Blockade of GABA _B receptors facilitates evoked neurotransmitter release at spinal dorsal horn synapse

Metabotropic GABA type B (GABA _B) receptors are abundantly expressed in the rat spinal dorsal horn. Activation of GABA _B receptors by exogenous agonists inhibits synaptic transmission, which is believed to underlie the GABA _B receptor-mediated analgesia. However, little effort has been made to test whether endogenous GABA might also mediate inhibition by acting on GABA _B receptors. In this study, whole-cell recording techniques were employed to study the effect of endogenous GABA on GABA _B receptors in substantia gelatinosa (SG) neurons in adult rat spinal cord slices. In current-clamp mode, blockade of GABA _B receptors by their selective antagonist 3-[[[(3,4-dichlorophenyl)methyl]amino]propyl] (diethoxy-methyl) phosphinic acid (CGP 52432) facilitated presynaptic stimulation-induced action potential discharge and increased amplitude of postsynaptic potentials (PSPs), meaning a GABA _B receptor-mediated inhibition of SG neuron excitability. In voltage-clamp mode, blockade of GABA _B receptors increased the amplitude of evoked excitatory postsynaptic currents (eEPSCs) and decreased paired-pulse ratio, indicating a presynaptic CGP 52432 action. Primary afferent Aδ or C fiber-evoked EPSCs were also facilitated by CGP 52432 application. Amplitudes of evoked GABAergic and glycinergic inhibitory postsynaptic currents (eIPSCs) were enhanced by GABA _B receptor blockade. The facilitation of amplitude persisted in the presence of a specific GABA transporter 1 (GAT-1) blocker, tiagabine, or GAT-2/3 blocker SNAP5114. However, blockade of GABA _B receptors had no effect on action potential-independent miniature EPSCs (mEPSCs), miniature IPSCs (mIPSCs), or membrane conductance. Taken together, these results suggest that endogenous GABA modulates evoked synaptic transmission in SG neurons by acting on GABA _B receptors. This GABA _B receptor-mediated homeostatic regulation of neuronal excitability and neurotransmitter release might contribute to modulation of nociception in spinal dorsal horn.