Pharmacological enhancement of delta-subunit-containing GABA(A) receptors that generate a tonic inhibitory conductance in spinal neurons attenuates acute nociception in mice
Pharmacological enhancement of delta-subunit-containing GABA(A) receptors that generate a tonic inhibitory conductance in spinal neurons attenuates acute nociception in mice
(EN)
Bonin, R. P.
(EN)
Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών και Τεχνολογιών. Τμήμα Βιολογικών Εφαρμογών και Τεχνολογιών
(EL)
Bonin, R. P.
(EN)
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 (deltaGABA(A)Rs) in neurons of the spinal cord dorsal horn generate a tonic inhibitory conductance in vitro and whether deltaGABA(A)R activity regulates acute nociception. Whole-cell recordings revealed that deltaGABA(A)Rs generate a tonic inhibitory conductance in cultured spinal neurons and lamina II neurons in spinal cord slices. Increasing deltaGABA(A)R function by applying the deltaGABA(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 deltaGABA(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 deltaGABA(A)Rs in spinal neurons play a major physiological and pharmacological role in the regulation of acute nociception and central sensitization. Spinal delta-subunit-containing GABA(A) receptors were identified with electrophysiological methods and behavioral models as novel targets for the treatment of acute pain.
(EN)
