Intrathecal administration of the excitatory amino acid (EAA) agonists, N-methyl-D-aspartate (NMDA), quisqualate (Quis) or kainic acid (KA), in the spinal subarachnoid space of mice produced a dose-related biting and scratching behavior. Higher doses appeared aversive, suggesting a nociceptive action for EAAs in the spinal cord. Intrathecally administered NMDA, but not Quis or KA, produced a hyperalgesic effect in the tail-flick and hot-plate tests. To test the hypothesis that EAA agonists are involved in transmission of nociceptive information in the spinal cord, we tested the effect of various opioid, sigma and phencyclidine compounds on the action of NMDA in the tail-flick, hot-plate and biting and scratching nociceptive tests. Our results indicated that the involvement of mu, sigma and phencyclidine receptors was predominant in blockade of the behavioral and hyperalgesic effects of intrathecally administered NMDA. Delta receptors appeared less involved, and involvement of kappa receptors was not detectable in blockade of the behavioral and hyperalgesic effects of intrathecally administered NMDA. Quis and KA effects were not altered by any of these agonists. Agonist doses required to inhibit NMDA-induced hyperalgesia in the tail-flick and hot-plate tests were significantly less than those needed to inhibit biting and scratching behavior. The adrenergic agonist norepinephrine inhibited NMDA- but not Quis- or KA-induced biting and scratching behavior. This action appeared to be alpha-1 mediated because it was reversed by phentolamine but not by yohimbine. These results suggest that the actions of EAAs in the spinal cord are differentially affected by various opioid phencyclidine, sigma and adrenergic receptor agonists and support the hypothesis that EAAs are involved in the transmission of nociceptive information in the spinal cord.