Browsing School of Dentistry by Author "Zhu, Yi"
Switch of GABAA signaling with persistent inflammationZhu, Yi; Gold, Michael S., Ph.D. (2012)Following inflammation there is a switch in spinal GABAA signaling from inhibition to excitation such that GABA receptors contribute to inflammatory hyperalgesia. We hypothesized that this switch occurs in primary afferent neurons, as a result of a steady state and/or dynamic depolarizing shift in the reversal potential of GABAA currents (EGABA) which is coupled to an increase in high affinity extrasynaptic GABAA receptors. To test this hypothesis, back labeled, acutely dissociated cutaneous dorsal root ganglion (DRG) neurons from naïve and inflamed rats were studied with a variety of techniques including Ca2+ imaging and patch-clamp electrophysiology. With calcium imaging, GABAA receptor activation was shown to be inhibitory in neurons from naïve animal but was facilitatory or directly exciting in neurons from inflamed rats. Results from gramidicin perforated patch showed that a steady-state depolarizing shift in EGABA was not responsible for this shift in signaling. Rather, the shift appeared to be due to a combination of changes including an increase in GABAA current, a decrease in K+ current, and a depolarizing shift in resting membrane potential. The increase in GABAA current was associated with an increase in both high and low affinity currents which was due to a persistent increase in the relative activity of tyrosine kinase, resulting in part to a decrease in receptor internalization, rather than a change in subunit expression or protein. Dynamic regulation of EGABA was also observed in association with neural activity, but the shift in EGABA was hyperpolarizing, and likely to be due to the activation of a Cl- channel rather than a change in secondary ion transporter activity. Interestingly, inflammation was associated with a decrease in the activity dependent shift in EGABA. Our results indicate that the inflammation-induced switch in GABAA signaling is a complex process that involves the modulation of multiple channels and Cl- equilibrium potential and suggested different approaches to prevent the hyperalgesic effect of GABA.