AN ISOBOLOGRAPHIC ANALYSIS OF THE EFFECTS OF N-METHYL-D-ASPARTATE ANDNK1 TACHYKININ RECEPTOR ANTAGONISTS ON INFLAMMATORY HYPERALGESIA IN THE RAT

1 The interaction between N-methyl-D-aspartate (NMDA) and NK1 tachykin in receptors was analyzed isobolographically in rats with inflammatory hyperalgesia induced by intraplantar injection of complete Freund's a djuvant-saline emulsion (CFA, 100 mu g Mycobacterium tuberculosis). 2 Thermal hyperalgesia of the inflamed paw, determined by paw withdrawal response to a heat stimulus, was dose-dependently attenuated by intra thecal administration of an NMDA receptor antagonist, dextrorphan (2.5 -40 mu g, ED(50)=7.2 mu g), and two NK1 tachykinin receptor antagonist s, WIN 51,708 (0.01-200 mu g, ED(50)=10.4 mu g) or CP-96,345 (5-200 mu g, ED(50)=82.1 mu g). There was no effect of these agents on the noci ceptive threshold of the non-inflamed paw. CP-96,344, an enantiomer of CP-96,345 that is inactive as an NK, tachykinin receptor antagonist, slightly attenuated hyperalgesia at a dose of 200 mu g. 3 Combinations of dextrorphan and WIN 51,708 were administered at fixed ratios (10%: 90%; 41%:59%; 90%:10%). Isobolographic analysis revealed that the ED(5 0)s obtained from the three combination ratios were not significantly different from those that were expected from a simple additive effect. 4 Thus, an additive interaction was demonstrated between NMDA and NK1 tachykinin receptor systems at the spinal level. These results sugges t that both NMDA and NK1 tachykinin receptors are activated in respons e to peripheral inflammation, but that they may contribute independent ly to development of hyperalgesia.