Intervention of electroacupuncture on spinal p38 MAPK/ATF-2/VR-1 pathway in treating inflammatory pain induced by CFA in rats

Molecular Pain

Jun-Fan Fang¹  Yi Liang¹  Jun-Ying Du¹  Jian-Qiao Fang¹ 

[1] Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, 548 Binwen Road, Binjiang District, Hangzhou, Zhejiang Province 310053, China

关键词: Signal transduction pathway;    COX-2;    VR-1;    ATF-2;    p38 MAPK;    CFA;    Anti-inflammatory pain;    Electroacupuncture;    Chronic inflammatory pain;   

Others  :  862564
DOI  :  10.1186/1744-8069-9-13

 received in 2012-08-29, accepted in 2013-03-18,  发布年份 2013

【 摘 要 】

Background

Previous studies have demonstrated that p38 MAPK signal transduction pathway plays an important role in the development and maintenance of inflammatory pain. Electroacupuncture (EA) can suppress the inflammatory pain. However, the relationship between EA effect and p38 MAPK signal transduction pathway in inflammatory pain remains poorly understood. It is our hypothesis that p38 MAPK/ATF-2/VR-1 and/or p38 MAPK/ATF-2/COX-2 signal transduction pathway should be activated by inflammatory pain in CFA-injected model. Meanwhile, EA may inhibit the activation of p38 MAPK signal transduction pathway. The present study aims to investigate that anti-inflammatory and analgesic effect of EA and its intervention on the p38 MAPK signal transduction pathway in a rat model of inflammatory pain.

Results

EA had a pronounced anti-inflammatory and analgesic effect on CFA-induced chronic inflammatory pain in rats. EA could quickly raise CFA-rat’s paw withdrawal thresholds (PWTs) and maintain good and long analgesic effect, while it subdued the ankle swelling of CFA rats only at postinjection day 14. EA could down-regulate the protein expressions of p-p38 MAPK and p-ATF-2, reduced the numbers of p-p38 MAPK-IR cells and p-ATF-2-IR cells in spinal dorsal horn in CFA rats, inhibited the expressions of both protein and mRNA of VR-1, but had no effect on the COX-2 mRNA expression.

Conclusions

The present study indicates that inhibiting the activation of spinal p38 MAPK/ATF-2/VR-1 pathway may be one of the main mechanisms via central signal transduction pathway in the process of anti-inflammatory pain by EA in CFA rats.

