Acute inflammation reveals GABA_A receptor-mediated nociception in mouse dorsal root ganglion neurons via PGE₂ receptor 4 signaling

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 (PGE₂) 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 PGE₂ 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 (10 μmol/L). Furthermore, potentiation of GABA responses by PGE₂ was prevented by the selective Na_v1.8 antagonist A887826 (100 nmol/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 PGE₂-EP4 signaling and Na⁺ channel sensitization.