The whole-cell patch-clamp technique was used to examine effects of mu-opioid receptor agonist Tyr-D-Ala-Gly-Me-Phe-Gly-ol-enkephalin (DAGO) on N-methyl-D-aspartate (NMDA)-induced currents in freshly enzymatically and/or mechanically dissociated rat spinal dorsal horn neurons (laminae I-III). Here we report that the responses of dorsal horn neurons to NMDA were modulated by DAGO in a complex manner. When applied simultaneously with, or prior to NMDA, DAGO (10-100 nM) initially suppressed the response to NMDA in 52% of examined cells. Following removal of DAGO, the NMDA responses were potentiated in 71% of the cells. The enhancing effect of DAGO was rapid in onset and lasted up to 50 min after removal of the peptide. Both the initial depressant and the late enhancing effect were reversed by naloxone. These results are consistent with the possibility that DAGO might directly modulate the NMDA receptor-ion channel complex and that this action may contribute to the regulation of the strength of excitatory amino acid-mediated primary afferent neurotransmission, including nociception.