Down-regulation of astroglial glutamate transporter-1 in the locus coeruleus impairs pain-evoked endogenous analgesia in rats

NEUROSCIENCE LETTERS

卷:608

Article

Kimura, Masafumi^1,2  Suto, Takashi²  Eisenach, James C.¹  Hayashida, Ken-ichiro^1,3 

[1] Wake Forest Sch Med, Dept Anesthesiol, Pain Mech Lab, Winston Salem, NC 27157 USA

[2] Gunma Univ, Sch Med, Dept Anesthesiol, Maebashi, Gunma 3718511, Japan

[3] Akita Univ, Sch Med, Dept Neurophysiol, Akita 0108543, Japan

关键词: Locus coeruleus;    Astrocytes;    Glutamate transporter-1;    Endogenous analgesia;    Small interfering RNA;   

DOI  :  10.1016/j.neulet.2015.09.036

来源: Elsevier

【 摘 要 】

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. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

【 授权许可】

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