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 : 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. Conclusion: 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. Abstract : Nerve injury reduced the γ-aminobutyric acid (GABA) receptor type A α2 subunit expression in dorsal root ganglia (DRG). In vivo knockdown of the α2 subunit in the DRG enhanced nociception whereas pharmacologic prevention of GABA uptake reduced pain behavior. The results are consistent with the notion that modulation of GABAergic tone in the DRG may offer a novel therapeutic option for the treatment of neuropathic pain.