Glutamate-mediated astrocyte-to-neuron signaling in the rat dorsal horn

By releasing neuroactive agents, including proinflammatory cytokines, prostaglandinsand neurotrophins, microglia and astrocytes are proposed to be involved in nociceptivetransmission, especially in conditions of persistent, pathological pain. The specificaction on dorsal horn neurons of agents released from astrocytes, such as glutamate, hasbeen, however, poorly investigated. By using patch-clamp and confocal microscopecalcium imaging techniques in rat spinal cord slices, we monitored the activity of dorsalhorn lamina II neurons following astrocyte activation. Results obtained revealed thatstimuli that triggered Ca2+ elevations in astrocytes, such as the purinergic receptoragonist BzATP and low extracellular Ca2+, induce in lamina II neurons slow inwardcurrents (SICs). Similarly to SICs triggered by astrocytic glutamate in neurons fromother central nervous system regions, these currents: i) are insensitive to TTX, ii) areblocked by the NMDA receptor antagonist D-AP5, iii) lack an AMPA component, andiv) have slow rise and decay times. Ca2+ imaging also revealed that astrocytic glutamateevokes NMDAR-mediated episodes of synchronous activity in groups of substantiagelatinosa neurons. Importantly, in a model of peripheral inflammation, thedevelopment of thermal hyperalgesia and mechanical allodynia was accompanied by a significant increase of spontaneous SICs in dorsal horn neurons. The NMDARmediatedastrocyte-to-neuron signaling thus represents a novel pathway that maycontribute to the control of central sensitization in pathological pai