Presynaptic α2-GABA_A receptors in primary afferent depolarization and spinal pain control

Spinal dorsal horn GABA_A receptors are found both postsynaptically on central neurons and presynaptically on axons and/or terminals of primary sensory neurons, where they mediate primary afferent depolarization (PAD) and presynaptic inhibition. Both phenomena have been studied extensively on a cellular level, but their role in sensory processing in vivo has remained elusive, due to inherent difficulties to selectively interfere with presynaptic receptors. Here, we address the contribution of a major subpopulation of GABA_A receptors (those containing theα2 subunit) to spinal pain control in mice lackingα2-GABA_A receptors specifically in primary nociceptors (sns-α2^-/- mice). sns-α2^-/- mice exhibited GABA_A receptor currents and dorsal root potentials of normal amplitude in vitro, and normal response thresholds to thermal and mechanical stimulation in vivo, and developed normal inflammatory and neuropathic pain sensitization. However, the positive allosteric GABA_A receptor modulator diazepam (DZP) had almost completely lost its potentiating effect onPADand presynaptic inhibition in vitro and a major part of its spinal antihyperalgesic action against inflammatory hyperalgesia in vivo. Our results thus show that part of the antihyperalgesic action of spinally applied DZP occurs through facilitated activation of GABA_A receptors residing on primary nociceptors.