Gabapentin loses efficacy over time after nerve injury in rats: role of glutamate transporter-1 in the locus coeruleus.
Despite being one of the first-choice analgesics for chronic neuropathic pain, gabapentin sometimes fails to provide analgesia, but the mechanisms for this lack of efficacy is unclear. Rats with nerve injury including L5-L6 spinal nerve ligation (SNL) respond uniformly and well to gabapentin, but many of these studies are performed within just a few weeks of injury, questioning their relevance to chronic neuropathic pain. In this study, intraperitoneal gabapentin showed a time-dependently reduction in antihypersensitivity after SNL, associated with downregulation of astroglial glutamate transporter-1 (GLT-1) in the locus coeruleus (LC). Consistently, SNL also time-dependently increased basal but masked gabapentin-induced noradrenergic neuronal activity in the LC. In rats 2 weeks after SNL, knock-down of GLT-1 in the LC reduced the antihypersensitivity effect of gabapentin. In rats 8 weeks after SNL, increasing GLT-1 expression by histone deacetylase inhibitor valproate restored the antihypersensitivity effect of gabapentin, associated with restored gabapentin-induced noradrenergic neuronal activity in the LC and subsequent spinal noradrenaline release. Knock-down of GLT-1 in the LC reversed the effect of valproate to restore gabapentin-induced antihypersensitivity. In addition, the antihypersensitivity effect of the intrathecal α2-adrenoceptor agonist clonidine also decreased with time after SNL injury. These results suggest that downregulation of GLT-1 in the LC and reduced spinal noradrenergic inhibition contribute to impaired analgesic efficacy from gabapentin in chronic neuropathic pain and that valproate can rescue this impaired efficacy.
Pain Mechanisms Laboratory, Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Department of Anesthesiology, Gunma University School of Medicine, Maebashi, Japan.
Masafumi
M
Kimura
Pain Mechanisms Laboratory, Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
James C
JC
Eisenach
Pain Mechanisms Laboratory, Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Department of Neurophysiology, Akita University School of Medicine, Akita, Japan.
Ken-Ichiro
KI
Hayashida
D000588:Amines / Q000627:therapeutic use*; D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001285:Atropine / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000494:pharmacology; D050882:CREB-Binding Protein / Q000378:metabolism; D003000:Clonidine / Q000494:pharmacology; D003509:Cyclohexanecarboxylic Acids / Q000627:therapeutic use*; D004195:Disease Models, Animal; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism*; D000077206:Gabapentin; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D017288:Pain Threshold / Q000187:drug effects; D059348:Peripheral Nerve Injuries / Q000188:drug therapy* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D066148:Spinal Cord Dorsal Horn / Q000378:metabolism; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000627:therapeutic use*
D000588:Amines; D000700:Analgesics; D000959:Antihypertensive Agents; D001993:Bronchodilator Agents; D003509:Cyclohexanecarboxylic Acids; D027342:Excitatory Amino Acid Transporter 2; D034741:RNA, Small Interfering; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D001285:Atropine; D050882:CREB-Binding Protein; D003000:Clonidine; D009638:Norepinephrine