ROLE OF GABA RECEPTOR SUBTYPES IN INHIBITION OF PRIMATE SPINOTHALAMICTRACT NEURONS - DIFFERENCE BETWEEN SPINAL AND PERIAQUEDUCTAL GRAY INHIBITION

1. gamma-Aminobutyric acid (GABA) is thought to inhibit both pre- and postsynaptically the transfer of nociceptive signals from primary affe rent fibers to spinal dorsal horn sensory cells, including spinothalam ic tract (STT) neurons. The inhibition can be mediated by both GABA(A) and GABA(B) receptors. We now attempt to characterize the synaptic in hibition of STT cells by spinal GABA(A) and GABA(B) receptors in anest hetized monkeys and to analyze the roles of these two receptor subtype s in the inhibition of STT cellular activity produced by stimulation i n the periaqueductal gray (FAG). 2. Iontophoretic release of GABA or m uscimol (a selective GABA(A) receptor agonist) onto STT cells elicited a profound and dose-related inhibition of the responses of all cells tested to noxious cutaneous stimuli. Only four cells (16.7%) were foun d to be inhibited when baclofen (a selective GABA(B) receptor agonist) was applied iontophoretically. However, a strong and dose-dependent i nhibition of the responses to cutaneous mechanical and thermal stimuli was obtained in all cells examined when baclofen was administered int o the dorsal horn through a microdialysis fiber. The inhibitory effect s were mainly on nociceptive inputs. 3. The inhibition of cellular act ivity by GABA(A) and GABA(B) agonists could be selectively antagonized by specific antagonists applied through a microdialysis fiber. 4. The excitatory responses evoked by pulsed release of glutamic acid (GLUT) were also inhibited in a dose-related manner by iontophoretic applica tion of GABA and muscimol, but not by baclofen. A high dose of baclofe n administered by microdialysis resulted in only a small decrease in G LUT-evoked excitatory responses. 5. Infusion of GABA(A) and GABA(B) an tagonists into the dorsal horn by microdialysis caused an increase in both background activity and responses to cutaneous stimuli, suggestin g that there is a tonic GABAergic inhibition of STT cells. 6. The inhi bition of responses to mechanical and thermal stimulation of the cutan eous excitatory receptive field resulting from stimulation in FAG was significantly antagonized in most of the STT cells tested when the GAB A(A) antagonist bicuculline was infused into the spinal dorsal horn th rough a microdialysis fiber. In contrast, the inhibition produced by F AG stimulation in most of the cells examined was not significantly ant agonized by the GABA(B) antagonists phaclofen or 3-amino-propyl(dietho xymethyl)phophinic acid (CGP35348) administered into the spinal dorsal horn by microdialysis. 7. Our results support the contention that GAB Aergic mechanisms in the spinal dorsal horn normally exert a tonic mod ulation of nociceptive inputs through both GABA(A) and GABA(B) recepto rs. The evidence provided here indicates that GABA(A) receptors locate d on primate STT neurons contribute to a postsynaptic inhibitory effec t on the transmission of peripheral nociceptive inputs. A possible pre synaptic GABA(A) action was not investigated. Our finding of a GABA(B) -receptor-mediated inhibition is consistent with the view that both pr e- and postsynaptic GABA(B) receptors are involved in inhibitory modul ation of spinal nociceptive transmission. Finally, it is suggested fro m this study that primate spinal GABA(A), but not GABA(B) receptors, a re involved in mediating the descending inhibition induced by FAG stim ulation.