Evans MS, Reid KH, Sharp JB, Jr. Dimethylsulfoxide (DMSO) blocks conduction in peripheral nerve C fibers: a possible mechanism of analgesia. Neurosci Lett 1993;150:145-148.
Field HL, Basbaum AI. Central nervous system mechanisms of pain modulation. In: Wall PD, Melzack R (eds) Textbook of Pain, 4th edn, Churchill Livingstone, Edinburgh, p 309-329, 1999.
Fields HL. Pain modulation: expectation, opioid analgesia and virtual pain. Prog Brain Res 2000;122:245-253.
Fu D, Guo Q, Ai Y, Cai H, Yan J, Dai R. Glial activation and segmental upregulation of interleukin-1beta (IL-1beta) in the rat spinal cord after surgical incision. Neurochemical Research 2006;31:333-340.
Fukazawa Y, Maeda T, Hamabe W, Kumamoto K, Gao Y, Yamamoto C, Ozaki M, Kishioka S. Activation of spinal anti-analgesic system following electroacupuncture stimulation in rats. J Pharmacol Sci 2005;99:408-414.
Furuichi K, Wada T, Iwata Y, Sakai N, Yoshimoto K, Kobayashi Ki K, Mukaida N, Matsushima K, Yokoyama H. Administration of FR167653, a new anti-inflammatory compound, prevents renal ischaemia/reperfusion injury in mice. Nephrol Dial Transplant 2002;17:399-407.
Gao YJ, Ji RR. Activation of JNK pathway in persistent pain. Neurosci Lett 2008;437:180-183.
Gorog P, Kovacs IB. Effect of dimethyl sulfoxide (DMSO) on various experimental inflammations. Curr Ther Res Clin Exp 1968;10:486-492.
Griffin RS, Costigan M, Brenner GJ, Ma CH, Scholz J, Moss A, Allchorne AJ, Stahl GL, Woolf CJ. Complement induction in spinal cord microglia results in anaphylatoxin C5a-mediated pain hypersensitivity. J Neurosci 2007;27:8699-8708.
Hains BC, Waxman SG. Activated microglia contribute to the maintenance of chronic pain after spinal cord injury. J Neurosci 2006;26:4308-4317.
Han JS, Terenius L. Neurochemical basis of acupuncture analgesia. Annu Rev Pharmacol Toxicol 1982;22:193-220.
Han JS. Acupuncture and endorphins. Neurosci Lett 2004;361:258-261.
Han JS. Acupuncture: neuropeptide release produced by electrical stimulation of different frequencies. Trends Neurosci 2003;26:17-22.
Hao S, Takahata O, Iwasaki H. Electroacupuncture potentiates the antinociceptive effect of intrathecal endomorphine-1 in the rat formalin test. Neurosci Lett 2000;287:9-12.
Harris JA. Using c-fos as a neural marker of pain. Brain Res Bull 1998;45:1-8.
Haydon PG. GLIA: listening and talking to the synapse. Nature Reviews Neuroscience 2001;2:185-193.
Honore P, Wade CL, Zhong C, Harris RR, Wu C, Ghayur T, Iwakura Y, Decker MW, Faltynek C, Sullivan J, Jarvis MF. Interleukin-1alphabeta gene-deficient mice show reduced nociceptive sensitivity in models of inflammatory and neuropathic pain but not post-operative pain. Behav Brain Res 2006;167:355-364.
Hunt SP, Pini A, Evan G. Induction of c-fos-like protein in spinal cord neurons following sensory stimulation, Nature 1987;328:632-634.
Hurley RW, Hammond DL. The analgesic effects of supraspinal mu and delta opioid receptor agonists are potentiated during persistent inflammation. J Neurosci 2000;20:1249-1259.
Inoue K, Koizumi S, Tsuda M. The role of nucleotides in the neuron--glia communication responsible for the brain functions. J Neurochem 2007;102:1447-1458.
