title: Down-regulation of astroglial glutamate transporter-1 in the locus coeruleus impairs pain-evoked endogenous analgesia in rats.
abstract: Descending noradrenergic inhibition to the spinal cord from the locus coeruleus (LC) is an important endogenous pain-relief mechanism which can be activated by local glutamate signaling. Here we tested whether dysregulation of extracellular glutamate level in the LC induced by down-regulating astroglial glutamate transporter-1(GLT-1) impairs endogenous analgesia. In rats treated with repeated LC injections of GLT-1 selective or non-targeting small interfering RNA (siRNA), a subdermal injection of capsaicin was used to examine noxious stimulation-induced analgesia (NSIA), evoked LC glutamate and spinal noradrenaline release, and evoked LC neuronal activity. LC-injected GLT-1 siRNA reduced expression of GLT-1 in the LC (P=0.02), increased basal activity of LC neurons (P<0.01), and increased basal extracellular concentrations of LC glutamate (P<0.01) and spinal noradrenaline (P<0.01), but did not affect mechanical withdrawal thresholds in the hindpaw (P=0.83), compared to non-targeting siRNA. LC-injected GLT-1 siRNA impaired capsaicin-evoked release of LC glutamate and spinal noradrenaline, capsaicin-evoked LC neuronal activation, and NSIA. These results suggest that astroglial GLT-1 is essential to normal LC function and that increased extracellular glutamate by down-regulating GLT-1 impairs evoked LC activity and NSIA, essentially taking the LC "off-line".
authors.affiliation: Pain Mechanisms Laboratory, Department of Anesthesiology, Wake Forest School of Medicine, Winston Salem, NC 27157, United states; Department of Anesthesiology, Gunma University School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kimura
authors.affiliation: Department of Anesthesiology, Gunma University School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Suto
authors.affiliation: Pain Mechanisms Laboratory, Department of Anesthesiology, Wake Forest School of Medicine, Winston Salem, NC 27157, United states.
authors.forename: James C
authors.initials: JC
authors.lastname: Eisenach
authors.affiliation: Pain Mechanisms Laboratory, Department of Anesthesiology, Wake Forest School of Medicine, Winston Salem, NC 27157, United states; Department of Neurophysiology, Akita University School of Medicine, Akita 010-8543, Japan. Electronic address: hayashida@med.akita-u.ac.jp.
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Hayashida
mesh_terms: D000698:Analgesia; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002211:Capsaicin / Q000494:pharmacology; D015536:Down-Regulation; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D018698:Glutamic Acid / Q000378:metabolism; D008125:Locus Coeruleus / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D010146:Pain / Q000378:metabolism* / Q000503:physiopathology; D017288:Pain Threshold / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D034741:RNA, Small Interfering; D018698:Glutamic Acid; D002211:Capsaicin; D009638:Norepinephrine
keywords: Astrocytes; Endogenous analgesia; Glutamate transporter-1; Locus coeruleus; Small interfering RNA