title: Gabapentin acts within the locus coeruleus to alleviate neuropathic pain.
abstract: BACKGROUND
  Gabapentin recruits descending inhibition to produce analgesia after nerve injury, but whether this is a local action in the brainstem is unknown. The authors hypothesized that gabapentin activates noradrenergic neurons in the locus coeruleus (LC) by a local action.
  
  
  METHODS
  Male rats underwent L5-L6 spinal nerve ligation (SNL) and received drugs by intra-LC or systemic routes for behavior testing, immunohistochemistry in the LC, and microdialysis in the spinal dorsal horn. In other studies, brainstem slices from normal and SNL animals were used for immunohistochemistry.
  
  
  RESULTS
  SNL increased phosphorylated cyclic adenosine monophosphate response element binding protein (pCREB)-expressing nuclei bilaterally in the LC, and increased noradrenaline release in the spinal dorsal horn. Gabapentin, whether in isolated brainstem slices or in conscious or anesthetized animals, increased pCREB-expressing nuclei in the LC. The net increase in pCREB expression by gabapentin did not differ between normal and SNL conditions. This gabapentin-induced pCREB activation in LC neurons was abolished by an AMPA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Intra-LC-injected gabapentin reduced hypersensitivity in SNL rats in a dose-dependent manner. Both intra-LC coadministration of CNQX and intrathecal administration of the alpha2-adrenoceptor antagonist idazoxan blocked antihypersensitivity by intra-LC gabapentin. Intravenous gabapentin induced noradrenaline release in the spinal dorsal horn. The net amount of noradrenaline release by gabapentin is larger in SNL rats compared with the normal condition, although the percentage increases from the baseline were the same.
  
  
  CONCLUSIONS
  These results suggest that gabapentin acts directly in the brainstem via a glutamate-dependent mechanism to stimulate descending inhibition to produce antihypersensitivity after peripheral nerve injury.
authors.affiliation: Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1009, USA.
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Hayashida
authors.forename: Hideaki
authors.initials: H
authors.lastname: Obata
authors.forename: Kunie
authors.initials: K
authors.lastname: Nakajima
authors.forename: James C
authors.initials: JC
authors.lastname: Eisenach
mesh_terms: D000588:Amines / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D000077206:Gabapentin; D008125:Locus Coeruleus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D009638:Norepinephrine