title: Activation of hippocampal MEK1 contributes to the cumulative antinociceptive effect of electroacupuncture in neuropathic pain rats.
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.
authors.affiliation: Department of Physiology, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
authors.forename: Yong-Hui
authors.initials: YH
authors.lastname: Gao
authors.affiliation: College of Acupuncture & Moxibustion and Tui-na, Hunan University of Chinese Medicine, Changsha, 410208, Hunan Province, China.|The First Affiliated Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, 412012, Hunan Province, China.
authors.forename: Cheng-Wen
authors.initials: CW
authors.lastname: Li
authors.affiliation: Department of Physiology, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
authors.forename: Jun-Ying
authors.initials: JY
authors.lastname: Wang
authors.affiliation: Department of Physiology, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Kan
authors.affiliation: Department of Physiology, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
authors.forename: Lian-Hong
authors.initials: LH
authors.lastname: Tan
authors.affiliation: Meridian Research Center, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China.
authors.forename: Xiang-Hong
authors.initials: XH
authors.lastname: Jing
authors.affiliation: Department of Physiology, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, 100700, China. 13521898023@163.com.
authors.forename: Jun-Ling
authors.initials: JL
authors.lastname: Liu
mesh_terms: D015667:Acupuncture Analgesia; D015669:Acupuncture Points; D000818:Animals; D015671:Electroacupuncture; D006624:Hippocampus / Q000201:enzymology*; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009437:Neuralgia / Q000201:enzymology* / Q000235:genetics / Q000628:therapy*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D048369:MAP Kinase Kinase 1
keywords: Acupuncture analgesia; Cumulative effect; Hippocampus; Mitogen-activated protein kinase kinase 1; Neuropathic pain