title: Silencing the α2 subunit of γ-aminobutyric acid type A receptors in rat dorsal root ganglia reveals its major role in antinociception posttraumatic nerve injury.
abstract: BACKGROUND
  Neuropathic pain (NPP) is likely the result of repetitive high-frequency bursts of peripheral afferent activity leading to long-lasting changes in synaptic plasticity in the spinal dorsal horn. Drugs that promote γ-aminobutyric acid (GABA) activity in the dorsal horn provide partial relief of neuropathic symptoms. The authors examined how in vivo silencing of the GABA receptor type A (GABAA) α2 gene in dorsal root ganglia (DRG) controls NPP.
  
  
  METHODS
  After crush injury to the right sciatic nerve of female rats, the α2 GABAA antisense and mismatch oligodeoxynucleotides or NO-711 (a GABA uptake inhibitor) were applied to the L5 DRG. In vivo behavioral assessment of nociception was conducted before the injury and ensuing 10 days (n = 4 to 10). In vitro quantification of α2 GABAA protein and electrophysiological studies of GABAA currents were performed on acutely dissociated L5 DRG neurons at relevant time points (n = 6 to 14).
  
  
  RESULTS
  NPP postcrush injury of a sciatic nerve in adult female rats coincides with significant down-regulation of the α2 subunit expression in the ipsilateral DRG (approximately 30%). Selective down-regulation of α2 expression in DRGs significantly worsens mechanical (2.55 ± 0.75 to 5.16 ± 1.16) and thermal (7.97 ± 0.96 to 5.51 ± 0.75) hypersensitivity in crush-injured animals and causes development of significant mechanical (2.33 ± 0.40 to 5.00 ± 0.33) and thermal (10.80 ± 0.29 to 7.34 ± 0.81) hypersensitivity in sham animals (data shown as mean ± SD). Conversely, up-regulation of endogenous GABA via blockade of its uptake in DRG alleviates NPP.
  
  
  CONCLUSIONS
  The GABAA receptor in the DRG plays an important role in pathophysiology of NPP caused by sciatic nerve injury and represents promising target for novel pain therapies.
authors.affiliation: From the Departments of Anesthesiology (A.L.O., J.S., H.P.O., J.L.W., J.-Y.P., S.P., A.P., Y.L., M.M.J., S.M.T., V.J.-T.) and Neuroscience (S.M.T., V.J.-T.), University of Virginia Health System, Charlottesville, Virginia; Department of Physiology, University of Belgrade School of Pharmacy, Belgrade, Serbia (A.L.O.); Icahn Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (J.S.); Department of Anesthesiology and Pain Medicine, College of Medicine, Korea University, Seoul, Republic of Korea (J.-Y.P.); and Department of Anesthesiology and Pain Medicine, Sanggye Paik Hospital, College of Medicine, Inje University, Seoul, Republic of Korea (Y.L.).
authors.forename: Aleksandar L
authors.initials: AL
authors.lastname: Obradovic
authors.forename: Joseph
authors.initials: J
authors.lastname: Scarpa
authors.forename: Hari P
authors.initials: HP
authors.lastname: Osuru
authors.forename: Janelle L
authors.initials: JL
authors.lastname: Weaver
authors.forename: Ji-Yong
authors.initials: JY
authors.lastname: Park
authors.forename: Sriyani
authors.initials: S
authors.lastname: Pathirathna
authors.forename: Alexander
authors.initials: A
authors.lastname: Peterkin
authors.forename: Yunhee
authors.initials: Y
authors.lastname: Lim
authors.forename: Miljenko M
authors.initials: MM
authors.lastname: Jagodic
authors.forename: Slobodan M
authors.initials: SM
authors.lastname: Todorovic
authors.forename: Vesna
authors.initials: V
authors.lastname: Jevtovic-Todorovic
mesh_terms: D000818:Animals; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism*; D009437:Neuralgia / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D009557:Nipecotic Acids / Q000494:pharmacology; D010091:Oximes / Q000494:pharmacology; D010147:Pain Measurement / Q000379:methods; D059348:Peripheral Nerve Injuries / Q000150:complications / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D020426:Sciatic Neuropathy / Q000150:complications / Q000378:metabolism*
chemical_list: D018756:GABA Antagonists; C520011:Gabra2 protein, rat; D009557:Nipecotic Acids; D010091:Oximes; D011963:Receptors, GABA-A; C078793:NNC 711