【 授权许可】

   
2013 Fang et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ, VIGOR StudyGroup: Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000, 343:1520-1528. 1522 p following 1528
• [2]Zhang B, He XL, Ding Y, Du GH: Gaultherin, a natural salicylate derivative from Gaultheria yunnanensis: towards a better non-steroidal anti-inflammatory drug. Eur J Pharmacol 2006, 530:166-171.
• [3]Kumar S, Boehm J, Lee JC: p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discov 2003, 2:717-726.
• [4]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.
• [5]Ji RR, Gereau RW 4th, Malcangio M, Strichartz GR: MAP kinase and pain. Brain Res Rev 2009, 60:135-148.
• [6]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.
• [7]Ji RR, Suter MR: p38 MAPK, microglial signaling, and neuropathic pain. Mol Pain 2007, 3:33. BioMed Central Full Text
• [8]Amantini C, Mosca M, Nabissi M, Lucciarini R, Caprodossi S, Arcella A, Giangaspero F, Santoni G: Capsaicin-induced apoptosis of glioma cells is mediated by TRPV1 vanilloid receptor and requires p38 MAPK activation. J Neurochem 2007, 102:977-990.
• [9]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.
• [10]Kim JH, Min BI, Schmidt D, Lee HJ, Park DS: The difference between electroacupuncture only and electroacupuncture with manipulation on analgesia in rats. Neurosci Lett 2000, 279:149-152.
• [11]Li A, Wang Y, Xin J, Lao L, Ren K, Berman BM, Zhang RX: Electroacupuncture suppresses hyperalgesia and spinal Fos expression by activating the descending inhibitory system. Brain Res 2007, 1186:171-179.
• [12]Zijlstra FJ, van den Berg-de LI, Huygen FJ, Klein J: Anti-inflammatory actions of acupuncture. Mediators Inflamm 2003, 12:59-69.
• [13]Chen R, Nickel JC: Acupuncture ameliorates symptoms in men with chronic prostatitis/chronic pelvic pain syndrome. Urology 2003, 61:1156-1159. discussion 1159
• [14]Woźniak PR, Stachowiak GP, Pieta-Dolińska AK, Oszukowski PJ: Anti-phlogistic and immunocompetent effects of acupuncture treatment in women suffering from chronic pelvic inflammatory diseases. Am J Chin Med 2003, 31:315-320.
• [15]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.
• [16]Zhang RX, Lao L, Wang X, Fan A, Wang L, Ren K, Berman BM: Electroacupuncture attenuates inflammation in a rat model. J Altern Complement Med 2005, 11:135-142.
• [17]Park DS, Seo BK, Baek YH: Analgesic effect of electroacupuncture on inflammatory pain in collagen-induced arthritis rats: mediation by alpha2- and beta-adrenoceptors. Rheumatol Int 2013, 33:309-314.
• [18]Sekido R, Ishimaru K, Sakita M: Differences of electroacupuncture-induced analgesic effect in normal and inflammatory conditions in rats. Am J Chin Med 2003, 31:955-965.
• [19]Huang C, Hu ZP, Long H, Shi YS, Han JS, Wan Y: Attenuation of mechanical but not thermal hyperalgesia by electroacupuncture with the involvement of opioids in rat model of chronic inflammatory pain. Brain Res Bull 2004, 63:99-103.
• [20]Lee JH, Jang KJ, Lee YT, Choi YH, Choi BT: Electroacupuncture inhibits inflammatory edema and hyperalgesia through regulation of cyclooxygenase synthesis in both peripheral and central nociceptive sites. Am J Chin Med 2006, 34:981-988.
• [21]Su TF, Zhao YQ, Zhang LH, Peng M, Wu CH, Pei L, Tian B, Zhang J, Shi J, Pan HL, Li M: Electroacupuncture reduces the expression of proinflammatory cytokines in inflamed skin tissues through activation of cannabinoid CB2 receptors. Eur J Pain 2012, 16:624-635.
• [22]Liang Y, Fang JQ, Du JY, Fang JF: Effect of Electroacupuncture on Activation of p38MAPK in Spinal Dorsal Horn in Rats with Complete Freund’s Adjuvant-Induced Inflammatory Pain. Evid Based Complementary Alternat Med 2012, 568273.
• [23]Krishna M, Narang H: The complexity of mitogen-activated protein kinases (MAPKs) made simple. Cell Mol Life Sci 2008, 65:3525-3544.
• [24]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 USA 2007, 104:10655-10660.
• [25]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.
• [26]Katsura H, Obata K, Mizushima T, Sakurai J, Kobayashi K, Yamanaka H, Dai Y, Fukuoka T, Sakagami M, Noguchi K: Activation of Src-family kinases in spinal microglia contributes to mechanical hypersensitivity after nerve injury. J Neurosci 2006, 26:8680-8690.
• [27]Wen YR, Suter MR, Kawasaki Y, Huang J, Pertin M, Kohno T, Berde CB, Decosterd I, Ji RR: 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 2007, 107:312-321.
• [28]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 2003, 23:4017-4022.
• [29]Schäfers M, Svensson CI, Sommer C, Sorkin LS: Tumor necrosis factor-α induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J Neurosci 2003, 23:2517-2521.
• [30]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.
• [31]Hains BC, Waxman SG: Activated microglia contribute to the maintenance of chronic pain after spinal cord injury. J Neurosci 2006, 26:4308-4317.
• [32]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. BioMed Central Full Text
• [33]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.
• [34]Fitzsimmons BL, Zattoni M, Svensson CI, Steinauer J, Hua XY, Yaksh TL: Role of spinal p38alpha and beta MAPK in inflammatory hyperalgesia and spinal COX-2 expression. Neuroreport 2010, 21:313-317.
