Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2011

Open Access 01-12-2011 | Research

Inhibition of spinal astrocytic c-Jun N-terminal kinase (JNK) activation correlates with the analgesic effects of ketamine in neuropathic pain

Authors: Xiao-Peng Mei, Hui Zhang, Wei Wang, Yan-Yan Wei, Ming-Zhu Zhai, Wen Wang, Li-Xian Xu, Yun-Qing Li

Published in: Journal of Neuroinflammation | Issue 1/2011

Login to get access

Abstract

Background

We have previously reported that inhibition of astrocytic activation contributes to the analgesic effects of intrathecal ketamine on spinal nerve ligation (SNL)-induced neuropathic pain. However, the underlying mechanisms are still unclear. c-Jun N-terminal kinase (JNK), a member of mitogen-activated protein kinase (MAPK) family, has been reported to be critical for spinal astrocytic activation and neuropathic pain development after SNL. Ketamine can decrease lipopolysaccharide (LPS)-induced phosphorylated JNK (pJNK) expression and could thus exert its anti-inflammatory effect. We hypothesized that inhibition of astrocytic JNK activation might be involved in the suppressive effect of ketamine on SNL-induced spinal astrocytic activation.

Methods

Immunofluorescence histochemical staining was used to detect SNL-induced spinal pJNK expression and localization. The effects of ketamine on SNL-induced mechanical allodynia were confirmed by behavioral testing. Immunofluorescence histochemistry and Western blot were used to quantify the SNL-induced spinal pJNK expression after ketamine administration.

Results

The present study showed that SNL induced ipsilateral pJNK up-regulation in astrocytes but not microglia or neurons within the spinal dorsal horn. Intrathecal ketamine relieved SNL-induced mechanical allodynia without interfering with motor performance. Additionally, intrathecal administration of ketamine attenuated SNL-induced spinal astrocytic JNK activation in a dose-dependent manner, but not JNK protein expression.

