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Anesthesiology. 2015 Sep;123(3):654-67. doi: 10.1097/ALN.0000000000000767.

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.

Author information

1
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.).

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.

PMID:
26164299
PMCID:
PMC4568754
DOI:
10.1097/ALN.0000000000000767
[Indexed for MEDLINE]
Free PMC Article

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