期刊
PAIN
卷 152, 期 6, 页码 1317-1326出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1016/j.pain.2011.02.011
关键词
Dorsal horn; GABA; Inhibition; Nociception; Sensitization
资金
- Canadian Institutes of Health Science [MOP-79428, MOP-21942]
The development of new strategies for the treatment of acute pain requires the identification of novel nonopioid receptor targets. This study explored whether delta-subunit-containing GABA(A)Rs (delta GABA(A)Rs) in neurons of the spinal cord dorsal horn generate a tonic inhibitory conductance in vitro and whether delta GABA(A)R activity regulates acute nociception. Whole-cell recordings revealed that delta GABA(A)Rs generate a tonic inhibitory conductance in cultured spinal neurons and lamina II neurons in spinal cord slices. Increasing delta GABA(A)R function by applying the delta GABA(A)R-preferring agonist 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridine- 3-ol (THIP) increased the tonic current and inhibited neuronal excitability in spinal neurons from wild-type (WT) but not delta subunit null-mutant (Gabrd (/) ) mice. In behavioral studies, baseline delta GABA(A)R activity did not regulate acute nociception; however, THIP administered intraperitoneally or intrathecally attenuated acute nociception in WT but not Gabrd (/) mice. In the formalin nociception assay, the phase 1 response was similar for WT and Gabrd (/) mice. In contrast, the phase 2 response, which models central sensitization, was greater in Gabrd (/) mice than WT. THIP administered intraperitoneally or intrathecally inhibited phase 1 responses of WT but not Gabrd (/) mice and had no effect on phase 2 responses of WT mice. Surprisingly, THIP reduced the enhanced phase 2 response in Gabrd (/) mice. Together, these results suggest that delta GABA(A)Rs in spinal neurons play a major physiological and pharmacological role in the regulation of acute nociception and central sensitization. (C) 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
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