鞘内预先注射布托啡诺和氯胺酮对福尔马林炎性痛大鼠脊髓背角PKA和pCREB表达的影响
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摘要
研究背景布托啡诺是一种合成的阿片受体激动-拮抗剂,其镇痛效应强、作用时间久而副反应(呼吸抑制、成瘾等)发生率较低,已广泛应用于临床,但鞘内给药局限于动物实验阶段。研究表明椎管内NMDA受体拮抗剂和阿片类药物合用有协同镇痛作用,前期动物实验已证实了氯胺酮(非竞争的NMDA受体拮抗剂)和布托啡诺鞘内联合用药可以减少布托啡诺的用药量并起到相似的镇痛效果。PKA、CREB信号转导系统在脊髓水平痛觉传递和调制及疼痛中枢敏感化的形成和维持中起着重要作用,cAMP/PKA信号通路能磷酸化多种底物,是细胞内最重要的信号转导通路之一,CREB可接受多种信号转导通路的调控。在布托啡诺复合氯胺酮镇痛机制中,是否抑制了cAMP/PKA-CREB信号通路值得研究。
目的本研究观察鞘内预先注射布托啡诺以及合用鞘内注射非竞争性的N-甲基-D-天门冬氨酸(NMDA)受体拮抗剂氯胺酮对于福尔马林炎性痛大鼠的镇痛作用,采用免疫组化的方法检测大鼠脊髓背角PKA和pCREB的表达来探讨其镇痛机制。
方法40只SD雄性大鼠均采用改良Yaksh法进行鞘内置管,置管5天后,被随机分为7组:对照组(C组,n=5);生理盐水组(NS组,n=5);低剂量布托啡诺组(LB组,n=6);高剂量布托啡诺组(HB组,n=6);低剂量氯胺酮组(LK组,n=6);高剂量氯胺酮组(HK组,n=6);低剂量布托啡诺复合低剂量氯胺酮组(LB+LK组,n=6)。在各组大鼠的左后足掌面皮下注射5%福尔马林50μl。致痛前30分钟,C组鞘内不注射任何药物,NS组大鼠鞘内预先注射生理盐水,LB组鞘内预先注射布托啡诺12.5μg,HB组鞘内预先注射布托啡诺25μg,LK组鞘内预先注射氯胺酮50μg,HK组鞘内预先注射氯胺酮100μg,LB+LK组鞘内预先注射布托啡诺12.5μg后立即注射氯胺酮50μg。采用疼痛加权评分法(PIS)评估福尔马林注射后1小时内的疼痛行为,所有大鼠均在注射福尔马林2小时后处死,取大鼠脊髓L_5节段标本,用免疫组化方法测定脊髓背角PKA和pCREB的表达,并进行相关性分析。
结果在福尔马林炎性痛的第一时相和第二时相中,C组和NS组的PIS值明显升高,HB组和LB+LK组的PIS值均低于C组(p＜0.05或0.01),LB组、LK组和HK组的PIS值稍降低,但与C组比较没有统计学差异。在大鼠脊髓背角免疫组化实验中,C组和NS组的PKA和pCREB表达明显增强,HB组和LB+LK组的PKA和pCREB表达均明显弱于C组(p＜0.01),LB组、LK组和HK组的PKA和pCREB表达稍弱于C组,但与C组比较没有统计学差异。对PKA和pCREB的免疫组化染色评分进行相关性分析,两者呈正相关。
结论
1.在大鼠福尔马林炎性痛模型中,鞘内预先注射布托啡诺25μg与鞘内预先注射布托啡诺12.5μg复合氯胺酮50μg可产生相似的镇痛效果。
2.在大鼠福尔马林炎性痛模型中,PKA与pCREB表达明显升高且呈正相关,表明PKA-CREB通路可能是炎性痛形成和维持的机制之一。
3.在大鼠福尔马林炎性痛模型中,鞘内预先注射布托啡诺12.5μg复合氯胺酮50μg,脊髓背角PKA与pCREB表达明显降低且呈正相关,其镇痛作用可能与抑制PKA-CREB信号通路有关。
Background Butorphanol is an agitation-antagon opioid receptor, which has stronger analgesia,longer action time and lower side effect (e.g.respiratory depression,addiction)and applied in clinic generally,but intrathecal administration stays at the animal experiment stage nowdays. Recent study found that the antagon of the NMDAR and opioid drug might generate synergistic effect.PKA and CREB play an important role in transmitting and modulating pain and development and maintain of central sensitization of spinal cord.Therefore,it is important meaning to investigate the feasibility of association from intrathecal administration and molecular level mechanisms of analgesia for pain mechanisms and therapy.
Objective To investigate the effect of preemptive intrathccal butorphanol tartrate and/or ketamine(non-competitive NMDA receptor antogonist)on PKA and pCREB expression in spinal dorsal horn and evaluate antinociception in the rats of formalin pain.
Methods microspinal catheters were inserted intrathecally according to the method of Yaksh.After 5 days,40 male rat were divided into 7 groups randomly:control group(C group,n=5);saline group(NS group,n=5);low-dose butorphanol(LB group,n=6);high-dose of butorphanol(HB group,n=6);low-dose of ketamine(LK group,n=6); high-dose of ketamine(HK group,n=6);low-dose of butorphanol and low-dose of ketamine(LB+LK group,n=6).At 30 minutes before left palmaris paw subcutaneous formalin injection,the control group received no agent prior to formalin injection,the NS group rats were intrathecally pretreated with saline,the LB group were intrathecally pretreated with low-dose of butorphanol 12.5μg,the HB group were intrathecally pretreated with high-dose of butorphanol 25μg,the LK group were intrathecally pretreated with low-dose of ketamine 50μg,the HK group were intrathecally pretreated with high-dose of ketamine 100μg,the LB+LK group were intrathecally pretreated with butorphanol 12.5μg and ketamine 50μg.Pain intensity scoring(PIS)was utilized to assess pain behavior within 1 hour after formalin injection.2 hours later,PKA and pCREB expression in the spinal dorsal horn of the L_5 segment was assayed using immunohistochemistry and done the analysis of correlation.
Result Intrathccal injection high-dose butorphanol 25μg or butorphanol 12.5μg with ketamine 50μg were both capable of inhibition both phases of formalin response,the PIS was decreased(p＜0.05 or 0.01). However,the expression of both the early and later phases was not significantly affected in other groups.Intrathecal pretreatment of high-dose butorphanol 25μg or ketamine 50μg with butorphanol 12.5μg both lowered the expression of spinal cord PKA and pCREB(p＜0.01).
Conclusion
1.In rat of formalin induced inflammatory pain,the effect of the antinociception of the intrathecal pre-treatment of butorphanol 25μg is similar with the effect of the intrathecal administration of the combination of butorphanol 12.5μg and ketamine 50μg.
2.The expression of PKA and pCREB in the spinal dorsal horn is higher obviously,as well positive correlation,which indicates that the PKA-CREB pathway may be the formation and maintenance of the formalin induced inflammatory pain.
3.In rat of formalin induced inflammatory pain,the expression of PKA and pCREB in the spinal dorsal horn is decreased obviously,as well positive correlation after the intrathecal pre-treatment of butorphanol 12.5μg and ketamine 50μg,the antinociception mechanisms may be connects with the inhibition of the PKA-CREB pathway.