• [35]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.
• [36]Xing J, Kornhauser JM, Xia Z, Thiele EA, Greenberg ME: Nerve growth factor activates extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways to stimulate CREB serine 133 phosphorylation. Mol Cell Biol 1998, 18:1946-1955.
• [37]Gingras AC, Raught B, Sonenberg N: eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem 1999, 68:913-963.
• [38]Ji RR, Woolf CJ: Neuronal plasticity and signal transduction in nociceptive neurons: implications for the initiation and maintenance of pathological pain. Neurobiol Dis 2001, 8:1-10.
• [39]Faour WH, He Y, He QW, de Ladurantaye M, Quintero M, Mancini A, Di Battista JA: Prostaglandin E(2) regulates the level and stability of cyclooxygenase-2 mRNA through activation of p38 mitogen-activated protein kinase in interleukin-1 beta-treated human synovial fibroblasts. J Biol Chem 2001, 276:31720-31731.
• [40]Vlahopoulos SA, Logotheti S, Mikas D, Giarika A, Gorgoulis V, Zoumpourlis V: The role of ATF‐2 in oncogenesis. Bioessays 2008, 30:314-327.
• [41]Eferl R, Wagner EF: AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer 2003, 3:859-868.
• [42]Maekawa T, Jin W, Ishii S: The role of ATF-2 family transcription factors in adipocyte differentiation: antiobesity effects of p38 inhibitors. Mol Cell Biol 2010, 30:613-625.
• [43]Johnson GL, Lapadat R: Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 2002, 298:1911-1912.
• [44]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.
• [45]Vogel G: Hot pepper receptor could help manage pain. Science 2000, 288:241-242.
• [46]Palazzo E, Luongo L, de Novellis V, Rossi F, Marabese I, Maione S: Transient receptor potential vanilloid type 1 and pain development. Curr Opin Pharmacol 2012, 12:9-17.
• [47]Keeble J, Russell F, Curtis B, Starr A, Pinter E, Brain SD: Involvement of transient receptor potential vanilloid 1 in the vascular and hyperalgesic components of joint inflammation. Arthritis Rheum 2005, 52:3248-3256.
• [48]Brain SD: TRPV1 and TRPA1 channels in inflammatory pain: elucidating mechanisms. Ann N Y Acad Sci 2011, 1245:36-37.
• [49]Barton NJ, McQueen DS, Thomson D, Gauldie SD, Wilson AW, Salter DM, Chessell IP: Attenuation of experimental arthritis in TRPV1R knockout mice. Exp Mol Pathol 2006, 81:166-170.
• [50]Broom DC, Samad TA, Kohno T, Tegeder I, Geisslinger G, Woolf CJ: Cyclooxygenase 2 expression in the spared nerve injury model of neuropathic pain. Neuroscience 2004, 124:891-900.
• [51]Hay CH, Trevethick MA, Wheeldon A, Bowers JS, de Belleroche JS: The potential role of spinal cord cyclooxygenase-2 in the development of Freund’s complete adjuvant-induced changes in hyperalgesia and allodynia. Neuroscience 1997, 78:843-850.
• [52]Ichitani Y, Shi T, Haeggstrom JZ, Samuelsson B, Hőkfelt T: Increased levels of cyclooxygenase-2 mRNA in the rat spinal cord after peripheral inflammation: an in situ hybridization study. Neuroreport 1997, 8:2949-2952.
• [53]Tonai T, Taketani Y, Ueda N, Nishisho T, Ohmoto Y, Sakata Y, Muraguchi M, Wada K, Yamamoto S: Possible Involvement of Interleukin‐1 in Cyclooxygenase‐2Induction After Spinal Cord Injury in Rats. J Neurochem 1999, 72:302-309.
• [54]Resnick DK, Graham SH, Dixon CE, Marion DW: Role of cyclooxygenase 2 in acute spinal cord injury. J Neurotrauma 1998, 15:1005-1013.
• [55]Beiche F, Scheuerer S, Brune K, Geisslinger G, Goppeil-Struebe M: Up-regulation of cyclooxygenase-2 mRNA in the rat spinal cord following peripheral inflammation. FEBS Lett 1996, 390:165-169.
• [56]Narita M, Shimamura M, Imai S, Kubota C, Yajima Y, Takagi T, Shiokawa M, Inoue T, Suzuki M, Suzuki T: Role of interleukin-1β and tumor necrosis factor-α-dependent expression of cyclooxygenase-2 mRNA in thermal hyperalgesia induced by chronic inflammation in mice. Neuroscience 2008, 152:477-486.
• [57]Xu KD, Liang T, Wang K, Tian DA: Effect of pre-electroacupuncture on p38 and c-Fos expression in the spinal dorsal horn of rats suffering from visceral pain. Chin Med J (Engl) 2010, 123:1176-1181.
• [58]Wang K, Wu H, Wang G, Li M, Zhang Z, Gu G: The effects of electroacupuncture on TH1/TH2 cytokine mRNA expression and mitogen-activated protein kinase signaling pathways in the splenic T cells of traumatized rats. Anesth Analg 2009, 109:1666-1673.
• [59]Prochazkova M, Dolezal T, Sliva J, Krsiak M: Different Patterns of Spinal Cyclooxygenase-1 and Cyclooxygenase-2 mRNA Expression in Inflammatory and Postoperative Pain. Basic Clin Pharmacol Toxicol 2006, 99:173-179.
• [60]Palazzo E, Luongo L, de Novellis V, Berrino L, Rossi F, Maione S: Moving towards supraspinal TRPV1 receptors for chronic pain relief. Mol Pain 2010, 6:66. BioMed Central Full Text
• [61]Li WM, Cui KM, Li N, Gu QB, Schwarz W, Ding GH, Wu GC: Analgesic effect of electroacupuncture on complete Freund’s adjuvant-induced inflammatory pain in mice: a model of antipain treatment by acupuncture in mice. Jpn J Physiol 2005, 55:339-344.
• [62]Zhang YQ, Ji GC, Wu GC, Zhao ZQ: Excitatory amino acid receptor antagonists and electroacupuncture synergetically inhibit carrageenan-induced behavioral hyperalgesia and spinal fos expression in rats. Pain 2002, 99:525-535.