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

Metabotropic GABA type B (GABAB) receptors are abundantly expressed in the rat spinal dorsal horn. Activation of GABAB receptors by exogenous agonists inhibits synaptic transmission, which is believed to underlie the GABAB receptor-mediated analgesia. However, little effort has been made to test whether endogenous GABA might also mediate inhibition by acting on GABAB receptors. In this study, whole-cell recording techniques were employed to study the effect of endogenous GABA on GABAB receptors in substantia gelatinosa (SG) neurons in adult rat spinal cord slices. In current-clamp mode, blockade of GABAB 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 GABAB receptor-mediated inhibition of SG neuron excitability. In voltage-clamp mode, blockade of GABAB 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 GABAB 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 GABAB 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 GABAB receptors. This GABAB receptor-mediated homeostatic regulation of neuronal excitability and neurotransmitter release might contribute to modulation of nociception in spinal dorsal horn.

▶Blockade of GABAB receptor facilitates evoked synaptic transmission. ▶Blockade of GABAB receptor has no effect on mEPSCs, mIPSCs or membrane conductance. ▶GABAB receptors mediate a homeostatic regulation of neuronal excitability.