Modulation of P2X3 receptors by Mg2+ on rat DRG neurons in culture

On nociceptive neurons the commonest response to ATP is a rapidly desensitizing current mediated by P2X(3) receptors and believed to be involved in certain forms of pain. P2X(3) receptor recovery from desensitization is a slow process. We studied whether Mg2+ might modulate such ATP-evoked currents on rat cultured DRG neurons, and thus account for its analgesic action in vivo. Transient increases in extracellular Mg2+ strongly and reversibly depressed ATP currents which had not recovered from desensitization. Ca2+-free solution had the same action as Mg2+. High Mg2+ or Ca2+-free modulation depended on exposure length to modified divalent cation solutions, whereas it was independent from membrane potential or intracellular Ca2+ buffering. Paired-pulse protocols showed that high Mg2+ or Ca2+-free medium delayed ATP receptor recovery from desensitization, while leaving desensitization onset apparently unchanged. Tests with various concentrations of Ca2+ and Mg2+ showed that the depressant action by Mg2+ was primarily due to functional antagonism of a facilitatory effect of Ca2+ on ATP receptor function. The present results suggest that, on sensory neurons, P2X(3) receptors could be inhibited by high Mg2+ or lack of Ca2+, representing a negative feedback process to limit ATP-mediated nociception. (C) 2002 Elsevier Science Ltd. All rights reserved.