title: Over-expression of astrocytic ET-1 attenuates neuropathic pain by inhibition of ERK1/2 and Akt(s) via activation of ETA receptor.
abstract: A differential role of endothelin-1 (ET-1) in pain processing has recently been suggested. However, the function of central ET-1 in neuropathic pain (NP) has not been fully elucidated to date. We report here the action of endogenous central ET-1 in sciatic nerve ligation-induced NP (SNL-NP) in a transgenic animal model that over-expresses ET-1 in the astrocytes (GET-1 mice). We hypothesized that the over-expression of astrocytic ET-1 would exert anti-allodynic and anti-hyperalgesic effects in NP, as demonstrated by mechanical threshold and plantar withdrawal latency using the von Frey filament and heat stimuli. In our animal model, GET-1 mice showed an increase in the withdrawal threshold and latency in response to the mechanical and thermal stimuli, respectively, in pain behavior tests after SNL. ET-1 and endothelin type A receptor (ETA-R) levels were increased significantly in L4-L6 segments of the spinal cord (ipsilateral to SNL) of GET-1 mice at 7 and 21days after surgery. Moreover, intrathecal administration of a specific ETA-R antagonist, BQ-123, attenuated the anti-allodynic and anti-hyperalgesic phenotype in GET-1 mice. The effects of BQ-123 on the mRNA expression of extracellular signal-regulated protein kinase 1/2 (ERK1/2) and protein kinase B/serine protein kinase (Akt(s)) were assessed in the ipsilateral L4-L6 segments harvested 30min after BQ-123 administration on day 7 after surgery. Phosphorylation of ERK1/2 and Akt(s) in the ipsilateral spinal cord of GET-1 mice was reduced following SNL, whereas no reduction was observed after intrathecal injection of BQ-123. In conclusion, our results showed that the xover-expression of astrocytic ET-1 reduced SNL-induced allodynia and hyperalgesia by inhibiting the activation of ERK1/2 and Akt(s) via the ETA-R-mediated pathway.
authors.affiliation: Department of Anaesthesiology, The University of Hong Kong, HKSAR, China; Laboratory and Clinical Research Institute for Pain, The University of Hong Kong, HKSAR, China.
authors.forename: Victor K L
authors.initials: VK
authors.lastname: Hung
authors.affiliation: Department of Anaesthesiology, The University of Hong Kong, HKSAR, China; Laboratory and Clinical Research Institute for Pain, The University of Hong Kong, HKSAR, China.
authors.forename: Lydia W
authors.initials: LW
authors.lastname: Tai
authors.affiliation: Department of Anaesthesiology, The University of Hong Kong, HKSAR, China; Laboratory and Clinical Research Institute for Pain, The University of Hong Kong, HKSAR, China.
authors.forename: Qiu
authors.initials: Q
authors.lastname: Qiu
authors.affiliation: Department of Anaesthesiology, The University of Hong Kong, HKSAR, China; Laboratory and Clinical Research Institute for Pain, The University of Hong Kong, HKSAR, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Anaesthesiology, The University of Hong Kong, HKSAR, China; Laboratory and Clinical Research Institute for Pain, The University of Hong Kong, HKSAR, China; Department of Anaesthesiology, China Medical University, Taichung, Taiwan.
authors.forename: K L
authors.initials: KL
authors.lastname: Wong
authors.affiliation: Department of Anatomy, The University of Hong Kong, HKSAR, China; Laboratory and Clinical Research Institute for Pain, The University of Hong Kong, HKSAR, China; Research Center of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, HKSAR, China.
authors.forename: Sookja K
authors.initials: SK
authors.lastname: Chung
authors.affiliation: Department of Anaesthesiology, The University of Hong Kong, HKSAR, China; Laboratory and Clinical Research Institute for Pain, The University of Hong Kong, HKSAR, China; Research Center of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, HKSAR, China. Electronic address: cheucw@hku.hk.
authors.forename: C W
authors.initials: CW
authors.lastname: Cheung
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D065128:Endothelin Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011930:Reaction Time; D044022:Receptor, Endothelin A / Q000378:metabolism*; D012584:Sciatic Nerve / Q000293:injuries / Q000378:metabolism; D014110:Touch
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C072247:cyclo(Trp-Asp-Pro-Val-Leu)
keywords: Allodynia; Astrocytes; Endothelin-1; Hyperalgesia; Neuropathic pain