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Published in: BMC Complementary Medicine and Therapies 1/2016

Open Access 01-12-2016 | Research article

Activation of hippocampal MEK1 contributes to the cumulative antinociceptive effect of electroacupuncture in neuropathic pain rats

Authors: Yong-Hui Gao, Cheng-Wen Li, Jun-Ying Wang, Yu Kan, Lian-Hong Tan, Xiang-Hong Jing, Jun-Ling Liu

Published in: BMC Complementary Medicine and Therapies | Issue 1/2016

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Abstract

Background

Electroacupuncture (EA) intervention can relieve a variety of pain; however, optimal EA protocols have not been clearly determined. In addition, although central mitogen-activated protein kinase kinase (MEK) signaling has been shown to be involved in the antinociceptive effect of acupuncture stimulation, its characteristics at different time-points of EA intervention have not been fully elucidated. Therefore, the present study investigated the relationship between the effects of different numbers of EA intervention sessions and the activation of MEK1 in the hippocampus and hypothalamus in a rat model of neuropathic pain.

Methods

After ligation of the left sciatic nerve, which induces chronic constriction injury (CCI), the acupoints Zusanli (ST36) and Yanglingquan (GB34) were applied. The thermal withdrawal latency of the hind paw was used to evaluate the effect of EA on pain thresholds. Intra-hippocampus microinjection of PD98059, a MEK inhibitor, was performed to validate the involvement of MEK in EA analgesia. The hippocampus and hypothalamus were harvested to examine the phosphorylation levels of MEK (pMEK) by western blotting.

Results

In CCI rats, the thermal pain threshold of the affected hind paw decreased significantly relative to the control. Following subsequent daily EA interventions, CCI-induced ipsilateral hyperalgesia was markedly improved from day 4 and the analgesic effect of EA lasted 3 days after cessation of EA. Four sessions of EA markedly suppressed CCI-induced decrease of hippocampal pMEK1 (normalized to the total MEK level). In contrast, successive sessions of EA intervention gradually down-regulated the CCI-induced up-regulation of hypothalamic pMEK1 along with the increase numbers of EA intervention. However, EA did not exert the same analgesic effect after microinjection of PD98059 into the contralateral hippocampus during the first 3 days of EA intervention.

