Fig. 12.

Model of inflammation-induced changes in GABA_A receptor (GAR) signaling. A: at a cellular level, in the absence of inflammation (top), the relative level of tyrosine kinase activity is low. Consequently, turnover of GABA_A receptors is high, with many receptors internalized in clathrin-coated pits via a dynamin-dependent process. In the presence of inflammation (bottom), there is an increase in the relative level of tyrosine kinase activity and consequently an increase in the phosphorylation of GABA_A receptors. As this phosphorylation of receptors can mask an AP2 binding site, internalization of GABA_A receptors is decreased and current density is increased. Application of genistein reduces tyrosine kinase activity, resulting in a decrease in phosphorylation of GABA_A receptors, an increase in receptor internalization, and a decrease in current. The P4 peptide is designed to block the binding of dynamin to amphiphysin and thereby prevent endocytosis, attenuating the decrease in GABA_A current associated with genistein. B: GABA_A receptor activation in the spinal cord in normally inhibitory, where a presynaptic site of action is the primary target illustrated. In the presence of inflammation, there is an increase in both synaptic and extrasynaptic GABA_A receptors. However, to account for our previous observation (Anseloni and Gold 2008) as well as those of others (Knabl et al. 2008; Witschi et al. 2011) that benzodiazepines retain their analgesic efficacy in the presence of inflammation, we hypothesize that the pronociceptive actions of GABA are due to activity at extrasynaptic GABA_A receptors that are coupled to a relatively depolarized Cl⁻ equilibrium potential. These receptors are targeted by the low dose of muscimol used in the present study. A decrease in GABA_A current density via genistein eliminates the pronociceptive actions of muscimol, leaving only a residual antinociceptive activity as synaptic receptors.