目的本研究观察鞘内预先注射布托啡诺以及合用鞘内注射非竞争性的N-甲基-D-天门冬氨酸(NMDA)受体拮抗剂氯胺酮对于福尔马林炎性痛大鼠的镇痛作用,采用免疫组化的方法检测大鼠脊髓背角PKA和pCREB的表达来探讨其镇痛机制。
方法40只SD雄性大鼠均采用改良Yaksh法进行鞘内置管,置管5天后,被随机分为7组:对照组(C组,n=5);生理盐水组(NS组,n=5);低剂量布托啡诺组(LB组,n=6);高剂量布托啡诺组(HB组,n=6);低剂量氯胺酮组(LK组,n=6);高剂量氯胺酮组(HK组,n=6);低剂量布托啡诺复合低剂量氯胺酮组(LB+LK组,n=6)。在各组大鼠的左后足掌面皮下注射5%福尔马林50μl。致痛前30分钟,C组鞘内不注射任何药物,NS组大鼠鞘内预先注射生理盐水,LB组鞘内预先注射布托啡诺12.5μg,HB组鞘内预先注射布托啡诺25μg,LK组鞘内预先注射氯胺酮50μg,HK组鞘内预先注射氯胺酮100μg,LB+LK组鞘内预先注射布托啡诺12.5μg后立即注射氯胺酮50μg。采用疼痛加权评分法(PIS)评估福尔马林注射后1小时内的疼痛行为,所有大鼠均在注射福尔马林2小时后处死,取大鼠脊髓L_5节段标本,用免疫组化方法测定脊髓背角PKA和pCREB的表达,并进行相关性分析。
结果在福尔马林炎性痛的第一时相和第二时相中,C组和NS组的PIS值明显升高,HB组和LB+LK组的PIS值均低于C组(p＜0.05或0.01),LB组、LK组和HK组的PIS值稍降低,但与C组比较没有统计学差异。在大鼠脊髓背角免疫组化实验中,C组和NS组的PKA和pCREB表达明显增强,HB组和LB+LK组的PKA和pCREB表达均明显弱于C组(p＜0.01),LB组、LK组和HK组的PKA和pCREB表达稍弱于C组,但与C组比较没有统计学差异。对PKA和pCREB的免疫组化染色评分进行相关性分析,两者呈正相关。
结论
1.在大鼠福尔马林炎性痛模型中,鞘内预先注射布托啡诺25μg与鞘内预先注射布托啡诺12.5μg复合氯胺酮50μg可产生相似的镇痛效果。
2.在大鼠福尔马林炎性痛模型中,PKA与pCREB表达明显升高且呈正相关,表明PKA-CREB通路可能是炎性痛形成和维持的机制之一。
3.在大鼠福尔马林炎性痛模型中,鞘内预先注射布托啡诺12.5μg复合氯胺酮50μg,脊髓背角PKA与pCREB表达明显降低且呈正相关,其镇痛作用可能与抑制PKA-CREB信号通路有关。
Background Butorphanol is an agitation-antagon opioid receptor, which has stronger analgesia,longer action time and lower side effect (e.g.respiratory depression,addiction)and applied in clinic generally,but intrathecal administration stays at the animal experiment stage nowdays. Recent study found that the antagon of the NMDAR and opioid drug might generate synergistic effect.PKA and CREB play an important role in transmitting and modulating pain and development and maintain of central sensitization of spinal cord.Therefore,it is important meaning to investigate the feasibility of association from intrathecal administration and molecular level mechanisms of analgesia for pain mechanisms and therapy.
Objective To investigate the effect of preemptive intrathccal butorphanol tartrate and/or ketamine(non-competitive NMDA receptor antogonist)on PKA and pCREB expression in spinal dorsal horn and evaluate antinociception in the rats of formalin pain.
Methods microspinal catheters were inserted intrathecally according to the method of Yaksh.After 5 days,40 male rat were divided into 7 groups randomly:control group(C group,n=5);saline group(NS group,n=5);low-dose butorphanol(LB group,n=6);high-dose of butorphanol(HB group,n=6);low-dose of ketamine(LK group,n=6); high-dose of ketamine(HK group,n=6);low-dose of butorphanol and low-dose of ketamine(LB+LK group,n=6).At 30 minutes before left palmaris paw subcutaneous formalin injection,the control group received no agent prior to formalin injection,the NS group rats were intrathecally pretreated with saline,the LB group were intrathecally pretreated with low-dose of butorphanol 12.5μg,the HB group were intrathecally pretreated with high-dose of butorphanol 25μg,the LK group were intrathecally pretreated with low-dose of ketamine 50μg,the HK group were intrathecally pretreated with high-dose of ketamine 100μg,the LB+LK group were intrathecally pretreated with butorphanol 12.5μg and ketamine 50μg.Pain intensity scoring(PIS)was utilized to assess pain behavior within 1 hour after formalin injection.2 hours later,PKA and pCREB expression in the spinal dorsal horn of the L_5 segment was assayed using immunohistochemistry and done the analysis of correlation.
Result Intrathccal injection high-dose butorphanol 25μg or butorphanol 12.5μg with ketamine 50μg were both capable of inhibition both phases of formalin response,the PIS was decreased(p＜0.05 or 0.01). However,the expression of both the early and later phases was not significantly affected in other groups.Intrathecal pretreatment of high-dose butorphanol 25μg or ketamine 50μg with butorphanol 12.5μg both lowered the expression of spinal cord PKA and pCREB(p＜0.01).
Conclusion
1.In rat of formalin induced inflammatory pain,the effect of the antinociception of the intrathecal pre-treatment of butorphanol 25μg is similar with the effect of the intrathecal administration of the combination of butorphanol 12.5μg and ketamine 50μg.
2.The expression of PKA and pCREB in the spinal dorsal horn is higher obviously,as well positive correlation,which indicates that the PKA-CREB pathway may be the formation and maintenance of the formalin induced inflammatory pain.
3.In rat of formalin induced inflammatory pain,the expression of PKA and pCREB in the spinal dorsal horn is decreased obviously,as well positive correlation after the intrathecal pre-treatment of butorphanol 12.5μg and ketamine 50μg,the antinociception mechanisms may be connects with the inhibition of the PKA-CREB pathway.
引文
[1]Vogelsng J,Hayes SR.Butorphanol tartrate(stadol):a review.J Post Anesth Nurs,1991,6(2):129-35.
[2]Lee H,Naughton NN,Woods JH,et al.Effects of butorphanol on morphine-induced itch and analgesia in primates.Anesthesiology,2007,107(3):478-85.
[3]Tsang BK,He Z,Wongchanapai W,et al.Visceral analgesic tolerance to intrathecal butorphanol in rats.Can J Anaesth,1998,45(10):1019-23.
[4]Schatzman U,Armbruster S,Stucki F,et al.Analgesic effect of butorphanol and levomethadone in detomidine sedated horses.J A PhysiolPathol Clin Med,2001,48(6):337-342.
[5]Tsang BK,He Z,Wongchanapai W,et al.Induction of tolerance to intrathecal butorphanol in rats.Acta Anaesthesiol Sin,1997,35(4):237-40.
[6]Kelly DJ,Abroad M,Brull SJ.Preemptive analgesia Ⅱ:recent advancesand current trends.Can J Anacsth,2001,48:1091-1101.