Conclusions

EA intervention can induce time-dependent cumulative analgesia in neuropathic pain rats after 4 successive sessions of daily EA intervention, which is at least in part related to the activation of hippocampal MEK1.
Literature
1.
go back to reference Vickers AJ, Cronin AM, Maschino AC, Lewith G, MacPherson H, Foster NE, Sherman KJ, Witt CM, Linde K. Acupuncture for chronic pain: individual patient data meta-analysis. Arch Intern Med. 2012;172(19):1444–53.CrossRefPubMedPubMedCentral Vickers AJ, Cronin AM, Maschino AC, Lewith G, MacPherson H, Foster NE, Sherman KJ, Witt CM, Linde K. Acupuncture for chronic pain: individual patient data meta-analysis. Arch Intern Med. 2012;172(19):1444–53.CrossRefPubMedPubMedCentral
2.
3.
go back to reference Goldman N, Chen M, Fujita T, Xu Q, Peng W, Liu W, Jensen TK, Pei Y, Wang F, Han X, et al. Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture. Nat Neurosci. 2010;13(7):883–8.CrossRefPubMedPubMedCentral Goldman N, Chen M, Fujita T, Xu Q, Peng W, Liu W, Jensen TK, Pei Y, Wang F, Han X, et al. Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture. Nat Neurosci. 2010;13(7):883–8.CrossRefPubMedPubMedCentral
4.
go back to reference Wang C, Yang F, Liu X, Liu M, Zheng Y, Guo J. Neurotrophic signaling factors in brain ischemia/reperfusion rats: differential modulation pattern between single-time and multiple electroacupuncture stimulation. Evid Based Complement Alternat Med. 2014;2014:625050.PubMedPubMedCentral Wang C, Yang F, Liu X, Liu M, Zheng Y, Guo J. Neurotrophic signaling factors in brain ischemia/reperfusion rats: differential modulation pattern between single-time and multiple electroacupuncture stimulation. Evid Based Complement Alternat Med. 2014;2014:625050.PubMedPubMedCentral
5.
go back to reference Wang GB, Wu LZ, Yu P, Li YJ, Ping XJ, Cui CL. Multiple 100 Hz electroacupuncture treatments produced cumulative effect on the suppression of morphine withdrawal syndrome: Central preprodynorphin mRNA and p-CREB implicated. Peptides. 2011;32(4):713–21.CrossRefPubMed Wang GB, Wu LZ, Yu P, Li YJ, Ping XJ, Cui CL. Multiple 100 Hz electroacupuncture treatments produced cumulative effect on the suppression of morphine withdrawal syndrome: Central preprodynorphin mRNA and p-CREB implicated. Peptides. 2011;32(4):713–21.CrossRefPubMed
6.
go back to reference Li J, Hu Y, Tong L, Wang D, Zhang D. Effects of electroacupuncture plus intra-carotid drug injection on rheoencephalogram in patients with cerebral infarction. J Tradit Chin Med. 2004;24(1):28–9.PubMed Li J, Hu Y, Tong L, Wang D, Zhang D. Effects of electroacupuncture plus intra-carotid drug injection on rheoencephalogram in patients with cerebral infarction. J Tradit Chin Med. 2004;24(1):28–9.PubMed
8.
go back to reference Han JS. Acupuncture analgesia: areas of consensus and controversy. Pain. 2011;152(3 Suppl):S41–8.CrossRefPubMed Han JS. Acupuncture analgesia: areas of consensus and controversy. Pain. 2011;152(3 Suppl):S41–8.CrossRefPubMed
9.
go back to reference Li C, Yang J, Park K, Wu H, Hu S, Zhang W, Bu J, Xu C, Qiu B, Zhang X. Prolonged repeated acupuncture stimulation induces habituation effects in pain-related brain areas: an FMRI study. PLoS One. 2014;9(5):e97502.CrossRefPubMedPubMedCentral Li C, Yang J, Park K, Wu H, Hu S, Zhang W, Bu J, Xu C, Qiu B, Zhang X. Prolonged repeated acupuncture stimulation induces habituation effects in pain-related brain areas: an FMRI study. PLoS One. 2014;9(5):e97502.CrossRefPubMedPubMedCentral
10.
go back to reference Gao YH, Wang JY, Qiao LN, Chen SP, Tan LH, Xu QL, Liu JL. NK cells mediate the cumulative analgesic effect of electroacupuncture in a rat model of neuropathic pain. BMC Complement Altern Med. 2014;14:316.CrossRefPubMedPubMedCentral Gao YH, Wang JY, Qiao LN, Chen SP, Tan LH, Xu QL, Liu JL. NK cells mediate the cumulative analgesic effect of electroacupuncture in a rat model of neuropathic pain. BMC Complement Altern Med. 2014;14:316.CrossRefPubMedPubMedCentral
