We evaluated the role of spinal glutamate and substance P receptors in noxious stimulus-induced antinociception (NSIA). NSIA was produced by subdermal capsaicin administration in the hind paw of the rat and measured as attenuation of the jaw-opening reflex. NSIA was completely blocked by spinal intrathecal administration of the selective NMDA receptor antagonist LY235959 as well as the mGluR(5) antagonists MPEP and SIB-1757 and partially attenuated by the selective AMPA/kainate receptor antagonist NBQX; however, neither the mGluR(1) receptor antagonist LY367385 nor the NK1 antagonist L-703,606 affected NSIA. These results suggest that NSIA depends on glutamate. released from the central terminals of the primary afferent nociceptors, acting primarily on NMDA and mGluR(5) receptors. Although substance P is also known to be released by similar stimuli, NK1 receptors do not appear to play a role in NSIA. The implications of these findings in the context of a proposed spinal circuit that mediates NSIA are discussed. (C) 2003 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.10641671173179