Silencing the alpha(2) Subunit of gamma-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 -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 (GABA(A)) (2) gene in dorsal root ganglia (DRG) controls NPP. Methods: After crush injury to the right sciatic nerve of female rats, the (2) GABA(A) 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 (2) GABA(A) protein and electrophysiological studies of GABA(A) 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 (2) subunit expression in the ipsilateral DRG (approximately 30%). Selective down-regulation of (2) 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 GABA(A) 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.