11.
go back to reference Zhou HJ, Tang T, Zhong JH, Luo JK, Cui HJ, Zhang QM, Zhou JH, Zhang Q. Electroacupuncture improves recovery after hemorrhagic brain injury by inducing the expression of angiopoietin-1 and -2 in rats. BMC Complement Altern Med. 2014;14:127.CrossRefPubMedPubMedCentral Zhou HJ, Tang T, Zhong JH, Luo JK, Cui HJ, Zhang QM, Zhou JH, Zhang Q. Electroacupuncture improves recovery after hemorrhagic brain injury by inducing the expression of angiopoietin-1 and -2 in rats. BMC Complement Altern Med. 2014;14:127.CrossRefPubMedPubMedCentral
12.
go back to reference Tian XS, Zhou F, Yang R, Xia Y, Wu GC, Guo JC. Electroacupuncture protects the brain against acute ischemic injury via up-regulation of delta-opioid receptor in rats. Zhong Xi Yi Jie He Xue Bao. 2008;6(6):632–8.CrossRefPubMed Tian XS, Zhou F, Yang R, Xia Y, Wu GC, Guo JC. Electroacupuncture protects the brain against acute ischemic injury via up-regulation of delta-opioid receptor in rats. Zhong Xi Yi Jie He Xue Bao. 2008;6(6):632–8.CrossRefPubMed
13.
go back to reference Zeng F, Song WZ, Liu XG, Xie HJ, Tang Y, Shan BC, Liu ZH, Yu SG, Liang FR. Brain areas involved in acupuncture treatment on functional dyspepsia patients: a PET-CT study. Neurosci Lett. 2009;456(1):6–10.CrossRefPubMed Zeng F, Song WZ, Liu XG, Xie HJ, Tang Y, Shan BC, Liu ZH, Yu SG, Liang FR. Brain areas involved in acupuncture treatment on functional dyspepsia patients: a PET-CT study. Neurosci Lett. 2009;456(1):6–10.CrossRefPubMed
14.
go back to reference Bai L, Tian J, Zhong C, Xue T, You Y, Liu Z, Chen P, Gong Q, Ai L, Qin W, et al. Acupuncture modulates temporal neural responses in wide brain networks: evidence from fMRI study. Mol Pain. 2010;6:73.PubMedPubMedCentral Bai L, Tian J, Zhong C, Xue T, You Y, Liu Z, Chen P, Gong Q, Ai L, Qin W, et al. Acupuncture modulates temporal neural responses in wide brain networks: evidence from fMRI study. Mol Pain. 2010;6:73.PubMedPubMedCentral
15.
go back to reference Xu Q, Liu T, Chen S, Gao Y, Wang J, Qiao L, Liu J. The cumulative analgesic effect of repeated electroacupuncture involves synaptic remodeling in the hippocampal CA3 region. Neural Regen Res. 2012;7(18):1378–85.PubMedPubMedCentral Xu Q, Liu T, Chen S, Gao Y, Wang J, Qiao L, Liu J. The cumulative analgesic effect of repeated electroacupuncture involves synaptic remodeling in the hippocampal CA3 region. Neural Regen Res. 2012;7(18):1378–85.PubMedPubMedCentral
16.
go back to reference Vaccarino AL, Melzack R. Temporal processes of formalin pain: differential role of the cingulum bundle, fornix pathway and medial bulboreticular formation. Pain. 1992;49(2):257–71.CrossRefPubMed Vaccarino AL, Melzack R. Temporal processes of formalin pain: differential role of the cingulum bundle, fornix pathway and medial bulboreticular formation. Pain. 1992;49(2):257–71.CrossRefPubMed
17.
go back to reference McKenna JE, Melzack R. Blocking NMDA receptors in the hippocampal dentate gyrus with AP5 produces analgesia in the formalin pain test. Exp Neurol. 2001;172(1):92–9.CrossRefPubMed McKenna JE, Melzack R. Blocking NMDA receptors in the hippocampal dentate gyrus with AP5 produces analgesia in the formalin pain test. Exp Neurol. 2001;172(1):92–9.CrossRefPubMed
18.
go back to reference Gao YH, Chen SP, Wang JY, Qiao LN, Meng FY, Xu QL, Liu JL. Differential proteomics analysis of the analgesic effect of electroacupuncture intervention in the hippocampus following neuropathic pain in rats. BMC Complement Altern Med. 2012;12:241.CrossRefPubMedPubMedCentral Gao YH, Chen SP, Wang JY, Qiao LN, Meng FY, Xu QL, Liu JL. Differential proteomics analysis of the analgesic effect of electroacupuncture intervention in the hippocampus following neuropathic pain in rats. BMC Complement Altern Med. 2012;12:241.CrossRefPubMedPubMedCentral
19.
