Acute inflammation reveals GABA(A) receptor-mediated nociception in mouse dorsal root ganglion neurons via PGE(2) receptor 4 signaling

Abstract

Gamma-aminobutyric acid (GABA) depolarizes dorsal root ganglia (DRG) primary afferent neurons through activation of Cl- permeable GABA(A) receptors but the physiologic role of GABA(A) receptors in the peripheral terminals of DRG neurons remains unclear. In this study, we investigated the role of peripheral GABA(A) receptors in nociception using a mouse model of acute inflammation. In vivo, peripheral administration of the selective GABA(A) receptor agonist muscimol evoked spontaneous licking behavior, as well as spinal wide dynamic range (WDR) neuron firing, after pre-conditioning with formalin but had no effect in saline-treated mice. GABA(A) receptor-mediated pain behavior after acute formalin treatment was abolished by the GABA(A) receptor blocker picrotoxin and cyclooxygenase inhibitor indomethacin. In addition, treatment with prostaglandin E2 (PGE(2)) was sufficient to reveal muscimol-induced licking behavior. In vitro, GABA induced sub-threshold depolarization in DRG neurons through GABA(A) receptor activation. Both formalin and PGE(2) potentiated GABA-induced Ca2+ transients and membrane depolarization in capsaicin-sensitive nociceptive DRG neurons; these effects were blocked by the prostaglandin E2 receptor 4 (EP4) antagonist AH23848 (10mol/L). Furthermore, potentiation of GABA responses by PGE(2) was prevented by the selective Na(v)1.8 antagonist A887826 (100nmol/L). Although the function of the Na+-K+-2Cl(-) co-transporter NKCC1 was required to maintain the Cl- ion gradient in isolated DRG neurons, NKCC1 was not required for GABA(A) receptor-mediated nociceptive behavior after acute inflammation. Taken together, these results demonstrate that GABA(A) receptors may contribute to the excitation of peripheral sensory neurons in inflammation through a combined effect involving PGE(2)-EP4 signaling and Na+ channel sensitization.