[7]Eisenach JC,De Kock M,Klimscha W.[alpha]2-adrenergic agonists for regional anesthesia A clinical review of colnidine(1984-1995).Anesthesiology,1996,85:655-74.
[8]Mukherjee A,Park-sarge OK,Mayo KE.Gonadotropins induce rapid phosphorylation of 3',5' -cyclic adensine monophosphate response element binding protein in ovarian granulose cells.Endocrinology,1996,137:3234-3245.
[9]Adams SR,Harootunian AT,Buechler YJ,et al.Fluorescence ratio imaging of cyclic-AMP in single cell.Nature,1991,349:694-697.
[10]姚永兴,张励才,宋学军,等.鞘内注射H-89对神经病理痛大鼠脊髓背角磷酸化cAMP反应元件结合蛋白表达的影响.中华麻醉学杂志,2005,25(5):371-374.
[11]Woolf CJ,Chong MS.Preemptive analgesia-treating postoperative pain by preventing the establishment of central sensitization.Anesth Analg,1993,77:362-79.
[12]Bao L,Jin SX,Zhang C,et al.Activation of delta opioid receptors induces receptor insertion and neuropetide.Neuron,2003,37: 121-133.
[13]邹望远.鞘内泵入吗啡、曲马多对福尔马林炎性痛大鼠免疫功能的影响及镇痛效应的观察:[硕士学位论文].长沙:中南大学,2004.
[14]Okuda K,Sakurada C,TakahashiM,et al.Characterization of nociceptive responses and spinal releases of nitric oxide metabolites and glutamate evoked by different concentrations of formalin in rats.Pain,2001,92(1-2):107.
[15]Abbott FV,F ranklin KB,Westbrook RF.The formalin test:scoring properties of the first and second phases of the pain response in rats.Pain,1995,60(1):91-102.
[16]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):161-174.
[17]Wang B,Luo F,Han JS.Central areas and post-receptor mechanisms underlying opioid physical dependence.Chin J Neurosci,1999,15:63-68.
[18]Roche AK,Cook M,Wilcox GL,et al.A nitric oxide synthase inhibitor(L-NAME)reduce licking behavior and Fos-labeling in the spinal cord of rats during formalin-induced inflammation.Pain,1996,66:331-334.
[19]张园.鞘内注射布托啡诺对福尔马林试验大鼠行为学及脊髓NMDAR表达的影响:[硕士学位论文].长沙:中南大学,2007.
[20]Rawal N,Nuutinen L,RajPP,Lovering SL,Gobuty AH,Hargardine J,Lehmkuhl L,Herva R,Abouleish E.Behavioral and histopathologic effects following intrathecal administration of butorphanol,sufentanil,and nalbuphine in sheep.Anesthesiology.1991 Dec;75(6):1025-34.
[21]DeRossi R,Almeida RG,Medeiros U,et al.Subarachnoid butorphanol augments lidocaine sensory anaesthesia in calves.Vet J,2007,173(3):658-63.
[22]Wongchanapai W,Tsang BK,He Z,et al.Differential involvement of opioid receptors in intrathecal butorphanol-induced analgesia:compared to morphine.Pharmacol Biochem Behav,1998 Mar,59(3):723-7.
[23]Garner HR,Burke TF,Lawhorn CD,et al.Butvrphanol-Mediated Antinociception in Mice:Partial Agonist Effects and Mu Receptor Involvement.Pharmacology,1997,282(3):1253-1261.
[24]Okon T.Ketamine:an introduction for the pain and palliative medicine physician.Pain Physician,2007,10(3):493-500.
[25]张涛涛,张晓云,董源洪,等.蛛网膜下腔注射氯胺酮对神经痛大鼠痛行为的影响.中华麻醉学杂志,2001,21:223-225.
[26]曾静波,李文斌,陈晓玲,等.大鼠甲醛炎性痛过程中脊髓后角NOS变化及其时间过程.中国病理生理杂志,2000,16(10):1109-1113.
[27]Borgbjerg FM,Svensson BA,Frigast C,et al.Histopathology after repeated intrathecal injections of preservative-free ketamie in the rabbit:a light and electron microscopic examination.Anesth Analg,1994,79:105-111.
[28]Malinovsky JM.Ketaimine and midazolam neurotoxicity in the rabbit.Anesthesiology,1991,75:91-7.
[29]Pelissier T,Laurido C,Kramer V,et al.Antinociceptive interactions of katemine with morphine or methadone in mononeuropathic rats.Cur J Pharmacol,2003,477:23-28.
[30]Skarda RT,Muir WW.Comparison of electroacupuncture and butorphanol on respiratory and cardiovascular elects and rectal pain threshold after controlledrectal distention in mares.Am J Vet Res,2003,64(2):137-144.
[31]Honore P,Chapman V,Buritova J,et al.Concomitant administration of morphine and an N-methyl-D-aspartate receptor antagonist profoundly reduces inflammatory evoked spinal c-Fos expression.Anesthesiology,1996,85:150-160.
[32]Wong CS,Lu CC,Cherng CH,et al.Pre-emptive analgesia with ketamine,morphine an d epidural lidecaine or to total kneereplacement.Can J Anaesth,1997,44:31-37.
[33]Bhattacharya A,Gurnani A,Shurma PK,et al.Subcutaneous infusion of ketamine and morphine for relief of posoperative pain:a double-blind comparative study.Ann Acad Med Singapore,1994,23:456-459.
[34]Stubhaug A,Breivik H,Eide PK,et al.Mapping of punctuate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery.Acta Anaesthesiol Scand,1997,41:l124-1132.
[35]Dubner R,Ruda MA.Activity-dependent neuronal plasticity following tissue injury and inflammation.Trends Neurosci,1992,15:
?96-103.
[36] Levine JD, Fields HL. Basbaum Dipeptides and primary afferent nociceptor. J Neurosci, 1993,13(6):2273-2286.
[37] Adam JS, Michael EG. CREB:A Stimulus-Induced Transcription Factor Activated by A Diverse Array of Extracellular Signals. Annu Rev Biochem, 1999, 68:821-861.
[38] Korzus E. The relation of transcription to memory formation. Acta Biochim Pol, 2003, 50:775-882.
[39] Chen HS, Lei J, He X, et al. Peripheral involvement of PKA and PKC in subcutaneous bee venom-induced persistent nociception, mechanical hyperalgesia, and inflammation in rats. Pain, 2008,135(1-2):31-6.
[40] Zou X, LIN Q, Willis WD. Role of protein kinse A in phosphorylation of NMDA receptor 1 subunts in dorsal horn and spinothalamic tract neurons after intradermal injection of capsaicin in rats. Neuroscience, 2002,115(3):775-86.
[41] Jones TL, Sorkin LS. Activated PKA and PKC, but not CaMKIIalpha, are required for AMPA/Kainate-mediated pain behavior in the thermal stimulus model. Pain, 2005,117:259-70.
[42] Wang C, Gu Y, Li GW, et al. A critical role of the cAMP sensor Epac in switching protein kinase signalling in prostaglandin E2-induced potentiation of P2X3 receptor currents in inflamed rats. J Physiol, 2007, 584 (Pt 1): 191-203.
[43] Bourtchuladze R, Frenguelli B, Blendy J, et al. Deficient long-termmemory in mouse with a targeted mutation of the cAMP-response element-binding protein. Cell, 1994,79:59-68.