go back to reference Sweatt JD. Mitogen-activated protein kinases in synaptic plasticity and memory. Curr Opin Neurobiol. 2004;14(3):311–7.CrossRefPubMed Sweatt JD. Mitogen-activated protein kinases in synaptic plasticity and memory. Curr Opin Neurobiol. 2004;14(3):311–7.CrossRefPubMed
20.
go back to reference Ji RR, Gereau RW, Malcangio M, Strichartz GR. MAP kinase and pain. Brain Res Rev. 2009;60(1):135–48.CrossRefPubMed Ji RR, Gereau RW, Malcangio M, Strichartz GR. MAP kinase and pain. Brain Res Rev. 2009;60(1):135–48.CrossRefPubMed
21.
go back to reference Gao Y, Chen S, Xu Q, Yu K, Wang J, Qiao L, Meng F, Liu J. Proteomic analysis of differential proteins related to anti-nociceptive effect of electroacupuncture in the hypothalamus following neuropathic pain in rats. Neurochem Res. 2013;38(7):1467–78.CrossRefPubMed Gao Y, Chen S, Xu Q, Yu K, Wang J, Qiao L, Meng F, Liu J. Proteomic analysis of differential proteins related to anti-nociceptive effect of electroacupuncture in the hypothalamus following neuropathic pain in rats. Neurochem Res. 2013;38(7):1467–78.CrossRefPubMed
22.
go back to reference Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain. 1988;33(1):87–107.CrossRefPubMed Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain. 1988;33(1):87–107.CrossRefPubMed
23.
go back to reference Maranon C, Planelles L, Alonso C, Lopez MC. HSP70 from Trypanosoma cruzi is endowed with specific cell proliferation potential leading to apoptosis. Int Immunol. 2000;12(12):1685–93.CrossRefPubMed Maranon C, Planelles L, Alonso C, Lopez MC. HSP70 from Trypanosoma cruzi is endowed with specific cell proliferation potential leading to apoptosis. Int Immunol. 2000;12(12):1685–93.CrossRefPubMed
24.
go back to reference Cardoso-Cruz H, Lima D, Galhardo V. Impaired spatial memory performance in a rat model of neuropathic pain is associated with reduced hippocampus-prefrontal cortex connectivity. J Neurosci. 2013;33(6):2465–80.CrossRefPubMed Cardoso-Cruz H, Lima D, Galhardo V. Impaired spatial memory performance in a rat model of neuropathic pain is associated with reduced hippocampus-prefrontal cortex connectivity. J Neurosci. 2013;33(6):2465–80.CrossRefPubMed
25.
go back to reference Shim EJ, Seo YJ, Kwon MS, Ham YO, Choi OS, Lee JY, Choi SM, Suh HW. The intracerebroventricular kainic acid-induced damage affects animal nociceptive behavior. Brain Res Bull. 2007;73(4–6):203–9.CrossRefPubMed Shim EJ, Seo YJ, Kwon MS, Ham YO, Choi OS, Lee JY, Choi SM, Suh HW. The intracerebroventricular kainic acid-induced damage affects animal nociceptive behavior. Brain Res Bull. 2007;73(4–6):203–9.CrossRefPubMed
26.
go back to reference Mutso AA, Radzicki D, Baliki MN, Huang L, Banisadr G, Centeno MV, Radulovic J, Martina M, Miller RJ, Apkarian AV. Abnormalities in hippocampal functioning with persistent pain. J Neurosci. 2012;32(17):5747–56.CrossRefPubMedPubMedCentral Mutso AA, Radzicki D, Baliki MN, Huang L, Banisadr G, Centeno MV, Radulovic J, Martina M, Miller RJ, Apkarian AV. Abnormalities in hippocampal functioning with persistent pain. J Neurosci. 2012;32(17):5747–56.CrossRefPubMedPubMedCentral
27.
go back to reference Price TJ, Inyang KE. Commonalities between pain and memory mechanisms and their meaning for understanding chronic pain. Prog Mol Biol Transl Sci. 2015;131:409–34.CrossRefPubMedPubMedCentral Price TJ, Inyang KE. Commonalities between pain and memory mechanisms and their meaning for understanding chronic pain. Prog Mol Biol Transl Sci. 2015;131:409–34.CrossRefPubMedPubMedCentral
28.
go back to reference Liu MG, Wang RR, Chen XF, Zhang FK, Cui XY, Chen J. Differential roles of ERK, JNK and p38 MAPK in pain-related spatial and temporal enhancement of synaptic responses in the hippocampal formation of rats: multi-electrode array recordings. Brain Res. 2011;1382:57–69.CrossRefPubMed Liu MG, Wang RR, Chen XF, Zhang FK, Cui XY, Chen J. Differential roles of ERK, JNK and p38 MAPK in pain-related spatial and temporal enhancement of synaptic responses in the hippocampal formation of rats: multi-electrode array recordings. Brain Res. 2011;1382:57–69.CrossRefPubMed
