title: Targeted Overexpression of Astrocytic Endothelin-1 Attenuates Neuropathic Pain by Upregulating Spinal Excitatory Amino Acid Transporter-2.
abstract: We previously demonstrated that endogenous endothelin-1 (ET-1) inhibits pathological pain in a transgenic mouse model with astrocyte-specific ET-1 overexpression (GET-1 mice); however, the underlying mechanism is unclear. ET-1 regulates excitatory amino acid transporter-2 (EAAT-2), a predominant subtype of glutamate transporters that plays critical role in pain modulation in spinal astrocytes. We hypothesized that astrocytic ET-1 overexpression alleviates neuropathic pain through modulating EAAT-2. GET-1 or nontransgenic (NTg) mice either received sham operation or sciatic nerve ligation (SNL) with or without ceftriaxone (CEF, an EAAT-2 inducer, for 4 days before termination). In GET-1 mice, mRNA and protein expressions of EAAT-2, but not EAAT-1, were upregulated associated with reduced SNL-induced neuropathic pain. Despite that SNL induced a significant reduction of EAAT-2 mRNA expression in both genotypes of mice, post-SNL EAAT-2 mRNA expression was higher in GET-1 mice than that in NTg mice. EAAT-2 induction by CEF reduced SNL-induced neuropathic pain in both NTg and GET-1 mice. In cultured rat astrocytic cell line, overexpression of ET-1 mRNA expression also elevated EAAT-2 mRNA expression, which was reversed by ET receptor antagonists. In conclusion, overexpressed astrocytic ET-1 suppressed neuropathic pain by upregulating spinal EAAT-2 expression via ET receptors.
authors.affiliation: Department of Anaesthesiology, The University of Hong Kong, Rm 424, 4/F, Block K, Queen Mary Hospital, 102, Pokfulam, HKSAR, China.
authors.forename: Victor K L
authors.initials: VK
authors.lastname: Hung
authors.forename: Lydia W
authors.initials: LW
authors.lastname: Tai
authors.forename: Xin
authors.initials: X
authors.lastname: Luo
authors.forename: Xiao Min
authors.initials: XM
authors.lastname: Wang
authors.forename: Sookja K
authors.initials: SK
authors.lastname: Chung
authors.forename: Chi Wai
authors.initials: CW
authors.lastname: Cheung
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002460:Cell Line; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000378:metabolism*; D051381:Rats; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
chemical_list: D019332:Endothelin-1; D027342:Excitatory Amino Acid Transporter 2