Conclusions

The present results suggest that inhibition of JNK activation may be involved in the suppressive effects of ketamine on SNL-induced spinal astrocyte activation. Therefore, inhibition of spinal JNK activation may be involved in the analgesic effects of ketamine on SNL-induced neuropathic pain.
Appendix
Available only for authorised users
Literature
1.
Watkins LR, Martin D, Ulrich P, Tracey KJ, Maier SF: Evidence for the involvement of spinal cord glia in subcutaneous formalin induced hyperalgesia in the rat. Pain. 1997, 71: 225-235. 10.1016/S0304-3959(97)03369-1.CrossRefPubMed
2.
Meunier A, Mauborgne A, Masson J, Mallet J, Pohl M: Lentiviral-mediated targeted transgene expression in dorsal spinal cord glia: tool for the study of glial cell implication in mechanisms underlying chronic pain development. J Neurosci Methods. 2008, 167: 148-159. 10.1016/j.jneumeth.2007.07.022.CrossRefPubMed
3.
Garry EM, Delaney A, Blackburn-Munro G, Dickinson T, Moss A, Nakalembe I, Robertson DC, Rosie R, Robberecht P, Mitchell R, Fleetwood-Walker SM: Activation of p38 and p42/44 MAP kinase in neuropathic pain: involvement of VPAC2 and NK2 receptors and mediation by spinal glia. Mol Cell Neurosci. 2005, 30: 523-537. 10.1016/j.mcn.2005.08.016.CrossRefPubMed
4.
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.PubMed
5.
Watkins LR, Milligan ED, Maier SF: Spinal cord glia: new players in pain. Pain. 2001, 93: 201-205. 10.1016/S0304-3959(01)00359-1.CrossRefPubMed
6.
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. 10.1016/j.tins.2004.12.002.CrossRefPubMed
7.
Scholz J, Woolf CJ: The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci. 2007, 10: 1361-1368. 10.1038/nn1992.CrossRefPubMed
8.
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. J Neurosci. 2006, 26: 3551-3560. 10.1523/JNEUROSCI.5290-05.2006.CrossRefPubMed
9.
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. 10.1124/jpet.103.052407.CrossRefPubMed
10.
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. 10.1016/j.pain.2004.12.022.CrossRefPubMed
11.
12.
13.
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. 10.1523/JNEUROSCI.3728-06.2007.PubMedCentralCrossRefPubMed
14.
Piao ZG, Cho IH, Park CK, Hong JP, Choi SY, Lee SJ, Lee S, Park K, Kim JS, Oh SB: Activation of glia and microglial p38 MAPK in medullary dorsal horn contributes to tactile hypersensitivity following trigeminal sensory nerve injury. Pain. 2006, 121: 219-231. 10.1016/j.pain.2005.12.023.CrossRefPubMed
15.
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.PubMed
16.
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. 10.1002/glia.10308.CrossRefPubMed
17.
Gao YJ, Zhang L, Samad OA, Suter MR, Yasuhiko K, Xu ZZ, Park JY, Lind AL, Ma Q, Ji RR: JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J Neurosci. 2009, 29: 4096-4108. 10.1523/JNEUROSCI.3623-08.2009.PubMedCentralCrossRefPubMed
18.
Nadeson R, Tucker A, Bajunaki E, Goodchild CS: Potentiation by ketamine of fentanyl antinociception. I. An experimental study in rats showing that ketamine administered by non-spinal routes targets spinal cord antinociceptive systems. Br J Anaesth. 2002, 88: 685-691. 10.1093/bja/88.5.685.CrossRefPubMed
19.
Christoph T, Schiene K, Englberger W, Parsons CG, Chizh BA: The antiallodynic effect of NMDA antagonists in neuropathic pain outlasts the duration of the in vivo NMDA antagonism. Neuropharmacology. 2006, 51: 12-17. 10.1016/j.neuropharm.2006.02.007.CrossRefPubMed
20.
Kiefer RT, Rohr P, Ploppa A, Dieterich HJ, Grothusen J, Koffler S, Altemeyer KH, Unertl K, Schwartzman RJ: Efficacy of Ketamine in Anesthetic Dosage for the Treatment of Refractory Complex Regional Pain Syndrome: An Open-Label Phase II Study. Pain Med. 2008, 9: 1173-1201. 10.1111/j.1526-4637.2007.00402.x.CrossRefPubMed
21.
