title: Adenosine Monophosphate-activated Protein Kinase Regulates Interleukin-1β Expression and Glial Glutamate Transporter Function in Rodents with Neuropathic Pain.
abstract: BACKGROUND
  Neuroinflammation and dysfunctional glial glutamate transporters (GTs) in the spinal dorsal horn are implicated in the genesis of neuropathic pain. The authors determined whether adenosine monophosphate-activated protein kinase (AMPK) in the spinal dorsal horn regulates these processes in rodents with neuropathic pain.
  
  
  METHODS
  Hind paw withdrawal responses to radiant heat and mechanical stimuli were used to assess nociceptive behaviors. Spinal markers related to neuroinflammation and glial GTs were determined by Western blotting. AMPK activities were manipulated pharmacologically and genetically. Regulation of glial GTs was determined by measuring protein expression and activities of glial GTs.
  
  
  RESULTS
  AMPK activities were reduced in the spinal dorsal horn of rats (n = 5) with thermal hyperalgesia induced by nerve injury, which were accompanied with the activation of astrocytes, increased production of interleukin-1β and activities of glycogen synthase kinase 3β, and suppressed protein expression of glial glutamate transporter-1. Thermal hyperalgesia was reversed by spinal activation of AMPK in neuropathic rats (n = 10) and induced by inhibiting spinal AMPK in naive rats (n = 7 to 8). Spinal AMPKα knockdown (n = 6) and AMPKα1 conditional knockout (n = 6) induced thermal hyperalgesia and mechanical allodynia. These genetic alterations mimicked the changes of molecular markers induced by nerve injury. Pharmacological activation of AMPK enhanced glial GT activity in mice with neuropathic pain (n = 8) and attenuated glial glutamate transporter-1 internalization induced by interleukin-1β (n = 4).
  
  
  CONCLUSIONS
  These findings suggest that enhancing spinal AMPK activities could be an effective approach for the treatment of neuropathic pain.
authors.affiliation: From the Department of Pharmaceutical and Biomedical Sciences, University of Georgia College of Pharmacy, Athens, Georgia (D.W.M., X.Y., M.G., R.Y., H.-R.W.); and Department of Cardiovascular Medicine, The Third Hospital of Wuhan, Wuhan, Hubei Province, China (X.Y.).
authors.forename: Dylan W
authors.initials: DW
authors.lastname: Maixner
authors.forename: Xisheng
authors.initials: X
authors.lastname: Yan
authors.forename: Mei
authors.initials: M
authors.lastname: Gao
authors.forename: Ruchi
authors.initials: R
authors.lastname: Yadav
authors.forename: Han-Rong
authors.initials: HR
authors.lastname: Weng
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D027322:Amino Acid Transport System X-AG / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal; D005838:Genotype; D006930:Hyperalgesia / Q000139:chemically induced / Q000523:psychology; D007278:Injections, Spinal; D053583:Interleukin-1beta / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009437:Neuralgia / Q000378:metabolism*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D017288:Pain Threshold; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism
chemical_list: D027322:Amino Acid Transport System X-AG; D053583:Interleukin-1beta; D034741:RNA, Small Interfering; D013385:Succinate Dehydrogenase; D055372:AMP-Activated Protein Kinases; C568305:Prkaa1 protein, rat