Role of GABA receptor subtypes in inhibition of primate spinothalamic tract 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 afferent fibers to spinal dorsal horn sensory cells, including spinothalamic tract (STT) neurons. The inhibition can be mediated by both GABA(A) and GABA(B) receptors. We now attempt to characterize the synaptic inhibition of STT cells by spinal GABA(A) and GABA(B) receptors in anesthetized monkeys and to analyze the roles of these two receptor subtypes in the inhibition of STT cellular activity produced by stimulation in the periaqueductal gray (FAG). 2. Iontophoretic release of GABA or muscimol (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 found to be inhibited when baclofen (a selective GABA(B) receptor agonist) was applied iontophoretically. However, a strong and dose-dependent inhibition of the responses to cutaneous mechanical and thermal stimuli was obtained in all cells examined when baclofen was administered into the dorsal horn through a microdialysis fiber. The inhibitory effects were mainly on nociceptive inputs. 3. The inhibition of cellular activity 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 application of GABA and muscimol, but not by baclofen. A high dose of baclofen administered by microdialysis resulted in only a small decrease in GLUT-evoked excitatory responses. 5. Infusion of GABA(A) and GABA(B) antagonists into the dorsal horn by microdialysis caused an increase in both background activity and responses to cutaneous stimuli, suggesting that there is a tonic GABAergic inhibition of STT cells. 6. The inhibition of responses to mechanical and thermal stimulation of the cutaneous excitatory receptive field resulting from stimulation in FAG was significantly antagonized in most of the STT cells tested when the GABA(A) antagonist bicuculline was infused into the spinal dorsal horn through a microdialysis fiber. In contrast, the inhibition produced by FAG stimulation in most of the cells examined was not significantly antagonized by the GABA(B) antagonists phaclofen or 3-amino-propyl(diethoxymethyl)phophinic acid (CGP35348) administered into the spinal dorsal horn by microdialysis. 7. Our results support the contention that GABAergic mechanisms in the spinal dorsal horn normally exert a tonic modulation of nociceptive inputs through both GABA(A) and GABA(B) receptors. The evidence provided here indicates that GABA(A) receptors located on primate STT neurons contribute to a postsynaptic inhibitory effect on the transmission of peripheral nociceptive inputs. A possible presynaptic GABA(A) action was not investigated. Our finding of a GABA(B)-receptor-mediated inhibition is consistent with the view that both pre- and postsynaptic GABA(B) receptors are involved in inhibitory modulation of spinal nociceptive transmission. Finally, it is suggested from this study that primate spinal GABA(A), but not GABA(B) receptors, are involved in mediating the descending inhibition induced by FAG stimulation.