[44] Shiokawa M, Yamaguchi T, Narita M, et al. Effects of fasudil on neuropathic pain-like state in mice. Nihon Shinkei Seishin Yakurigaku Zasshi, 2007, 27(4): 153-9.
[45] Ji RR, Rupp F. Phosphorylation of transcription factor CREB in rat spinal cord after formalin-induced hyperalgesia: relationship to c-fos induction. J Neurosci, 1997,17:1776-1785.
[46] Ji RR, Baba H, Brenner GJ, et al. Nociceptive-specif ic activation of ERK in spinal neurons contributes to pain hypersensitivity. Nat Neurosci, 1999,2(12): 1114-1119.
[47] Wu J, Su G, Ma L, et al. The role of c-AMP-dependent protein kinase in spinal cord and post synaptic dorsal column neurons in a rat model of visceral pain. Neurochem Int, 2007, 50(5):710-8.
[48] Donahue RR, LaGraize SC, Fuches PN. Electrolytic lesion of the anterior cingulate cortex decrease inflammatory, but not neuropathic behavior in rats. Brain Res,2001,897(122):131-138.
[49] Kawasaki Y, Kohno T, Zhuang ZY, et al. Ionotropic and metabotropic receptors, protein kinase A, protein kinase C, and Src contribute to C-fiber-induced ERK activation and cAMP response element-binding protein phosphorylation in dorsal horn neurons, leading to central sensitization. J Neurosci, 2004, 24(38) :831.
[50] Hoeger-Bement MK, Sluka KA. Phosphorylation of CREB and mechanical hyperalgesia is reversed by blockade of the cAMP pathway in a time-dependent manner after repeated intramuscular acid injections. J Neurosci, 2003, 23(13):5437-45.
[51] Miletic G, Pankratz MT, Miletic V. Increases in the phosphorylation of cyclic AMP response element binding protein (CREB) and decreases in the content of calcineurin accompany thermal hyperalgesia following chronic constriction injury in rats. Pain, 2002,99: 493-500.
[1] Gonzalez G A, Yamamoto K K, Fischer W H, et al. A Cluster of phosphorylation sites on the cyclic AMP regulated nuclear factor CREB predicted by its sequence. Nature, 1989, 337:749-752.
[2] Walker w H, Sanborm B M, Habener J F. An isofom of transcription factor CREB expressed during spermatogenesis lacks the phosphorylation domain and represses cAMP induced transcription. Proc Nail Acad Sci USA, 1994,91: 12423-12427.
[3] Zhang H, Cang CL, Kawasaki Y, et al. Neurokinin-1 receptor enhances TRPV1 activity in primary sensory neurons via PKCepsilon: a novel pathway for heat hyperalgesia. J Neurosci, 2007, 27(44):12067-77.
[4] Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science, 2000, 288:1765-1769.
[5] Coull JA, Boudreau D, Bachand K, et al. Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature, 2003, 424:938-942.
[6] Porreca F, Ossipov MH, Gebhart GF. Chronic pain and medullary descending facilitation. Trends Neurosci, 2002, 25:319-325.
[7] Zhuo M. Neuronal mechanism for neuropathic pain. Mol Pain, 2007, 3:14.
[8] Wall PD , Melzack R. Edinburgh, et al. Pathophysiology of damaged nerves in relation to chronic pain. In Textbook of Pain, Volume 5, 4th edition,1999:129-164.
[9] Ma C, Shu Y, Zheng Z, et al. Similar electrophysiological changes in axotomized and neighboring intact dorsal root ganglion neurons. J Neurophysiol,2003, 89:1588-1602.
[10] Wu G, Ringkamp M, Hartke TV, et al. Early onset of spontaneous activity in uninjured C-fiber nociceptors after injury to neighboring nerve fibers. J Neurosci, 2001, 21:RC140.
[11] RR, Strichartz G. Cell signaling and the genesis of neuropathic pain. Sci STKE, 2004, 2004(252) :rel4.
[12] Ji RR, Rupp F. Phosphorylation of transcription factor CREB in rat spinal cord after formalin-induced hyperalgesia: relationship to c-fos induction. J Neurosci, 1997,17(5):1776-1785.
[13] J walker w H, SanbolTa B M, Habener J F. An isofom of transcription factor CREB expressed during spermatogenesis lacks the phosphorylation domain and represses cAMP induced transcription. Proc Nail Acad Sci UsA, 1994,91:12423-7.
[14] Ji RR, Baba H, Brenner GJ, et al. Nociceptive-specif ic activation of ERK in spinal neurons contributes to pain hypersensitivity. Nat Neurosci,1999, 2(12):1114-1119.
[15] Ji RR, Kohno T, Moore KA, et al. Central sensitization and LTP: do pain and memory share similar mechanisms?. Trends Neurosci, 2003, 26(12): 696-705.
[16] Ma W, Quirion R. Increased phosphorylation of cyclic AMP response element-binding protein(CREB) in the superficial dorsal horn neurons following partial sciatic nerve ligation. Pain, 2001, 93: 295-301.
[17] Miletic G, Pankratz MT, Miletic V. Increases in the phosphorylation of cyclic AMP response element binding protein (CREB) and decreases in the content of calcineurin accompany thermal hyperalgesia following chronic constriction injury in rats. Pain, 2002, 99(3) :493-500.
[18] Ma W, Quirion R. Increased phosphorylation of cyclic AMP response element-binding protein (CREB) in the superficial dorsal horn neurons following partial sciatic nerve ligation. Pain, 2001, 93(3): 295-301.
[19] Ma W, Eisenach JC. Morphological and pharmacological evidence for the role of peripheral prostaglandins in the pathogenesis of neuropathic pain. Eur J Neurosci, 2002,15(6):1037-47.
[20] Ahn DK, Choi HS, Yeo SP, et al. Blockade of central cyclooxygenase (COX) pathways enhances the cannabinoid-induced antinociceptive effects on inflammatory temporomandibular joint (TMJ) nociception. Pain, 2007,132(1-2):23-32.
[21] Wang C, Gu Y, Li GW, et al. A critical role of the cAMP sensor Epac in switching protein kinase signalling in prostaglandin E2-induced potentiation of P2X3 receptor currents in inflamed rats. J Physiol, 2007, 584 (Pt 1): 191-203.
[22] Parada CA, Reichling DB, Levine JD. Chronic hyperalgesic priming in the rat involves a novel interaction between cAMP and PKCepsilon second messenger pathways. Pain, 2005,113(1-2):185-90.
[23] Miletic G, PankratzMT, Miletic V. Increases in the phosphorylation of cyclic AMP response element binding protein (CREB) and decreases in the content of calcineurin accompany thermal hyperalgesia following chronic constriction injury in rats. Pain, 2002, 99: 493-500.
[24] Kim H, Moon C, Ahn M, et al. Increased phosphorylation of cyclic AMP response element-binding protein in the spinal cord of Lewis rats with experimental autoimmune encephalomyelitis. Brain Res, 2007, 1162:113-20.
[25] Adam JS, Michael EG. CREB:A Stimulus-Induced Transcription Factor Activated by A Diverse Array of Extracellular Signals. Annu Rev Biochem, 1999, 68:821-861.
[26] J Adams S R, Harootunian A T, Buechler Y J, et al. Fluorescence ratio imaging of cyclic-AMP in single cells. Nature, 1991, 349:694-697.