Ji RR, Kawasaki Y, Zhuang ZY, Wen YR, Decosterd I. Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway. Neuron Glia Biol 2006;2:259-269.
Ji RR, Kawasaki Y, Zhuang ZY, Wen YR, Zhang YQ. Protein kinases as potential targets for the treatment of pathological pain. Handbook of Experimental Pharmacology 2007;359-389.
Ji R-R, Kohno T, Moore KA, Woolf CJ. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends in Neurosciences 2003;26:696-705.
Ji RR, Samad TA, Jin SX, Schmoll R, Woolf CJ. p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 2002;36:57-68.
Ji RR, Strichartz G. Cell signaling and the genesis of neuropathic pain. Sci STKE 2004;2004:reE14.
Ji RR, Suter MR. p38 MAPK, microglial signaling, and neuropathic pain. Mol Pain 2007;3:33.
Ji RR, Woolf CJ. Neuronal plasticity and signal transduction in nociceptive neurons: implications for the initiation and maintenance of pathological pain. Neurobiology of Disease 2001;8:1-10.
Jin SX, Zhuang ZY, Woolf CJ, Ji RR. 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 2003b;23:4017-4022.
Kawamata M, Narimatsu E, Kozuka Y, Takahashi T, Sugino S, Niija T, Namiki A. Effects of halothane and isoflurane on hyperexcitability of spinal dorsal horn neurons after incision in the rat. Anesthesiology 2005;102:165-74.
Kawamata M, Takahashi T, Kozuka Y, Nawa Y, Nishikawa K, Narimatsu E, Watanabe H, Namiki A. Experimental incision-induced pain in human skin: effects of systemic lidocaine on flare formation and hyperalgesia. Pain 2002;100:77-89.
Kawashima Y, Takeyoshi I, Otani Y, Koibuchi Y, Yoshinari D, Koyama T, Kobayashi M, Matsumoto K, Morishita Y. FR167653 attenuates ischemia and reperfusion injury of the rat lung with suppressing p38 mitogen-activated protein kinase. J Heart Lung Transplant 2001;20:568-574.
Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet 2006;367:1618-1625.
Kim D, Kim MA, Cho I-H, Kim MS, Lee S, Jo E-K, Choi S-Y, Park K, Kim JS, Akira S, Na HS, Oh SB, Lee SJ. A critical role of toll-like receptor 2 in nerve injury-induced spinal cord glial cell activation and pain hypersensitivity. Journal of Biological Chemistry 2007;282:14975-14983.
Kim SK, Park JH, Bae SJ, Kim JH, Hwang BG, Min BI, Park DS, Na HS. Effects of electroacupuncture on cold allodynia in a rat model of neuropathic pain: mediation by spinal adrenergic and serotonergic receptors. Exp Neurol 2005;195:430-436.
Kim SY, Bae JC, Kim JY, Lee HL, Lee KM, Kim DS, Cho HJ. 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.
Kissin I. Preemptive analgesia. Anesthesiology 2000;93:1138-1143.
Kobayashi M, Takeyoshi I, Yoshinari D, Matsumoto K, Morishita Y. P38 mitogen-activated protein kinase inhibition attenuates ischemia-reperfusion injury of the rat liver. Surgery 2002;131:344-349.
Koistinaho M, Koistinaho J. Role of p38 and p44/42 mitogen-activated protein kinases in microglia. Glia 2002;40:175-183.
Koo ST, Lim KS, Chung K, Ju H, Chung JM. Electroacupuncture-induced analgesia in a rat model of ankle sprain pain is mediated by spinal alpha-adrenoceptors. Pain 2008;135:11-19.
Koo ST, Park YI, Lim KS, Chung K, Chung JM. Acupuncture analgesia in a new rat model of ankle sprain pain. Pain 2002;99:423-431.
