Pharmacological Evidence for Involvement of Excitatory Amino Acids in Aversive Responses Induced by Intrathecal Substance P in Rats

Rats given an intrathecal injection of substance P (0.3-10 nmol) or any of the excitatory amino acid agonists, N-methyl-D-aspartate (NMDA, 1-10 nmol), kainate (1 and 3 nmol) or α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA, 0.3-3 nmol), showed biting or licking the hind paws, scratching with the hind paws (only after substance P) and vocalization (only after excitatory amino acid agonists). The intrathecal co-administration of the NMDA antagonist, 2-amino-5-phosphonovaleric acid (APV, 10 nmol), inhibited behavioral responses to NMDA (10 nmol) and substance P (10 nmol) but not to kainate (3 nmol). Co-administration of the non-NMDA antagonist, 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX, 10 nmol), suppressed responses to kainate (3 nmol), AMPA (3 nmol) and substance P (10 nmol) but not to NMDA (10 nmol). Co-administration of the substance P antagonist, CP-96, 345 (3 nmol), inhibited the behavioral responses to substance P (10 nmol), but not to NMDA (10 nmol), kainate (3 nmol) and AMPA (3 nmol). The results suggest that the aversive behavior induced by intrathecal NMDA and non-NMDA agonists is mediated by activation of the corresponding glutamate receptors, but not by NK-1 receptors, and that the behavioral action of intrathecal substance P is mediated not only by direct activation of NK-1 receptors but also indirectly by NMDA and non-NMDA receptors for glutamate.