[27] Marie K, Hoeger-Bement MK, Sluka KA. Phosphorylation of CREB and mechanical hyperalgesia is reversed by blockade of the cAMP pathway in a time-dependent manner after repeated intramuscular acid injections. J Neurosci, 2003, 23:5437-5445.
[28] Liou JT, Liu FC, Hsin ST, et al. Inhibition of the cyclic adenosine monophosphate pathway attenuates neuropathic pain and reduces phosphorylation of cyclic adenosine monophosphate response element-binding in the spinal cord after partial sciatic nerve ligation in rats. Anesth Analg, 2007,105(6):1830-7.
[29] Bement MK, Sluka KA. Co-localization of p-CREB and p-NR1 in spinothalamic neurons in a chronic muscle pain model. Neurosci Lett, 2007, 418(1): 22-7.
[30] Hoeger-Bement MK, Sluka KA. Phosphorylation of CREB and mechanical hyperalgesia is reversed by blockade of the cAMP pathway in a time-dependent manner after repeated intramuscular acid injections. J Neurosci, 2003, 23(13): 5437-45.
[31] Hoeger-Bement MK, Sluka KA. Phosphorylation of CREB and mechanical hyperalgesia is reversed by blockade of the cAMP pathway in a time-dependent manner after repeated intramuscular acid injections. J Neurosci,2003,23(13):5437-45.
[32] Wu J, Su G, Ma L, et al. The role of c-AMP-dependent protein kinase in spinal cord and post synaptic dorsal column neurons in a rat model of visceral pain. Neurochem Int,2007, 50(5):710-8.
[33] Wei F, Qiu CS, Kim SJ, et al. Genetic elimination of behavioral sensitization in mice lacking calmodulin-stimulated adenylyl cyclases. Neuron, 2002, 36(4): 713-26.
[34] Doya H, Ohtori S, Fujitani M, et al. C-Jun N-terminal kinase activation in dorsal root ganglion contributes to pain hypersensitivity. Biochem Biophys Res Commun, 2005, 335:132-8.
[35] Siegel G J, Albers R W, Fisher S K, et al. Basic Neurochemistry: Molecular, Cellular and Medical Aspects, Lippincott-Raven, Philadelphia, 1999:471-495.
[36] Fang L, Wu J, Zhang X, et al. Calcium/calmodulin dependent protein kinase II regulates the phosphorylation of cyclic AMP-responsive element-binding protein of spinal cord in rats following noxious stimulation. Neurosci Lett, 2005, 374(1): 1-4.
[37] Ji RR. Mitogen-activated protein kinase as potential targets for pain killers. Curr Opin Investig Drugs, 2004, 5(1):71-75.
[38] Obata K, Nogachi K. MAPK activation in nociceptive neurons and pain hypersensitivity. Life Sci,2004, 74(21):2643-2653.
[39] Hao J, Liu MG, Yu YQ, et al. Roles of peripheral mitogen-activated protein kinases in melittin-induced nociception and hyperalgesia. Neuroscience, 2008,152(4):1067-1075.
[40] SweitzeraSM, Petersa MC, Mab JY, et al. Peripheral and central p38 MAPK mediates capsaicin-induced hyperalgesia. Pain, 2004, 111: 278-85.
[41] Jin SX, Zhuang ZY, Woolf CJ, et al. p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons ans contributed to the generation of neuropathic pain. J Neurosci, 2003, 23(10):4017-22.
[42] Ru-Rong Ji, Clifford J. Neuronal Plasticity and Signal Transduction in Nocice ptive Neurons: Implications for the Initiation and Maintenance of Pathological Pain. Neurobiology of Disease, 2001, 8: 1-10.
[43] Song XS, Xu YB, Cao JL, et al. cAMP response-element binding protein participates in the phosphorylated extracellular signal-regulate kinase mediated neuropathic pain. Sheng Li Xue Bao, 2005, 57(2): 139-146.
[44] Kim KS, Kim J, Back SK, et al. Markedly attenuated acute and chronic pain responses in mice lacking adenylyl cyclase-5. Genes Brain Behav,2007,6(2):120-7.
[45] Kawasaki Y, Kohno T, Zhuang ZY, et al. Ionotropic and metabotropic receptors, protein kinase A, protein kinase C, and Src contribute to C-f iber-induced ERK activation and cAMP response element-binding protein phosphorylation in dorsal horn neurons, leading to central sensitization. J Neurosci, 2004, 24(38):8310-21.
[46] Miyabe T, Miletic V. Multip le kinase pathways mediate the early sciatic ligation-associated activation of CREB in the rat spinal dorsal horn. Neurosci Lett, 2005, 381:80-85.
[47] Xin WJ, Gong QJ, Xu JT, et al. Role of phosphorylation of ERK in induction and maintenance of LTP of the C-fiber evoked field potentials in spinal dorsal horn. J Neurosci Res, 2006, 84(5):934-43.
[48] Miletic G, PankratzMT, Miletic V. Increases in the phosphorylation of cyclic AMP response element binding protein (CREB) and decreases in the content of calcineurin accompany thermal hyperalgesia following chronic constriction injury in rats. Pain, 2002, 99: 493-500.
[49] Khasabov SG, Rogers SD, Ghilardi JR, et al. Spinal neurons that possess the substance P receptor are required for the development of central sensitization. J Neurosci, 2002, 22:9086-9098.
[50] Anderson LE, Seybold VS. Phosphorylated cAMP response element binding protein increases in neurokinin-1 receptor-immunoreactive neurons in rat spinal cord in response to formalin-induced nociception. Neurosci Lett, 2000, 283:29-32.
[51] Song XY, Li F, Zhang FH, et al. Peripherally-derived BDNF promotes regeneration of ascending sensory neurons after spinal cord injury. PLoS ONE, 2008, 3(3):e1707.
[52] Miletic G, Hanson EN, Miletic V. Brain-derived neurotrophic factor-elicited or sciatic ligation-associated phosphorylation of cyclic AMP response element binding p rotein in the rat spinal dorsal horn is reduced by block of tyrosine kinase receptors. Neurosci Lett, 2004, 361: 269-271.
[53] Duric V, McCarson KE. Neurokinin-1 (NK-1) receptor and brain-derived neurotrophic factor (BDNF) gene expression is differentially modulated in the rat spinal dorsal horn and hippocampus during inflammatory pain. Mol Pain, 2007, 3:32.
[54] VinclerMA, Eisenach JC. Knock down of the alpha nicotinic acetylcholine receptor in spinal nerve-ligated rats alleviates mechanical allodynia. Pharmacol Biochem Behav, 2005, 80:135-143.
[55] Michael GJ, Priestley JV. Differential expression of the mRNA for the vanilloid receptor subtype 1 in cells of the adult rat dorsal root and nodose ganglia and its downregulation by axotomy. JNeurosci, 1999, 19: 1844-1854.
[2]Lee H,Naughton NN,Woods JH,et al.Effects of butorphanol on morphine-induced itch and analgesia in primates.Anesthesiology,2007,107(3):478-85.
[3]Tsang BK,He Z,Wongchanapai W,et al.Visceral analgesic tolerance to intrathecal butorphanol in rats.Can J Anaesth,1998,45(10):1019-23.
[4]Schatzman U,Armbruster S,Stucki F,et al.Analgesic effect of butorphanol and levomethadone in detomidine sedated horses.J A PhysiolPathol Clin Med,2001,48(6):337-342.
