A shift in GABA_A 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 GABA_A current equilibrium potential (E_GABA) has been described in CNS neurons which drives a shift in GABA_A signaling from inhibition to excitation. The purpose of the present study was to determine if such an activity-dependent depolarization of E_GABA 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 E_GABA in cutaneous neurons from naïve rats. No such hyperpolarization was observed in neurons from inflamed rats. The shift in E_GABA was not blocked by 10 μM bumetanide. Furthermore, because activity-dependent hyperpolarization of E_GABA 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 E_GABA in the presence of HCO₃⁻. While the mechanism underlying the activity-dependent hyperpolarization of E_GABA 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.