The roles of N-methyl-D-aspartate (NMDA) receptors and protein kinase C (PKC) are critical in generating and maintaining a variety of sustained neuronal responses. In the nociceptive (pain-sensing) system, tissue injury or repetitive stimulation of small-diameter afferent fibres triggers a dramatic increase in discharge (wind-up) or prolonged depolarization of spinal cord neurons. This central sensitization can neither be induced nor maintained when NMDA receptor channels are blocked1,2. In the trigeminal subnu-cleus caudalis (a centre for processing nociceptive information from the orofacial areas3), a μ-opioid receptor agonist causes a sustained increase in NMDA-activated currents by activating intracellular PKC4. There is also evidence that PKC enhances NMDA-receptor-mediated glutamate responses4-7 and regulates long-term potentiation of synaptic transmission8-14. Despite the importance of NMDA-receptors and PKC, the mechanism by which PKC alters the NMDA response has remained unclear. Here we examine the actions of intracellularly applied PKC on NMDA-activated currents in isolated trigeminal neurons. We find that PKC potentiates the NMDA response by increasing the probability of channel openings and by reducing the voltage-dependent Mg2+ block of NMDA-receptor channels.
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