title: Gabapentin inhibits γ-amino butyric acid release in the locus coeruleus but not in the spinal dorsal horn after peripheral nerve injury in rats.
abstract: BACKGROUND
  Gabapentin reduces acute postoperative and chronic neuropathic pain, but its sites and mechanisms of action are unclear. Based on previous electrophysiologic studies, the authors tested whether gabapentin reduced γ-amino butyric acid (GABA) release in the locus coeruleus (LC), a major site of descending inhibition, rather than in the spinal cord.
  
  
  METHODS
  Male Sprague-Dawley rats with or without L5-L6 spinal nerve ligation (SNL) were used. Immunostaining for glutamic acid decarboxylase and GABA release in synaptosomes and microdialysates were examined in the LC and spinal dorsal horn.
  
  
  RESULTS
  Basal GABA release and expression of glutamic acid decarboxylase increased in the LC but decreased in the spinal dorsal horn after SNL. In microdialysates from the LC, intravenously administered gabapentin decreased extracellular GABA concentration in normal and SNL rats. In synaptosomes prepared from the LC, gabapentin and other α2δ ligands inhibited KCl-evoked GABA release in normal and SNL rats. In microdialysates from the spinal dorsal horn, intravenous gabapentin did not alter GABA concentrations in normal rats but slightly increased them in SNL rats. In synaptosomes from the spinal dorsal horn, neither gabapentin nor other α2δ ligands affected KCl-evoked GABA release in normal and SNL rats.
  
  
  CONCLUSIONS
  These results suggest that peripheral nerve injury induces plasticity of GABAergic neurons differently in the LC and spinal dorsal horn and that gabapentin reduces presynaptic GABA release in the LC but not in the spinal dorsal horn. The current study supports the idea that gabapentin activates descending noradrenergic inhibition via disinhibition of LC neurons.
authors.affiliation: Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Masaru
authors.initials: M
authors.lastname: Yoshizumi
authors.forename: Renee A
authors.initials: RA
authors.lastname: Parker
authors.forename: James C
authors.initials: JC
authors.lastname: Eisenach
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Hayashida
mesh_terms: D000588:Amines / Q000494:pharmacology*; D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D000077206:Gabapentin; D005968:Glutamate Decarboxylase / Q000378:metabolism; D007150:Immunohistochemistry; D008026:Ligation; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D059348:Peripheral Nerve Injuries / Q000378:metabolism*; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013127:Spinal Nerves / Q000293:injuries; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D005968:Glutamate Decarboxylase