Lao L, Zhang G, Wei F, Berman BM, Ren K. Electro-acupuncture attenuates behavioral hyperalgesia and selectively reduces spinal Fos protein expression in rats with persistent inflammation. J Pain 2001;2:111-117.
Lao L, Zhang RX, Zhang G, Wang X, Berman BM, Ren K. A parametric study of electroacupuncture on persistent hyperalgesia and Fos protein expression in rats. Brain Res 2004;1020:18-29.
Lau WK, Chan WK, Zhang JL, Yung KK, Zhang HQ. Electroacupuncture inhibits cyclooxygenase-2 up-regulation in rat spinal cord after spinal nerve ligation. Neuroscience 2008;155:463-468.
Le Bars D, Dickenson AH, Besson JM. Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat. Pain 1979a;6:283-304.
Le Bars D, Dickenson AH, Besson JM. Diffuse noxious inhibitory controls (DNIC). II. Lack of effect on non-convergent neurones, supraspinal involvement and theoretical implications. Pain 1979b;6:305-327.
Ledeboer A, Sloane EM, Milligan ED, Frank MG, Mahony JH, Maier SF, Watkins LR. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain 2005;115:71-83.
Lee JH, Beitz AJ. Electroacupuncture modifies the expression of c-fos in the spinal cord induced by noxious stimulation. Brain Res 1992;577:80-91.
Lee JH, Beitz AJ. The distribution of brain-stem and spinal cord nuclei associated with different frequencies of electroacupuncture analgesia. Pain 1993;52:11-28.
Lewis JW, Cannon JT, Liebeskind JC. Opioid and nonopioid mechanisms of stress analgesia. Science 1980;208:623-625.
Li A, Lao L, Wang Y, Xin J, Ren K, Berman BM, Tan M, Zhang R. Electroacupuncture activates corticotrophin-releasing hormone-containing neurons in the paraventricular nucleus of the hypothalammus to alleviate edema in a rat model of inflammation. BMC Complement Altern Med 2008;8:20.
Li JJ, Chen RM, Liu L, Wang SY, Yu P, Xie Y, Li M, Shi J. Effects of electroacupuncture on the immunoreactivity of focal cutaneous CB2 receptor positive cells in arthritis rats. Zhen Ci Yan Jiu 2007;32:9-15.
Lin CS, Tsaur ML, Chen CC, Wang TY, Lin CF, Lai YL, Hsu TC, Pan YY, Yang CH, Cheng JK. Chronic intrathecal infusion of minocycline prevents the development of spinal-nerve ligation-induced pain in rats. Reg Anesth Pain Med 2007;32:209-216.
Lin JG, Lo MW, Wen YR, Hsieh CL, Tsai SK, Sun WZ, Lin JG, Lo MW, Wen YR, Hsieh CL, Tsai SK, Sun WZ. The effect of high and low frequency electroacupuncture in pain after lower abdominal surgery. Pain 2002;99:509-514.
Linde K, Streng A, Jürgens S, Hoppe A, Brinkhaus B, Witt C, Wagenpfeil S, Pfaffenrath V, Hammes MG, Weidenhammer W, Willich SN, Melchart D. Acupuncture for patients with migraine: A randomized controlled trial. JAMA 2005;293:2118-2125.
Ma W, Quirion R. Partial sciatic nerve ligation induces increase in the phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in astrocytes in the lumbar spinal dorsal horn and the gracile nucleus. Pain 2002;99:175-184.
Marquez C, Belda X, Armario A. Post-stress recovery of pituitary-adrenal hormones and glucose, but not the response during exposure to the stressors, is a marker of stress intensity in highly stressful situations. Brain Res 2002;926:181-185.
Michael GJ, Averill S, Nitkunan A, Rattray M, Bennett DL, Yan Q, Priestley JV. Nerve growth factor treatment increases brain-derived neurotrophic factor selectively in TrkA-expressing dorsal root ganglion cells and in their central terminations within the spinal cord. J Neurosci 1997;17:8476-8490.
