Acute inflammation reveals GABA_Areceptor-mediated nociception in mouse dorsal root ganglion neurons via PGE₂receptor 4 signaling

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.

Molecular mechanisms underlying the actions of arachidonic acid-derived prostaglandins on peripheral nociception

“…Jang and colleagues recently showed that PGE 2 potentiates GABA A -mediated Ca 2+ transients and membrane depolarization in nociceptive DRG neurons via EP4 activation [38]. This potentiation does not seem to be caused by directly altering GABA A activity or intracellular Cl − homeostasis, but by increasing Nav1.8 activity [38]. TTX-S in Aδ nociceptors also appears to be sensitized in an adenylyl cyclase-PKA dependent fashion, which awaits replication [130,131].…”

“…Moreover, Rush and colleagues have shown that PGE 2 enhances Nav1.9-specific Na + currents in Nav1.8-deficient DRG neurons [129]. Jang and colleagues recently showed that PGE 2 potentiates GABA A -mediated Ca 2+ transients and membrane depolarization in nociceptive DRG neurons via EP4 activation [38]. This potentiation does not seem to be caused by directly altering GABA A activity or intracellular Cl − homeostasis, but by increasing Nav1.8 activity [38].…”

“…Those authors suggest that nociceptive signals caused by Cl − currents could be augmented. However, a more recent study conducted by the Oh group demonstrated that Slc12a2 (which encodes NKCC1 protein)-null mice show no difference in the PGE 2 -induced potentiation of GABA A -mediated nociception compared with wild type mice [38]. It remains controversial whether DRG express KCC2 and which KCC subtypes are predominantly expressed [172][173][174][175][176][177].…”

Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop?

“…It is also noteworthy that this would appear to be contrary to the effects of systemic inflammation on the GABA system, leading to its activation, which is considered to be one source of apparently idiopathic chronic pain (Jang et al 2017). This may be a mechanism underpinning the presence of the chronic intractable pain reported by many CFS patients (Nijs et al 2012).…”

A New Method for Primary Culture of Mouse Dorsal Root Ganglion Neurons

“…Based on the previous studies [10][11][12][13], this scheme simplifies the cultivation process, aiming to cultivate a large number of high-purity nerve cells and providing a stable and convenient model for neuropathophysiology research.…”