Mei X, Wang W, Wang W, Li Y, Zhang H, Wu S, Li Y, Xu L: Inhibiting astrocytic activation: a novel analgesic mechanism of ketamine at the spinal level?. J Neurochem. 2009, 109: 1691-1700. 10.1111/j.1471-4159.2009.06087.x.CrossRefPubMed
22.
Shibakawa YS, Sasaki Y, Goshima Y, Echigo N, Kamiya Y, Kurahashi K, Yamada Y, Andoh T: Effects of ketamine and propofol on inflammatory responses of primary glial cell cultures stimulated with lipopolysaccharide. Br J Anaesth. 2005, 95: 803-810. 10.1093/bja/aei256.CrossRefPubMed
23.
Wu GJ, Chen TL, Ueng YF, Chen RM: Ketamine inhibits tumor necrosis factor-alpha and interleukin-6 gene expressions in lipopolysaccharide-stimulated macrophages through suppression of toll-like receptor 4-mediated c-Jun N-terminal kinase phosphorylation and activator protein-1 activation. Toxicol Appl Pharmacol. 2008, 228: 105-113. 10.1016/j.taap.2007.11.027.CrossRefPubMed
24.
Zimmermann M: Ethical guidelines for investigations of experimental pain in conscious animals. Pain. 1983, 16: 109-110. 10.1016/0304-3959(83)90201-4.CrossRefPubMed
25.
Kim SH, Chung JM: An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain. 1992, 50: 355-363. 10.1016/0304-3959(92)90041-9.CrossRefPubMed
26.
Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL: Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994, 53: 55-63. 10.1016/0165-0270(94)90144-9.CrossRefPubMed
27.
Guo W, Wang H, Watanabe M, Shimizu K, Zou S, LaGraize SC, Wei F, Dubner R, Ren K: Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. J Neurosci. 2007, 27: 6006-6018. 10.1523/JNEUROSCI.0176-07.2007.PubMedCentralCrossRefPubMed
28.
Wang W, Wang W, Mei X, Huang J, Wei Y, Wang Y, Wu S, Li Y: Crosstalk between spinal astrocytes and neurons in nerve injury-induced neuropathic pain. PLoS One. 2009, 4: e6973-10.1371/journal.pone.0006973.PubMedCentralCrossRefPubMed
29.
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. 10.1016/S0304-3959(02)00097-0.CrossRefPubMed
30.
Katsura H, Obata K, Miyoshi K, Kondo T, Yamanaka H, Kobayashi K, Dai Y, Fukuoka T, Sakagami M, Noguchi K: Transforming growth factor-activated kinase 1 induced in spinal astrocytes contributes to mechanical hypersensitivity after nerve injury. Glia. 2008, 56: 723-733. 10.1002/glia.20648.CrossRefPubMed
31.
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. 10.1523/JNEUROSCI.3388-04.2004.CrossRefPubMed
32.
Chang HC, Lin KH, Tai YT, Chen JT, Chen RM: Lipoteichoic acid-induced TNF-alpha and IL-6 gene expressions and oxidative stress production in macrophages are suppressed by ketamine through downregulating Toll-like receptor 2-mediated activation oF ERK1/2 aND NFkappaB. Shock. 2010, 33: 485-492. 10.1097/SHK.0b013e3181b2fe0c.CrossRefPubMed
33.
34.
Kato H, Narita M, Miyatake M, Yajima Y, Suzuki T: Role of neuronal NR2B subunit-containing NMDA receptor-mediated Ca2+ influx and astrocytic activation in cultured mouse cortical neurons and astrocytes. Synapse. 2006, 59: 10-17. 10.1002/syn.20213.CrossRefPubMed
35.
Wu CY, Hsieh HL, Sun CC, Yang CM: IL-1beta induces MMP-9 expression via a Ca2+-dependent CaMKII/JNK/c-JUN cascade in rat brain astrocytes. Glia. 2009, 57: 1775-1789. 10.1002/glia.20890.CrossRefPubMed
36.
Wang X, Fu S, Wang Y, Yu P, Hu J, Gu W, Xu XM, Lu P: Interleukin-1beta mediates proliferation and differentiation of multipotent neural precursor cells through the activation of SAPK/JNK pathway. Mol Cell Neurosci. 2007, 36: 343-354. 10.1016/j.mcn.2007.07.005.CrossRefPubMed
37.
Park C, Lee S, Cho IH, Lee HK, Kim D, Choi SY, Oh SB, Park K, Kim JS, Lee SJ: TLR3-mediated signal induces proinflammatory cytokine and chemokine gene expression in astrocytes: differential signaling mechanisms of TLR3-induced IP-10 and IL-8 gene expression. Glia. 2006, 53: 248-256. 10.1002/glia.20278.CrossRefPubMed