Millan MJ. Descending control of pain. Prog Neurobiol 2002;66:355-474.
Miller G. Neuroscience. The dark side of glia. Science 2005;308:778-781.
Milligan ED, Twining C, Chacur M, Biedenkapp J, O'Connor K, Poole S, Tracey K, Martin D, Maier SF, Watkins LR. Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats. J Neurosci 2003;23:1026-1040.
Milligan ED, Watkins LR. Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 2009;10:23-36.
Mitchell JM, Lowe D, Fields HL. The contribution of the rostral ventromedial medulla to the antinociceptive effects of systemic morphine in restrained and unrestrained rats. Neuroscience 1998;87:123-133 .
Mizushima T, Obata K, Yamanaka H, Dai Y, Fukuoka T, Tokunaga A, Mashimo T, Noguchi K. Activation of p38 MAPK in primary afferent neurons by noxious stimulation and its involvement in the development of thermal hyperalgesia. Pain 2005;113:51-60.
Mogensen T, Eliasen K, Ejlersen E, Vegger P, Nielsen IK, Kehlet H. Epidural clonidine enhances postoperative analgesia from a combined low-dose epidural bupivacaine and morphine regimen. Anesth Analg 1992;75:607-610.
Molander C, Xu Q, Grant G. The cytoarchitectonic organization of the spinal cord in the rat. I. The lower thoracic and lumbosacral cord. J Comp Neurol 1984;230:133-141.
Murase K, Kawakita K. Diffuse noxious inhibitory controls in antinociception produced by acupuncture and moxibustion on trigeminal caudalis neurons in rats. Jpn J Physiol 2000;50:133-140.
Mylius V, Engau I, Teepker M, Stiasny-Kolster K, Schepelmann K, Oertel WH, Lautenbacher S, Moller JC. Pain sensitivity and descending inhibition of pain in Parkinson's disease. J Neurol Neurosurg Psychiatry 2009;80:24-28.
Nikodemova M, Duncan ID, Watters JJ. Minocycline exerts inhibitory effects on multiple mitogen-activated protein kinases and IkappaBalpha degradation in a stimulus-specific manner in microglia. J Neurochem 2006;96:314-323.
Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005;308:1314-1318.
Noviova NS, Kazakova TB, Rogers V, Korneva EA. Expression of the c-Fos gene in spinal cord and rain cells in rats subjected to stress in conditions of exposure to various types halothane anesthesia. Neurosci Behav Physiol 2004;34:407-412.
O’Connor TC, Abram SE. Inhibition of nociception-induced spinal sensitization by anesthetic agents. Anesthesiology 1995;82:259-266..
Obata H, Eisenach JC, Hussain H, Bynum T, Vincler M. Spinal glial activation contributes to postoperative mechanical hypersensitivity in the rat. J Pain 2006;7:816-822.
Obata K, Yamanaka H, Kobayashi K, Dai Y, Mizushima T, Katsura H, Fukuoka T, Tokunaga A, Noguchi K. Role of mitogen-activated protein kinase activation in injured and intact primary afferent neurons for mechanical and heat hypersensitivity after spinal nerve ligation. J Neurosci 2004;24:10211-10222.
Okada C. The relationship between diffuse noxious inhibitory control effects and the magnitude of noxious stimuli. Kokubyo Gakkai Zasshi 2005;72:49-55.
Oliveira R, Prado WA. Anti-hyperalgesic effect of electroacupuncture in a model of post-incisional pain in rats. Brazilian Journal of Medical & Biological Research 2000;33:957-960.
Pan B, Castro-Lopes JM, Coimbra A. C-fos expression in the hypothalamo-pituitary system induced by electroacupuncture or noxious stimulation. NeuroReport 1994;5:1649-1652 .