[5]Tsang BK,He Z,Wongchanapai W,et al.Induction of tolerance to intrathecal butorphanol in rats.Acta Anaesthesiol Sin,1997,35(4):237-40.
[6]Kelly DJ,Abroad M,Brull SJ.Preemptive analgesia Ⅱ:recent advancesand current trends.Can J Anacsth,2001,48:1091-1101.
[7]Eisenach JC,De Kock M,Klimscha W.[alpha]2-adrenergic agonists for regional anesthesia A clinical review of colnidine(1984-1995).Anesthesiology,1996,85:655-74.
[8]Mukherjee A,Park-sarge OK,Mayo KE.Gonadotropins induce rapid phosphorylation of 3',5' -cyclic adensine monophosphate response element binding protein in ovarian granulose cells.Endocrinology,1996,137:3234-3245.
[9]Adams SR,Harootunian AT,Buechler YJ,et al.Fluorescence ratio imaging of cyclic-AMP in single cell.Nature,1991,349:694-697.
[10]姚永兴,张励才,宋学军,等.鞘内注射H-89对神经病理痛大鼠脊髓背角磷酸化cAMP反应元件结合蛋白表达的影响.中华麻醉学杂志,2005,25(5):371-374.
[11]Woolf CJ,Chong MS.Preemptive analgesia-treating postoperative pain by preventing the establishment of central sensitization.Anesth Analg,1993,77:362-79.
[12]Bao L,Jin SX,Zhang C,et al.Activation of delta opioid receptors induces receptor insertion and neuropetide.Neuron,2003,37: 121-133.
[13]邹望远.鞘内泵入吗啡、曲马多对福尔马林炎性痛大鼠免疫功能的影响及镇痛效应的观察:[硕士学位论文].长沙:中南大学,2004.
[14]Okuda K,Sakurada C,TakahashiM,et al.Characterization of nociceptive responses and spinal releases of nitric oxide metabolites and glutamate evoked by different concentrations of formalin in rats.Pain,2001,92(1-2):107.
[15]Abbott FV,F ranklin KB,Westbrook RF.The formalin test:scoring properties of the first and second phases of the pain response in rats.Pain,1995,60(1):91-102.
[16]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):161-174.
[17]Wang B,Luo F,Han JS.Central areas and post-receptor mechanisms underlying opioid physical dependence.Chin J Neurosci,1999,15:63-68.
[18]Roche AK,Cook M,Wilcox GL,et al.A nitric oxide synthase inhibitor(L-NAME)reduce licking behavior and Fos-labeling in the spinal cord of rats during formalin-induced inflammation.Pain,1996,66:331-334.
[19]张园.鞘内注射布托啡诺对福尔马林试验大鼠行为学及脊髓NMDAR表达的影响:[硕士学位论文].长沙:中南大学,2007.
[20]Rawal N,Nuutinen L,RajPP,Lovering SL,Gobuty AH,Hargardine J,Lehmkuhl L,Herva R,Abouleish E.Behavioral and histopathologic effects following intrathecal administration of butorphanol,sufentanil,and nalbuphine in sheep.Anesthesiology.1991 Dec;75(6):1025-34.
[21]DeRossi R,Almeida RG,Medeiros U,et al.Subarachnoid butorphanol augments lidocaine sensory anaesthesia in calves.Vet J,2007,173(3):658-63.
[22]Wongchanapai W,Tsang BK,He Z,et al.Differential involvement of opioid receptors in intrathecal butorphanol-induced analgesia:compared to morphine.Pharmacol Biochem Behav,1998 Mar,59(3):723-7.
[23]Garner HR,Burke TF,Lawhorn CD,et al.Butvrphanol-Mediated Antinociception in Mice:Partial Agonist Effects and Mu Receptor Involvement.Pharmacology,1997,282(3):1253-1261.
[24]Okon T.Ketamine:an introduction for the pain and palliative medicine physician.Pain Physician,2007,10(3):493-500.
[25]张涛涛,张晓云,董源洪,等.蛛网膜下腔注射氯胺酮对神经痛大鼠痛行为的影响.中华麻醉学杂志,2001,21:223-225.
[26]曾静波,李文斌,陈晓玲,等.大鼠甲醛炎性痛过程中脊髓后角NOS变化及其时间过程.中国病理生理杂志,2000,16(10):1109-1113.
[27]Borgbjerg FM,Svensson BA,Frigast C,et al.Histopathology after repeated intrathecal injections of preservative-free ketamie in the rabbit:a light and electron microscopic examination.Anesth Analg,1994,79:105-111.
[28]Malinovsky JM.Ketaimine and midazolam neurotoxicity in the rabbit.Anesthesiology,1991,75:91-7.
[29]Pelissier T,Laurido C,Kramer V,et al.Antinociceptive interactions of katemine with morphine or methadone in mononeuropathic rats.Cur J Pharmacol,2003,477:23-28.
[30]Skarda RT,Muir WW.Comparison of electroacupuncture and butorphanol on respiratory and cardiovascular elects and rectal pain threshold after controlledrectal distention in mares.Am J Vet Res,2003,64(2):137-144.
[31]Honore P,Chapman V,Buritova J,et al.Concomitant administration of morphine and an N-methyl-D-aspartate receptor antagonist profoundly reduces inflammatory evoked spinal c-Fos expression.Anesthesiology,1996,85:150-160.
[32]Wong CS,Lu CC,Cherng CH,et al.Pre-emptive analgesia with ketamine,morphine an d epidural lidecaine or to total kneereplacement.Can J Anaesth,1997,44:31-37.
[33]Bhattacharya A,Gurnani A,Shurma PK,et al.Subcutaneous infusion of ketamine and morphine for relief of posoperative pain:a double-blind comparative study.Ann Acad Med Singapore,1994,23:456-459.
[34]Stubhaug A,Breivik H,Eide PK,et al.Mapping of punctuate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery.Acta Anaesthesiol Scand,1997,41:l124-1132.
[35]Dubner R,Ruda MA.Activity-dependent neuronal plasticity following tissue injury and inflammation.Trends Neurosci,1992,15:
?96-103.
[36] Levine JD, Fields HL. Basbaum Dipeptides and primary afferent nociceptor. J Neurosci, 1993,13(6):2273-2286.
[37] Adam JS, Michael EG. CREB:A Stimulus-Induced Transcription Factor Activated by A Diverse Array of Extracellular Signals. Annu Rev Biochem, 1999, 68:821-861.
[38] Korzus E. The relation of transcription to memory formation. Acta Biochim Pol, 2003, 50:775-882.
[39] Chen HS, Lei J, He X, et al. Peripheral involvement of PKA and PKC in subcutaneous bee venom-induced persistent nociception, mechanical hyperalgesia, and inflammation in rats. Pain, 2008,135(1-2):31-6.
[40] Zou X, LIN Q, Willis WD. Role of protein kinse A in phosphorylation of NMDA receptor 1 subunts in dorsal horn and spinothalamic tract neurons after intradermal injection of capsaicin in rats. Neuroscience, 2002,115(3):775-86.
[41] Jones TL, Sorkin LS. Activated PKA and PKC, but not CaMKIIalpha, are required for AMPA/Kainate-mediated pain behavior in the thermal stimulus model. Pain, 2005,117:259-70.
