GABA receptors-mediated tonic inhibition of glutamate release from Aβ fibers in rat laminae III/IV of the spinal cord dorsal horn.

Presynaptic GABA receptors (GABARs) are highly expressed in dorsal root ganglion neurons and spinal cord dorsal horn. GABARs located in superficial dorsal horn play an important antinociceptive role, by acting at both pre- and postsynaptic sites. GABARs expressed in deep dorsal horn could be involved in the processing of touch sensation and possibly in the generation of tactile allodynia in chronic pain. The objective of this study was to characterize the morphological and functional properties of GABARs expressed on Aβ fibers projecting to lamina III/IV and to understand their role in modulating excitatory synaptic transmission. We performed high-resolution electron microscopic analysis, showing that GABA subunit is expressed on 71.9% of terminals in rat lamina III-IV. These terminals were engaged in axodendritic synapses and, for the 46%, also expressed glutamate immunoreactivity. Monosynaptic excitatory postsynaptic currents, evoked by Aβ fiber stimulation and recorded from lamina III/IV neurons in spinal cord slices, were strongly depressed by application of baclofen (0.1-2.5 µM), acting as a presynaptic modulator. Application of the GABAR antagonist CGP 55845 caused, in a subpopulation of neurons, the potentiation of the first of two excitatory postsynaptic currents recorded with the paired-pulse protocol, showing that GABARs are endogenously activated. A decrease in the paired-pulse ratio accompanied the effect of CGP 55845, implying the involvement of presynaptic GABARs. CGP 55845 facilitated only the first excitatory postsynaptic current also during a train of four consecutive stimuli applied to Aβ fibers. These results suggest that GABARs tonically inhibit glutamate release from Aβ fibers at a subset of synapses in deep dorsal horn. This modulation specifically affects only the early phase of synaptic excitation in lamina III-IV neurons.