29.
go back to reference Toyoda H, Zhao MG, Xu H, Wu LJ, Ren M, Zhuo M. Requirement of extracellular signal-regulated kinase/mitogen-activated protein kinase for long-term potentiation in adult mouse anterior cingulate cortex. Mol Pain. 2007;3:36.CrossRefPubMedPubMedCentral Toyoda H, Zhao MG, Xu H, Wu LJ, Ren M, Zhuo M. Requirement of extracellular signal-regulated kinase/mitogen-activated protein kinase for long-term potentiation in adult mouse anterior cingulate cortex. Mol Pain. 2007;3:36.CrossRefPubMedPubMedCentral
30.
go back to reference McCracken LM, Iverson GL. Predicting complaints of impaired cognitive functioning in patients with chronic pain. J Pain Symptom Manage. 2001;21(5):392–6.CrossRefPubMed McCracken LM, Iverson GL. Predicting complaints of impaired cognitive functioning in patients with chronic pain. J Pain Symptom Manage. 2001;21(5):392–6.CrossRefPubMed
31.
32.
go back to reference He X, Yan T, Chen R, Ran D. Acute effects of electro-acupuncture (EA) on hippocampal long term potentiation (LTP) of perforant path-dentate gyrus granule cells synapse related to memory. Acupunct Electrother Res. 2012;37(2–3):89–101.CrossRefPubMed He X, Yan T, Chen R, Ran D. Acute effects of electro-acupuncture (EA) on hippocampal long term potentiation (LTP) of perforant path-dentate gyrus granule cells synapse related to memory. Acupunct Electrother Res. 2012;37(2–3):89–101.CrossRefPubMed
34.
go back to reference Meunier M, Barbeau E. Recognition memory and the medial temporal lobe: from monkey research to human pathology. Rev Neurol (Paris). 2013;169(6–7):459–69.CrossRef Meunier M, Barbeau E. Recognition memory and the medial temporal lobe: from monkey research to human pathology. Rev Neurol (Paris). 2013;169(6–7):459–69.CrossRef
35.
go back to reference Reichling DB, Green PG, Levine JD. The fundamental unit of pain is the cell. Pain. 2013;154 Suppl 1. Reichling DB, Green PG, Levine JD. The fundamental unit of pain is the cell. Pain. 2013;154 Suppl 1.
36.
go back to reference Forkmann K, Wiech K, Ritter C, Sommer T, Rose M, Bingel U. Pain-specific modulation of hippocampal activity and functional connectivity during visual encoding. J Neurosci. 2013;33(6):2571–81.CrossRefPubMed Forkmann K, Wiech K, Ritter C, Sommer T, Rose M, Bingel U. Pain-specific modulation of hippocampal activity and functional connectivity during visual encoding. J Neurosci. 2013;33(6):2571–81.CrossRefPubMed
37.
go back to reference Seo YJ, Kwon MS, Choi HW, Choi SM, Kim YW, Lee JK, Park SH, Jung JS, Suh HW. Differential expression of phosphorylated Ca2+/calmodulin-dependent protein kinase II and phosphorylated extracellular signal-regulated protein in the mouse hippocampus induced by various nociceptive stimuli. Neuroscience. 2008;156(3):436–49.CrossRefPubMed Seo YJ, Kwon MS, Choi HW, Choi SM, Kim YW, Lee JK, Park SH, Jung JS, Suh HW. Differential expression of phosphorylated Ca2+/calmodulin-dependent protein kinase II and phosphorylated extracellular signal-regulated protein in the mouse hippocampus induced by various nociceptive stimuli. Neuroscience. 2008;156(3):436–49.CrossRefPubMed
38.
go back to reference Cervero F. Spinal cord mechanisms of hyperalgesia and allodynia: role of peripheral input from nociceptors. Prog Brain Res. 1996;113:413–22.CrossRefPubMed Cervero F. Spinal cord mechanisms of hyperalgesia and allodynia: role of peripheral input from nociceptors. Prog Brain Res. 1996;113:413–22.CrossRefPubMed
Metadata
Title
Activation of hippocampal MEK1 contributes to the cumulative antinociceptive effect of electroacupuncture in neuropathic pain rats
Authors
Yong-Hui Gao
Cheng-Wen Li
Jun-Ying Wang
Yu Kan
Lian-Hong Tan
Xiang-Hong Jing
Jun-Ling Liu
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2016
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-016-1508-z

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