38.
Lee KM, Jeon SM, Cho HJ: Tumor necrosis factor receptor 1 induces interleukin-6 upregulation through NF-kappaB in a rat neuropathic pain model. Eur J Pain. 2009, 13: 794-806. 10.1016/j.ejpain.2008.09.009.CrossRefPubMed
39.
Blanco AM, Perez-Arago A, Fernandez-Lizarbe S, Guerri C: Ethanol mimics ligand-mediated activation and endocytosis of IL-1RI/TLR4 receptors via lipid rafts caveolae in astroglial cells. J Neurochem. 2008, 106: 625-639. 10.1111/j.1471-4159.2008.05425.x.CrossRefPubMed
40.
Chen TL, Chang CC, Lin YL, Ueng YF, Chen RM: Signal-transducing mechanisms of ketamine-caused inhibition of interleukin-1 beta gene expression in lipopolysaccharide-stimulated murine macrophage-like Raw 264.7 cells. Toxicol Appl Pharmacol. 2009, 240: 15-25. 10.1016/j.taap.2009.06.013.CrossRefPubMed
41.
Mazar J, Rogachev B, Shaked G, Ziv NY, Czeiger D, Chaimovitz C, Zlotnik M, Mukmenev I, Byk G, Douvdevani A: Involvement of adenosine in the antiinflammatory action of ketamine. Anesthesiology. 2005, 102: 1174-1181. 10.1097/00000542-200506000-00017.CrossRefPubMed
42.
Shaked G, Czeiger D, Dukhno O, Levy I, Artru AA, Shapira Y, Douvdevani A: Ketamine improves survival and suppresses IL-6 and TNFalpha production in a model of Gram-negative bacterial sepsis in rats. Resuscitation. 2004, 62: 237-242. 10.1016/j.resuscitation.2004.02.015.CrossRefPubMed
43.
Hill GE, Anderson JL, Lyden ER: Ketamine inhibits the proinflammatory cytokine-induced reduction of cardiac intracellular cAMP accumulation. Anesth Analg. 1998, 87: 1015-1019. 10.1097/00000539-199811000-00006.PubMed
44.
Cao L, Tanga FY, Deleo JA: The contributing role of CD14 in toll-like receptor 4 dependent neuropathic pain. Neuroscience. 2009, 158: 896-903. 10.1016/j.neuroscience.2008.10.004.PubMedCentralCrossRefPubMed
45.
Bettoni I, Comelli F, Rossini C, Granucci F, Giagnoni G, Peri F, Costa B: Glial TLR4 receptor as new target to treat neuropathic pain: efficacy of a new receptor antagonist in a model of peripheral nerve injury in mice. Glia. 2008, 56: 1312-1319. 10.1002/glia.20699.CrossRefPubMed
46.
Obata K, Katsura H, Miyoshi K, Kondo T, Yamanaka H, Kobayashi K, Dai Y, Fukuoka T, Akira S, Noguchi K: Toll-like receptor 3 contributes to spinal glial activation and tactile allodynia after nerve injury. J Neurochem. 2008, 105: 2249-2259. 10.1111/j.1471-4159.2008.05353.x.CrossRefPubMed
47.
Yu M, Shao D, Yang J, Feng S, Xu J: Ketamine suppresses intestinal TLR4 expression and NF-kappaB activity in lipopolysaccharide-treated rats. Croat Med J. 2006, 47: 825-831.PubMedCentralPubMed
Metadata
Title
Inhibition of spinal astrocytic c-Jun N-terminal kinase (JNK) activation correlates with the analgesic effects of ketamine in neuropathic pain
Authors
Xiao-Peng Mei
Hui Zhang
Wei Wang
Yan-Yan Wei
Ming-Zhu Zhai
Wen Wang
Li-Xian Xu
Yun-Qing Li
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2011
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-8-6

Other articles of this Issue 1/2011

Journal of Neuroinflammation 1/2011 Go to the issue

Research

Lymph node-derived donor encephalitogenic CD4+T cells in C57BL/6 mice adoptive transfer experimental autoimmune encephalomyelitis highly express GM-CSF and T-bet

Research

Peripheral anti-inflammatory effects explain the ginsenosides paradox between poor brain distribution and anti-depression efficacy

Research

Signal pathways in astrocytes activated by cross-talk between of astrocytes and mast cells through CD40-CD40L

Research

Low plasma progranulin levels in children with autism

Research

Atorvastatin prevents age-related and amyloid-β-induced microglial activation by blocking interferon-γ release from natural killer cells in the brain

Research

Increased local concentration of complement C5a contributes to incisional pain in mice