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

In Jeong Jang,Seung Keun Back,Heung Sik Na,Yong Ho Kim,Alexander J. Davies,Hidemasa Furue,Nozomi Akimoto,Pa Reum Lee,Seog Bae Oh,Sung Jun Jung

doi:10.14814/phy2.13178

Abstract

Gamma‐aminobutyric acid (GABA) depolarizes dorsal root ganglia (DRG) primary afferent neurons through activation of Cl− permeable GABAA receptors but the physiologic role of GABAA receptors in the peripheral terminals of DRG neurons remains unclear. In this study, we investigated the role of peripheral GABAA receptors in nociception using a mouse model of acute inflammation. In vivo, peripheral administration of the selective GABAA 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. GABAA receptor‐mediated pain behavior after acute formalin treatment was abolished by the GABAA 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 GABAA 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 (10 μmol/L). Furthermore, potentiation of GABA responses by PGE 2 was prevented by the selective Nav1.8 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 GABAA receptor‐mediated nociceptive behavior after acute inflammation. Taken together, these results demonstrate that GABAA 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.

Highlights

Doral root ganglion (DRG) neurons are primary afferent neurons which conduct sensory information from the environment to the spinal cord
It has previously been demonstrated that co-application of a low dose (2 lmol/L, 30 lL) of the GABAA receptor agonist muscimol with formalin into the mouse hind paw reduced formalin-induced biphasic nocifensive behavior (Carlton et al 1999), a result consistent with the inhibition associated with primary afferent depolarization (PAD)
We found that peripheral GABAA receptor activation induces de novo pain behavior after formalin and prostaglandin E2 (PGE2) pre-conditioning through a signaling pathway involving E2 receptor 4 (EP4) receptor activation

Summary

Introduction

Doral root ganglion (DRG) neurons are primary afferent neurons which conduct sensory information from the environment to the spinal cord. A high dose of muscimol (1 mmol/L) was found to increase formalin-induced biphasic nocifensive behavior (Carlton et al 1999; BravoHernandez et al 2014), a phenomenon that was blocked by pre-treatment with the GABAA receptor antagonist bicuculline (Bravo-Hernandez et al 2014). These findings suggest that near-maximally activated GABAA receptors may participate in nociceptive sensory transduction in pathological conditions. The molecular mechanism(s) underlying the contribution of peripheral GABAA receptors to inflammatory pain remain unclear

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Conclusion