Gabapentin increases extracellular glutamatergic level in the locus coeruleus via astroglial glutamate transporter-dependent mechanisms.
Gabapentin has shown to be effective in animals and humans with acute postoperative and chronic pain. Yet the mechanisms by which gabapentin reduces pain have not been fully addressed. The current study performed in vivo microdialysis in the locus coeruleus (LC) in normal and spinal nerve ligated (SNL) rats to examine the effect of gabapentin on extracellular glutamate concentration and its mechanisms of action with focus on presynaptic GABA-B receptors, astroglial glutamate transporter-1 (GLT-1), and interactions with α2δ subunits of voltage-gated Ca(2+) channels and endogenous noradrenaline. Basal extracellular concentration and tissue content of glutamate in the LC were greater in SNL rats than normal ones. Intravenously administered and LC-perfused gabapentin increased extracellular glutamate concentration in the LC. The net amount of glutamate increased by gabapentin is larger in SNL rats compared with normal ones, although the percentage increases from the baseline did not differ. The gabapentin-related α2δ ligand pregabalin increased extracellular glutamate concentration in the LC, whereas another α2δ ligand, 3-exo-aminobicyclo [2.2.1] heptane-2-exo-carboxylic acid (ABHCA), did not. Selective blockade by the dihydrokainic acid or knock-down of GLT-1 by the small interfering RNA abolished the gabapentin-induced glutamate increase in the LC, whereas blockade of GABA-B receptors by the CGP-35348 and depletion of noradrenalin by the dopamine-β-hydroxylase antibody conjugated to saporin did not. These results suggest that gabapentin induces glutamate release from astrocytes in the LC via GLT-1-dependent mechanisms to stimulate descending inhibition. The present study also demonstrates that this target of gabapentin in astrocytes does not require interaction with α2δ subunits in neurons.
Department of Anesthesiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Takashi
T
Suto
Department of Anesthesiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Amie L
AL
Severino
Department of Anesthesiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
James C
JC
Eisenach
Department of Anesthesiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA. Electronic address: khayashi@wakehealth.edu.
Ken-ichiro
K
Hayashida
D000588:Amines / Q000494:pharmacology* / Q000627:therapeutic use; D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects*; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D018756:GABA Antagonists / Q000494:pharmacology; D000077206:Gabapentin; D008125:Locus Coeruleus / Q000187:drug effects*; D008297:Male; D009437:Neuralgia / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D009638:Norepinephrine / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000378:metabolism; D013127:Spinal Nerves / Q000601:surgery; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology* / Q000627:therapeutic use
D000588:Amines; D027322:Amino Acid Transport System X-AG; D003509:Cyclohexanecarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D009943:Organophosphorus Compounds; D018080:Receptors, GABA-B; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; C066430:CGP 35348; D009638:Norepinephrine
Astrocyte; Gabapentin; Glutamate; Glutamate transporters; Locus coeruleus; Peripheral nerve injury