• Aleksandar L Obradovic, Joseph Scarpa, Hari P Osuru, Janelle L Weaver, Ji-Yong Park, Sriyani Pathirathna, Alexander Peterkin, Yunhee Lim, Miljenko M Jagodic, Slobodan M Todorovic, and Vesna Jevtovic-Todorovic.
• 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.).
• Anesthesiology. 2015 Sep 1; 123 (3): 654667654-67.

BackgroundNeuropathic 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.MethodsAfter 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).ResultsNPP 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.ConclusionThe 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.

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