Enhancement of GABAergic tonic currents by midazolam and noradrenaline in rat substantia gelatinosa neurons in vitro

Background: Substantia gelatinosa of the spinal dorsal horn is crucial for transmission and modification of noxious stimuli. Previous studies have demonstrated that intrathecal midazolam, a benzodiazepine agonist, enhanced perioperative analgesia. Not only synaptic but also extrasynaptic inhibitory currents contribute to modification of noxious stimuli. Thus, the effects of midazolam on extrasynaptic γ-aminobutyric acid (GABA) type A receptors in substantia gelatinosa neurons and interaction with noradrenaline, a transmitter of the descending inhibitory systems, were investigated. Methods: Using whole cell patch-clamp technique in the adult rat spinal cord slices, extrasynaptic GABAergic currents were recorded in substantia gelatinosa neurons in the presence of gabazine (1 μm), which blocked synaptic GABAergic currents, and then midazolam (5 μM) and noradrenaline (20 μM) were applied. Results: Bath application of midazolam induced tonic outward currents in the presence of gabazine. Although the decay time of synaptic current was prolonged, neither frequency nor amplitude was affected by midazolam. In contrast, the application of noradrenaline markedly increased both frequency and amplitude of synaptic currents with a slight enhancement of tonic currents. Coapplication of noradrenaline and midazolam markedly increased tonic currents, and the increase was much greater than the sum of currents induced by noradrenaline and midazolam. Conclusions: Midazolam had much larger effects on extrasynaptic GABA type A receptors than the synaptic receptors, suggesting a role of the enhancement of GABAergic extrasynaptic currents in the midazolam-induced analgesia. Because noradrenaline is shown to increase extrasynaptic GABA concentration, simultaneous administration of noradrenaline and midazolam may enhance the increased GABA action by midazolam, thereby resulting in an increase in tonic extrasynaptic currents.