Kazuhiko Okano (1), Yasushi Kuraishi (2) and Masamichi Satoh (1,*)
(1) Department of Molecular Pharmacology, Faculty of Pharmaceutical Sciences, Kyoto University, Kyoto 606-01, Japan
(2) Department of Applied Pharmacology, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Toyama 930-01, Japan
(*) To whom correspondence should be addressed.
Abstract: To reveal possible involvement of NK-1 substance P receptors and N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors in the production of inflammatory hyperalgesia, we examined the effects of intrathecal injections of antagonists at those receptors on the nociceptive threshold of inflammatory hyperalgesia rats in the paw-pressure test. Intrathecal injections of the NK-1 antagonist CP-96,345 (0.3 - 3 nmol/rat), the NMDA antagonist D-2-amino-5-phosphonovaleric acid (D-APV, 1 - 10 nmol/rat), and the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 1 - 10 nmol/rat) dose-dependently suppressed adjuvant- and carrageenin-induced hyperalgesia, without effect on the nociceptive threshold of non-inflamed paws. Furthermore, to estimate whether inflammatory hyperalgesia is accompanied with an alteration of the responsiveness to substance P and excitatory amino acids, we examined the effects of injections of complete Freund's adjuvant (intradermal) and carrageenin (subcutaneous) on the aversive responses to intrathecal substance P and excitatory amino acid agonists. Both injections significantly potentiated the aversive behaviors elicited by intrathecal injections of excitatory amino acid agonists, NMDA (1 nmol/rat), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA, I nmol/rat) and kainate (1 nmol/rat), but not those by substance P. The present results suggest that the enhancement of synaptic transmission mediated by substance P and excitatory amino acids in the spinal dorsal horn is at least partly involved in the production of inflammatory hyperalgesia, and that such a hyperalgesia is accompanied with the enhanced responsiveness to excitatory amino acids through MMDA and non-NMDA receptors, but not with changes in responsiveness to substance P.
Keywords: Substance P, Excitatory amino acid, Complete Freund's adjuvant, Carrageenin, Spinal cord