Peters ML, Schmidt AJ, Van den Hout MA, Koopmans R, Sluijter ME. Chronic back pain, acute postoperative pain and the activation of diffuse noxious inhibitory controls (DNIC). Pain 1992;50:177-187.
Pogatzki-Zahn EM, Shimizu I, Caterina M, Raja SN. Heat hyperalgesia after incision requires TRPV1 and is distinct from pure inflammatory pain. Pain 2005;115:296-307.
Pogatzki-Zahn EM, Zahn PK. From preemptive to preventive analgesia. Current Opinion in Anaesthesiology 2006;19:551-555.
Pomeranz B, Cheng R, Law P. Acupuncture reduces electrophysiological and behavioral responses to noxious stimulation: pituitary is implicated. Exp Neurol 1977;54:172-178.
Pomeranz B. Relation of stress-induced analgesia to acupuncture analgesia. Ann NY Acad Sci 1986;467:444-447.
Porreca F, Lai J, Bian D, Wegert S, Ossipov MH, Eglen RM, Kassotakis L, Novakovic S, Rabert DK, Sangameswaran L, Hunter JC. A comparison of the potential role of the tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2, in rat models of chronic pain. Proc Natl Acad Sci U S A 1999;96:7640-7644.
Presley RW, Mentry D, Levine J, Basbaum AI. Systemic morphine suppresses noxious stimulus-evoked fos protein-like immunoreactivity in the rat spinal cord. J Neurosci 1990;10:323-325.
Price DD, Mao J, Mayer DJ. Central neural mechanisms of normal and abnormal pain states. In: Field HL, Liebskind JC editors. Pharmacological Approaches to the Treatment of Chronic Pain: New Concepts and Critical issues. Seattle: IASP Press; 1994. p61-84.
Raghavendra V, Tanga F, DeLeo JA. 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.
Raghavendra V, Tanga FY, DeLeo JA. Complete Freunds adjuvant-induced peripheral inflammation evokes glial activation and proinflammatory cytokine expression in the CNS. European Journal of Neuroscience 2004;20:467-473.
Raivich G. Like cops on the beat: the active role of resting microglia. Trends in Neurosciences 2005;28:571-573.
Ren K, Dubner R. Neuron-glia crosstalk gets serious: role in pain hypersensitivity. Curr Opin Anaesthesiol 2008;21:570-579.
Ren K, Hylden JL, Williams GM, Ruda MA, Dubner R. The effects of a non-competitive NMDA receptor antagonist, MK-801, on behavioral hyperalgesia and dorsal horn neuronal activity in rats with unilateral inflammation. Pain 1992;50:331-344.
Reuben SS, Buvanendran A. Preventing the development of chronic pain after orthopaedic surgery with preventive multimodal analgesic techniques. Journal of Bone & Joint Surgery - American Volume 2007;89:1343-1358.
Romero-Sandoval A, Eisenach JC. Spinal cannabinoid receptor type 2 activation reduces hypersensitivity and spinal cord glial activation after paw incision. Anesthesiology 2007;106:787-794.
Romita VV, Henry JL. Intense peripheral electrical stimulation differentially inhibits tail vs. limb withdrawal reflexes in the rat. Brain Res 1996;720:45-53.
Romita VV, Suk A, Henry JL. Parametric studies on electroacupuncture-like stimulation in a rat model: effects of intensity, frequency, and duration of stimulation on evoked antinociception. Brain Res Bull 1997a;42:289-296.
Romita VV, Yashpal K, Christina WYH, Henry JL. Intense peripheral electrical stimulation evokes brief and persistent inhibition of the nociceptive tail withdrawal reflex in the rat. Brain Res 1997b;761:192-202.
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;23:2517-2521.
Scholz J, Woolf CJ. The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci 2007;10:1361-1368.
