Convergent control of synaptic GABA release from rat dorsal horn neurones by adenosine and GABA autoreceptors.

Perforated patch clamp recordings were performed on cultured superficial neonatal rat dorsal horn (DH) spinal cord neurones in order to study the presynaptic modulation of GABA release at unitary synaptic connections. Since ATP can be coreleased with GABA at about two-thirds of GABAergic synapses between DH neurones, and can be rapidly metabolized to adenosine in the extracellular space, we investigated the potential role of A1 adenosine receptors and GABAB receptors which might function as inhibitory autoreceptors. Adenosine and GABAB receptor agonists reduced the amplitude of electrically evoked GABAergic inhibitory postsynaptic currents (eIPSCs) as well as the frequency of GABAergic miniature IPSCs, suggesting a presynaptic action of these substances. The actions of adenosine were blocked by the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). The effects of adenosine and GABAB agonists were occlusive, indicating a functional convergence of the signalling pathways engaged by A1 and GABAB receptors. A1 and GABAB antagonists increased the amplitude of eIPSCs in a supra-additive manner, suggesting a tonic activation of these receptors by ambient adenosine and GABA. Moreover, using trains of electrical stimulations, we were able to unravel a phasic (activity-dependent) activation of presynaptic A1 and GABAB autoreceptors only in the case of neurones coreleasing ATP and GABA, despite the presence of functional presynaptic A1 and GABAB receptors on all GABAergic DH neurones. This selective, convergent and activity-dependent inhibition of GABA release by A1 and GABAB autoreceptors might modulate the integrative properties of postsynaptic DH neurones under physiological conditions and/or during the development of pathological pain states.