[42] Wang C, Gu Y, Li GW, et al. A critical role of the cAMP sensor Epac in switching protein kinase signalling in prostaglandin E2-induced potentiation of P2X3 receptor currents in inflamed rats. J Physiol, 2007, 584 (Pt 1): 191-203.
[43] Bourtchuladze R, Frenguelli B, Blendy J, et al. Deficient long-termmemory in mouse with a targeted mutation of the cAMP-response element-binding protein. Cell, 1994,79:59-68.
[44] Shiokawa M, Yamaguchi T, Narita M, et al. Effects of fasudil on neuropathic pain-like state in mice. Nihon Shinkei Seishin Yakurigaku Zasshi, 2007, 27(4): 153-9.
[45] Ji RR, Rupp F. Phosphorylation of transcription factor CREB in rat spinal cord after formalin-induced hyperalgesia: relationship to c-fos induction. J Neurosci, 1997,17:1776-1785.
[46] Ji RR, Baba H, Brenner GJ, et al. Nociceptive-specif ic activation of ERK in spinal neurons contributes to pain hypersensitivity. Nat Neurosci, 1999,2(12): 1114-1119.
[47] Wu J, Su G, Ma L, et al. The role of c-AMP-dependent protein kinase in spinal cord and post synaptic dorsal column neurons in a rat model of visceral pain. Neurochem Int, 2007, 50(5):710-8.
[48] Donahue RR, LaGraize SC, Fuches PN. Electrolytic lesion of the anterior cingulate cortex decrease inflammatory, but not neuropathic behavior in rats. Brain Res,2001,897(122):131-138.
[49] Kawasaki Y, Kohno T, Zhuang ZY, et al. Ionotropic and metabotropic receptors, protein kinase A, protein kinase C, and Src contribute to C-fiber-induced ERK activation and cAMP response element-binding protein phosphorylation in dorsal horn neurons, leading to central sensitization. J Neurosci, 2004, 24(38) :831.
[50] Hoeger-Bement MK, Sluka KA. Phosphorylation of CREB and mechanical hyperalgesia is reversed by blockade of the cAMP pathway in a time-dependent manner after repeated intramuscular acid injections. J Neurosci, 2003, 23(13):5437-45.
[51] Miletic G, Pankratz MT, Miletic V. Increases in the phosphorylation of cyclic AMP response element binding protein (CREB) and decreases in the content of calcineurin accompany thermal hyperalgesia following chronic constriction injury in rats. Pain, 2002,99: 493-500.
[1] Gonzalez G A, Yamamoto K K, Fischer W H, et al. A Cluster of phosphorylation sites on the cyclic AMP regulated nuclear factor CREB predicted by its sequence. Nature, 1989, 337:749-752.
[2] Walker w H, Sanborm B M, Habener J F. An isofom of transcription factor CREB expressed during spermatogenesis lacks the phosphorylation domain and represses cAMP induced transcription. Proc Nail Acad Sci USA, 1994,91: 12423-12427.
[3] Zhang H, Cang CL, Kawasaki Y, et al. Neurokinin-1 receptor enhances TRPV1 activity in primary sensory neurons via PKCepsilon: a novel pathway for heat hyperalgesia. J Neurosci, 2007, 27(44):12067-77.
[4] Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science, 2000, 288:1765-1769.
[5] Coull JA, Boudreau D, Bachand K, et al. Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature, 2003, 424:938-942.
[6] Porreca F, Ossipov MH, Gebhart GF. Chronic pain and medullary descending facilitation. Trends Neurosci, 2002, 25:319-325.
[7] Zhuo M. Neuronal mechanism for neuropathic pain. Mol Pain, 2007, 3:14.
[8] Wall PD , Melzack R. Edinburgh, et al. Pathophysiology of damaged nerves in relation to chronic pain. In Textbook of Pain, Volume 5, 4th edition,1999:129-164.
[9] Ma C, Shu Y, Zheng Z, et al. Similar electrophysiological changes in axotomized and neighboring intact dorsal root ganglion neurons. J Neurophysiol,2003, 89:1588-1602.
[10] Wu G, Ringkamp M, Hartke TV, et al. Early onset of spontaneous activity in uninjured C-fiber nociceptors after injury to neighboring nerve fibers. J Neurosci, 2001, 21:RC140.
[11] RR, Strichartz G. Cell signaling and the genesis of neuropathic pain. Sci STKE, 2004, 2004(252) :rel4.
[12] Ji RR, Rupp F. Phosphorylation of transcription factor CREB in rat spinal cord after formalin-induced hyperalgesia: relationship to c-fos induction. J Neurosci, 1997,17(5):1776-1785.
[13] J walker w H, SanbolTa B M, Habener J F. An isofom of transcription factor CREB expressed during spermatogenesis lacks the phosphorylation domain and represses cAMP induced transcription. Proc Nail Acad Sci UsA, 1994,91:12423-7.
[14] Ji RR, Baba H, Brenner GJ, et al. Nociceptive-specif ic activation of ERK in spinal neurons contributes to pain hypersensitivity. Nat Neurosci,1999, 2(12):1114-1119.
[15] Ji RR, Kohno T, Moore KA, et al. Central sensitization and LTP: do pain and memory share similar mechanisms?. Trends Neurosci, 2003, 26(12): 696-705.
[16] Ma W, Quirion R. Increased phosphorylation of cyclic AMP response element-binding protein(CREB) in the superficial dorsal horn neurons following partial sciatic nerve ligation. Pain, 2001, 93: 295-301.
[17] Miletic G, Pankratz MT, Miletic V. Increases in the phosphorylation of cyclic AMP response element binding protein (CREB) and decreases in the content of calcineurin accompany thermal hyperalgesia following chronic constriction injury in rats. Pain, 2002, 99(3) :493-500.
[18] Ma W, Quirion R. Increased phosphorylation of cyclic AMP response element-binding protein (CREB) in the superficial dorsal horn neurons following partial sciatic nerve ligation. Pain, 2001, 93(3): 295-301.
[19] Ma W, Eisenach JC. Morphological and pharmacological evidence for the role of peripheral prostaglandins in the pathogenesis of neuropathic pain. Eur J Neurosci, 2002,15(6):1037-47.
[20] Ahn DK, Choi HS, Yeo SP, et al. Blockade of central cyclooxygenase (COX) pathways enhances the cannabinoid-induced antinociceptive effects on inflammatory temporomandibular joint (TMJ) nociception. Pain, 2007,132(1-2):23-32.
[21] Wang C, Gu Y, Li GW, et al. A critical role of the cAMP sensor Epac in switching protein kinase signalling in prostaglandin E2-induced potentiation of P2X3 receptor currents in inflamed rats. J Physiol, 2007, 584 (Pt 1): 191-203.
[22] Parada CA, Reichling DB, Levine JD. Chronic hyperalgesic priming in the rat involves a novel interaction between cAMP and PKCepsilon second messenger pathways. Pain, 2005,113(1-2):185-90.
[23] Miletic G, PankratzMT, Miletic V. Increases in the phosphorylation of cyclic AMP response element binding protein (CREB) and decreases in the content of calcineurin accompany thermal hyperalgesia following chronic constriction injury in rats. Pain, 2002, 99: 493-500.
[24] Kim H, Moon C, Ahn M, et al. Increased phosphorylation of cyclic AMP response element-binding protein in the spinal cord of Lewis rats with experimental autoimmune encephalomyelitis. Brain Res, 2007, 1162:113-20.
