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. (September 2015)

• Record Type: Journal Article
• Authors: Obradovic´, Aleksandar L.; Scarpa, Joseph; Osuru, Hari P.; Weaver, Janelle L.; Park, Ji-Yong; Pathirathna, Sriyani; Peterkin, Alexander; Lim, Yunhee; Jagodic, Miljenko M.; Todorovic, Slobodan M.; Jevtovic-Todorovic, Vesna
• Is Part Of: Anesthesiology. Volume 123:Number 3(2015)
• Publication Date: 2015-09
• Subjects: Anesthesiology -- Periodicals; Anesthetics -- Periodicals; Anesthesia -- Periodicals; 617.9605
• DOI: 10.1097/ALN.0000000000000767
• Languages: English
• ISSNs: 0003-3022

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background:</title> <p>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 <italic>in vivo</italic> silencing of the GABA receptor type A (GABA<sub>A</sub>) α<sub>2</sub> gene in dorsal root ganglia (DRG) controls NPP.</p> </sec> <sec> <title>Methods:</title> <p>After crush injury to the right sciatic nerve of female rats, the α<sub>2</sub> GABA<sub>A</sub> antisense and mismatch oligodeoxynucleotides or NO-711 (a GABA uptake inhibitor) were applied to the L5 DRG. <italic>In vivo</italic> behavioral assessment of nociception was conducted before the injury and ensuing 10 days (n = 4 to 10)<italic>. In vitro</italic> quantification of α<sub>2</sub> GABA<sub>A</sub> protein and electrophysiological studies of GABA<sub>A</sub> currents were performed on acutely dissociated L5 DRG neurons at relevant time points (n = 6 to 14).</p> </sec> <sec> <title>Results:</title> <p>NPP postcrush injury of a sciatic nerve in adult female rats coincides with significant down-regulation of the α<sub>2</sub> subunit expression in the ipsilateral DRG (approximately 30%). Selective down-regulation of α<sub>2</sub> 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 <italic>via</italic> blockade of its uptake in DRG alleviates NPP.</p> </sec> <sec> <title>Conclusion:</title> <p>The GABA<sub>A</sub> 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.</p> </sec> </abstract>