Shan S, Qi-Liang MY, Hong C, Tingting L, Mei H, Haili P, Yan-Qing W, Zhi-Qi Z, Yu-Qiu Z. Is functional state of spinal microglia involved in the anti-allodynic and anti-hyperalgesic effects of electroacupuncture in rat model of monoarthritis? Neurobiol Dis 2007;26:558-568.
Shang AB, Gan TJ. Optimising postoperative pain management in the ambulatory patient. Drugs 2003;63:855-867.
Sheng LL, Nishiyama K, Honda T, Sugiura M, Yaginuma H, Sugiura Y. Suppressive effects of Neiting acupuncture on the toothache: an experimental analysis on Fos expression evoked by tooth pulp stimulation in the trigeminal subnucleus pars caudalis and the periaqueductal ray of rats. Neurosci Res 2001;38:331-339 .
Shieh JS, Dai CY, Wen YR, Sun WZ. A novel fuzzy pain demand index derived from patient-controlled analgesia for postoperative pain. IEEE Trans Biomed Eng 2007;54:2123-2132.
Sun S, Cao H, Han M, Li TT, Zhao ZQ, Zhang YQ. Evidence for suppression of electroacupuncture on spinal glial activation and behavioral hypersensitivity in a rat model of monoarthritis. Brain Res Bull 2008a;75:83-93.
Sun S, Chen WL, Wang PF, Zhao ZQ, Zhang YQ. Disruption of glial function enhances electroacupuncture analgesia in arthritic rats. Exp Neurol 2006;198:294-302.
Sun WZ, Shyu BC, Shieh JY. Nitrous oxide or halothane, or both, fail to suppress c-fos expression in rat spinal cord dorsal horn neurons after subcutaneous formalin. Brit J Anaesth 1996;76:99-105.
Sun X, Yokoyama M, Mizobuchi S, Kaku R, Nakatsuka H, Takahashi T, Morita K. The effects of pretreatment with lidocaine or bupivacaine on the spatial and temporal expression of c-Fos protein in the spinal cord caused by plantar incision in the rat. Anesthesia & Analgesia 2004;98:1093-1098.
Sun Y, Gan TJ, Dubose JW, Habib AS. Acupuncture and related techniques for postoperative pain: a systematic review of randomized controlled trials. Br J Anaesth 2008b;101:151-160.
Suter MR, Wen YR, Decosterd I, Ji RR. Do glial cells control pain? Neuron Glia Biol 2007;3:255-268.
Svensson CI, Fitzsimmons B, Azizi S, Powell HC, Hua XY, Yaksh TL. Spinal p38beta isoform mediates tissue injury-induced hyperalgesia and spinal sensitization. J Neurochem 2005;92:1508-1520.
Svensson CI, Marsala M, Westerlund A, Calcutt NA, Campana WM, Freshwater JD, Catalano R, Feng Y, Protter AA, Scott B, Yaksh TL. Activation of p38 mitogen-activated protein kinase in spinal microglia is a critical link in inflammation-induced spinal pain processing. J Neurochem 2003;86:1534-1544.
Svensson CI, Schafers M, Jones TL, Powell H, Sorkin LS. Spinal blockade of TNF blocks spinal nerve ligation-induced increases in spinal P-p38. Neurosci Lett 2005;379:209-213.
Sweitzer SM, Peters MC, Ma JY, Kerr I, Mangadu R, Chakravarty S, Dugar S, Medicherla S, Protter AA, Yeomans DC. Peripheral and central p38 MAPK mediates capsaicin-induced hyperalgesia. Pain 2004;111:278-285.
Takeshige C, Kobori M, Hishida F, Luo CP, Usami S. Analgesia inhibitory system involvement in nonacupuncture point-stimulation-produced analgesia. Brain Res Bull 1992;28:379-391.
Tanga FY, Nutile-McMenemy N, DeLeo JA. The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy. Proc Natl Acad Sci USA 2005;102:5856-5861.
