Activity-dependent hyperpolarization of EGABA is absent in cutaneous DRG neurons from inflamed rats

- There is a persistent inflammation-induced shift in spinal GABAA signaling.
- There is evidence for activity-dependent depolarization of EGABA in CNS neurons.
- Our results indicate activity drives a hyperpolarization of EGABA in cutaneous DRG neurons.
- This shift is due to neither an increase in NKCC1 nor a decrease in HCO3−-Cl− exchanger activity.
- Persistent inflammation is associated with a loss of the activity-dependent hyperpolarization of EGABA.

A shift in GABAA signaling from inhibition to excitation in primary afferent neurons appears to contribute to the inflammation-induced increase in afferent input to the CNS. An activity-dependent depolarization of the GABAA current equilibrium potential (EGABA) has been described in CNS neurons which drives a shift in GABAA signaling from inhibition to excitation. The purpose of the present study was to determine if such an activity-dependent depolarization of EGABA occurs in primary afferents and whether the depolarization is amplified with persistent inflammation. Acutely dissociated retrogradely labeled cutaneous dorsal root ganglion (DRG) neurons from naïve and inflamed rats were studied with gramicidin perforated patch recording. Rather than a depolarization, 200 action potentials delivered at 2 Hz resulted in a ∼10 mV hyperpolarization of EGABA in cutaneous neurons from naïve rats. No such hyperpolarization was observed in neurons from inflamed rats. The shift in EGABA was not blocked by 10 μM bumetanide. Furthermore, because activity-dependent hyperpolarization of EGABA was fully manifest in the absence of HCO3− in the bath solution, this shift was not dependent on a change in HCO3−-Cl− exchanger activity, despite evidence of HCO3−-Cl− exchangers in DRG neurons that may contribute to the establishment of EGABA in the presence of HCO3−. While the mechanism underlying the activity-dependent hyperpolarization of EGABA has yet to be identified, because this mechanism appears to function as a form of feedback inhibition, facilitating GABA-mediated inhibition of afferent activity, it may serve as a novel target for the treatment of inflammatory pain.