[25] Adam JS, Michael EG. CREB:A Stimulus-Induced Transcription Factor Activated by A Diverse Array of Extracellular Signals. Annu Rev Biochem, 1999, 68:821-861.
[26] J Adams S R, Harootunian A T, Buechler Y J, et al. Fluorescence ratio imaging of cyclic-AMP in single cells. Nature, 1991, 349:694-697.
[27] Marie K, Hoeger-Bement MK, Sluka KA. Phosphorylation of CREB and mechanical hyperalgesia is reversed by blockade of the cAMP pathway in a time-dependent manner after repeated intramuscular acid injections. J Neurosci, 2003, 23:5437-5445.
[28] Liou JT, Liu FC, Hsin ST, et al. Inhibition of the cyclic adenosine monophosphate pathway attenuates neuropathic pain and reduces phosphorylation of cyclic adenosine monophosphate response element-binding in the spinal cord after partial sciatic nerve ligation in rats. Anesth Analg, 2007,105(6):1830-7.
[29] Bement MK, Sluka KA. Co-localization of p-CREB and p-NR1 in spinothalamic neurons in a chronic muscle pain model. Neurosci Lett, 2007, 418(1): 22-7.
[30] Hoeger-Bement MK, Sluka KA. Phosphorylation of CREB and mechanical hyperalgesia is reversed by blockade of the cAMP pathway in a time-dependent manner after repeated intramuscular acid injections. J Neurosci, 2003, 23(13): 5437-45.
[31] Hoeger-Bement MK, Sluka KA. Phosphorylation of CREB and mechanical hyperalgesia is reversed by blockade of the cAMP pathway in a time-dependent manner after repeated intramuscular acid injections. J Neurosci,2003,23(13):5437-45.
[32] Wu J, Su G, Ma L, et al. The role of c-AMP-dependent protein kinase in spinal cord and post synaptic dorsal column neurons in a rat model of visceral pain. Neurochem Int,2007, 50(5):710-8.
[33] Wei F, Qiu CS, Kim SJ, et al. Genetic elimination of behavioral sensitization in mice lacking calmodulin-stimulated adenylyl cyclases. Neuron, 2002, 36(4): 713-26.
[34] Doya H, Ohtori S, Fujitani M, et al. C-Jun N-terminal kinase activation in dorsal root ganglion contributes to pain hypersensitivity. Biochem Biophys Res Commun, 2005, 335:132-8.
[35] Siegel G J, Albers R W, Fisher S K, et al. Basic Neurochemistry: Molecular, Cellular and Medical Aspects, Lippincott-Raven, Philadelphia, 1999:471-495.
[36] Fang L, Wu J, Zhang X, et al. Calcium/calmodulin dependent protein kinase II regulates the phosphorylation of cyclic AMP-responsive element-binding protein of spinal cord in rats following noxious stimulation. Neurosci Lett, 2005, 374(1): 1-4.
[37] Ji RR. Mitogen-activated protein kinase as potential targets for pain killers. Curr Opin Investig Drugs, 2004, 5(1):71-75.
[38] Obata K, Nogachi K. MAPK activation in nociceptive neurons and pain hypersensitivity. Life Sci,2004, 74(21):2643-2653.
[39] Hao J, Liu MG, Yu YQ, et al. Roles of peripheral mitogen-activated protein kinases in melittin-induced nociception and hyperalgesia. Neuroscience, 2008,152(4):1067-1075.
[40] SweitzeraSM, Petersa MC, Mab JY, et al. Peripheral and central p38 MAPK mediates capsaicin-induced hyperalgesia. Pain, 2004, 111: 278-85.
[41] Jin SX, Zhuang ZY, Woolf CJ, et al. p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons ans contributed to the generation of neuropathic pain. J Neurosci, 2003, 23(10):4017-22.
[42] Ru-Rong Ji, Clifford J. Neuronal Plasticity and Signal Transduction in Nocice ptive Neurons: Implications for the Initiation and Maintenance of Pathological Pain. Neurobiology of Disease, 2001, 8: 1-10.
[43] Song XS, Xu YB, Cao JL, et al. cAMP response-element binding protein participates in the phosphorylated extracellular signal-regulate kinase mediated neuropathic pain. Sheng Li Xue Bao, 2005, 57(2): 139-146.
[44] Kim KS, Kim J, Back SK, et al. Markedly attenuated acute and chronic pain responses in mice lacking adenylyl cyclase-5. Genes Brain Behav,2007,6(2):120-7.
[45] Kawasaki Y, Kohno T, Zhuang ZY, et al. Ionotropic and metabotropic receptors, protein kinase A, protein kinase C, and Src contribute to C-f iber-induced ERK activation and cAMP response element-binding protein phosphorylation in dorsal horn neurons, leading to central sensitization. J Neurosci, 2004, 24(38):8310-21.
[46] Miyabe T, Miletic V. Multip le kinase pathways mediate the early sciatic ligation-associated activation of CREB in the rat spinal dorsal horn. Neurosci Lett, 2005, 381:80-85.
[47] Xin WJ, Gong QJ, Xu JT, et al. Role of phosphorylation of ERK in induction and maintenance of LTP of the C-fiber evoked field potentials in spinal dorsal horn. J Neurosci Res, 2006, 84(5):934-43.
[48] Miletic G, PankratzMT, Miletic V. Increases in the phosphorylation of cyclic AMP response element binding protein (CREB) and decreases in the content of calcineurin accompany thermal hyperalgesia following chronic constriction injury in rats. Pain, 2002, 99: 493-500.
[49] Khasabov SG, Rogers SD, Ghilardi JR, et al. Spinal neurons that possess the substance P receptor are required for the development of central sensitization. J Neurosci, 2002, 22:9086-9098.
[50] Anderson LE, Seybold VS. Phosphorylated cAMP response element binding protein increases in neurokinin-1 receptor-immunoreactive neurons in rat spinal cord in response to formalin-induced nociception. Neurosci Lett, 2000, 283:29-32.
[51] Song XY, Li F, Zhang FH, et al. Peripherally-derived BDNF promotes regeneration of ascending sensory neurons after spinal cord injury. PLoS ONE, 2008, 3(3):e1707.
[52] Miletic G, Hanson EN, Miletic V. Brain-derived neurotrophic factor-elicited or sciatic ligation-associated phosphorylation of cyclic AMP response element binding p rotein in the rat spinal dorsal horn is reduced by block of tyrosine kinase receptors. Neurosci Lett, 2004, 361: 269-271.
[53] Duric V, McCarson KE. Neurokinin-1 (NK-1) receptor and brain-derived neurotrophic factor (BDNF) gene expression is differentially modulated in the rat spinal dorsal horn and hippocampus during inflammatory pain. Mol Pain, 2007, 3:32.
[54] VinclerMA, Eisenach JC. Knock down of the alpha nicotinic acetylcholine receptor in spinal nerve-ligated rats alleviates mechanical allodynia. Pharmacol Biochem Behav, 2005, 80:135-143.
[55] Michael GJ, Priestley JV. Differential expression of the mRNA for the vanilloid receptor subtype 1 in cells of the adult rat dorsal root and nodose ganglia and its downregulation by axotomy. JNeurosci, 1999, 19: 1844-1854.