Tanga FY, Raghavendra V, DeLeo JA. Quantitative real-time RT-PCR assessment of spinal microglial and astrocytic activation markers in a rat model of neuropathic pain. Neurochemistry International 2004;45:397-407.
Tsuda M, Inoue K, Salter MW. Neuropathic pain and spinal microglia: a big problem from molecules in "small" glia. Trends Neurosci 2005;28:101-107.
Tsuda M, Mizokoshi A, Shigemoto-Mogami Y, Koizumi S, Inoue K. Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury. Glia 2004;45:89-95.
Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, Inoue K. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 2003;424:778-783.
Ulett GA, Han S, Han JS. Electroacupuncture: Mechanisms and Clinical application. Biol Psychiatry 1998;44:129-138.
Umemoto S, Noguchi K, Kawai E, Senba E. Repeated stress reduces the subsequent stress-induced expression of Fos in rat brain. Neurosci Lett 1994;167:101-104.
Vaccarinoa AL, Kastina AJ. Endogenous opiates: 2000. Peptides 2001;22:2257-2328.
Viviani B, Bartesaghi S, Gardoni F, Vezzani A, Behrens MM, Bartfai T, Binaglia M, Corsini E, Di Luca M, Galli CL, Marinovich M. Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. Journal of Neuroscience 2003;23:8692-8700.
Wall PD. The prevention of postoperative pain. Pain 1988;33:289-290.
Wang SM, Kain ZN, White PF. Acupuncture analgesia: II. Clinical considerations. Anesth Analg 2008;106:611-621.
Wang Y, Zhang Y, Wang W, Cao Y, Han JS. Effects of synchronous or asynchronous electroacupuncture stimulation with low versus high frequency on spinal opioid release and tail flick nociception. Exp Neurol 2005;192:156-162.
Watkins LR, Maier SF. Glia: a novel drug discovery target for clinical pain. Nat Rev Drug Discov 2003;2:973-985.
Wen YR, Suter MR, Ji RR, Yeh GC, Wu YS, Wang KC, Kohno T, Sun WZ, Wang CC. Activation of p38 mitogen-activated protein kinase in spinal microglia contributes to incision-induced mechanical allodynia. Anesthesiology 2009;110:155-165.
Wen YR, Suter MR, Kawasaki Y, Huang J, Pertin M, Kohno T, Berde CB, Decosterd I, Ji R-R. Nerve conduction blockade in the sciatic nerve prevents but does not reverse the activation of p38 mitogen-activated protein kinase in spinal microglia in the rat spared nerve injury model. Anesthesiology 2007a;107:312-321.
Wen YR, Yeh GC, Shyu BC, Ling QD, Wang KC, Chen TL, Sun WZ. A minimal stress model for the assessment of electroacupuncture analgesia in rats under halothane. Eur J Pain 2007b;11:733-742.
Widmann C, Gibson S, Jarpe MB, Johnson GL. Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev 1999;79:143-180.
Winkelstein BA, DeLeo JA. Nerve root injury severity differentially modulates spinal glial activation in a rat lumbar radiculopathy model: considerations for persistent pain. Brain Res 2002;956:294-301.
Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management.[see comment]. Lancet 1999;353:1959-1964.
Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000;288:1765-1769.
Xie YF, Zhang S, Chiang CY, Hu JW, Dostrovsky JO, Sessle BJ. Involvement of glia in central sensitization in trigeminal subnucleus caudalis (medullary dorsal horn). Brain Behav Immun 2007;21:634-641.
Xu M, Bruchas MR, Ippolito DL, Gendron L, Chavkin C. Sciatic nerve ligation-induced proliferation of spinal cord astrocytes is mediated by kappa opioid activation of p38 mitogen-activated protein kinase. J Neurosci 2007;27:2570-2581.
Yaksh TL. The spinal pharmacology of facilitation of afferent processing evoked by high-threshold afferent input of the postinjury pain state. Curr Opin Neurol Neurosurg 1993;6:250-256.
Yamamoto N, Sakai F, Yamazaki H, Nakahara K, Okuhara M. Effect of FR167653, a cytokine suppressive agent, on endotoxin-induced disseminated intravascular coagulation. Eur J Pharmacol 1996;314:137-142.
Yamamoto N, Sakai F, Yamazaki H, Sato N, Nakahara K, Okuhara M. FR167653, a dual inhibitor of interleukin-1 and tumor necrosis factor-alpha, ameliorates endotoxin-induced shock. Eur J Pharmacol 1997;327:169-174.
Yamamoto T, Sakashita Y. The role of the spinal opioid receptor like1 receptor, the NK-1 receptor, and cyclooxygenase-2 in maintaining postoperative pain in the rat. Anesth Analg 1999;89:1203-1208.
Yamamoto T, Shimoyama N, Mizuguchi T. The effects of morphine, MK-801, an NMDA antagonist, and CP-96,345, an NK1 antagonist, on the hyperesthesia evoked by carageenan injection in the rat paw. Anesthesiology 1993;78:124-133.
Yang CH, Lee BB, Jung HS, Shim I, Roh PU, Golden GT. Effect of electroacupuncture on response to immobilization stress. Pharmacol Biochem Behav 2002;72:847-855.
Zahn PK, Brennan TJ, Zahn PK, Brennan TJ. Intrathecal metabotropic glutamate receptor antagonists do not decrease mechanical hyperalgesia in a rat model of postoperative pain. Anesthesia & Analgesia 1998;87:1354-1359.
Zahn PK, Brennan TJ. Lack of effect of intrathecally administered N-methyl-D-aspartate receptor antagonists in a rat model for postoperative pain. Anesthesiology 1998;88:143-156.
Zahn PK, Gysbers D, Brennan TJ. Effect of systemic and intrathecal morphine in a rat model of postoperative pain. Anesthesiology 1997;86:1066-1077.
Zahn PK, Pogatzki-Zahn EM, Brennan TJ. Spinal administration of MK-801 and NBQX demonstrates NMDA-independent dorsal horn sensitization in incisional pain. Pain 2005;114:499-510.
Zahn PK, Umali E, Brennan TJ. Intrathecal non-NMDA excitatory amino acid receptor antagonists inhibit pain behaviors in a rat model of postoperative pain. Pain 1998;74:213-223.
Zhang RX, Lao L, Wang L, Liu B, Wang X, Ren K, Berman BM. Involvement of opioid receptors in electroacupuncture-produced anti-hyperalgesia in rats with peripheral inflammation. Brain Res 2004;1020:12-17.
Zhang RX, Li A, Liu B, Wang L, Xin J, Ren K, Qiao JT, Berman BM, Lao L. Electroacupuncture attenuates bone-cancer-induced hyperalgesia and inhibits spinal preprodynorphin expression in a rat model. Eur J Pain 2008;12:870-878.
Zhu CZ, Hsieh G, Ei-Kouhen O, Wilson SG, Mikusa JP, Hollingsworth PR, Chang R, Moreland RB, Brioni J, Decker MW, Honore P. Role of central and peripheral mGluR5 receptors in post-operative pain in rats. Pain 2005;114:195-202.
Zhu CZ, Nikkel AL, Martino B, Bitner RS, Decker MW, Honore P, Zhu CZ, Nikkel AL, Martino B, Bitner RS, Decker MW, Honore P. Dissociation between post-surgical pain behaviors and spinal Fos-like immunoreactivity in the rat. European Journal of Pharmacology 2006;531:108-117.
Zhuang ZY, Gerner P, Woolf CJ, Ji RR. 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;114:149-159.
Zhuang ZY, Wen YR, Zhang DR, Borsello T, Bonny C, Strichartz GR, Decosterd I, Ji RR. A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. Journal of Neuroscience 2006;26:3551-3560.
Zimmermann M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain 1983;16:109-110.
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