Differential effects of calcitonin gene-related peptide and calcitonin gene-related peptide 8-37 upon responses to N-methyl-D-aspartate or (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate in spinal nociceptive neurons with knee joint input in the rat

Calcitonin gene-related peptide is involved in the spinal processing of noc iceptive input from the knee joint and in the generation and maintenance of joint inflammation-evoked hyperexcitability of spinal cord neurons. The pr esent study examined whether this peptide influences the excitation of noci ceptive spinal cord neurons by agonists at the N-methyl-D-aspartate and the non-N-methyl-D-aspartate [(R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4- propionate (AMPA)/kainate] receptors, both of which are essential for the e xcitation and hyperexcitability of spinal cord neurons. In anaesthetized ra ts extracellular recordings were made from dorsal horn neurons with knee in put, and compounds were administered ionophoretically close to the neurons recorded. When calcitonin gene-related peptide was administered the respons es of the neurons to the application of both N-methyl-D-aspartate and AMPA were increased. The coadministration of the antagonist calcitonin gene-rela ted peptide 8-37 had no effect on the responses to N-methyl-D-aspartate, bu t it prevented the enhancement of the responses to N-methyl-D-aspartate by calcitonin gene-related peptide. By contrast, the administration of calcito nin gene-related peptide 8-37 enhanced the responses of the neurons to AMPA , and it did not antagonize but rather increased the effects of calcitonin gene-related peptide on these responses. The data suggest that the facilitatory role of calcitonin gene-related pept ide on the development and maintenance of inflammation-evoked hyperexcitabi lity is caused at least in part by the modulation of the activation of the dorsal horn neurons through their N-methyl-D-aspartate and non-N-methyl-D-a spartate receptors. The different effects of calcitonin gene-related peptid e 8-37 on the respones to N-methyl-D-aspartate and AMPA suggest that differ ent intracellular pathways may facilitate the activation of N-methyl-D-aspa rtate and ionotropic non-N-methyl-D-aspartate receptors. (C) 2000 IBRO. Pub lished by Elsevier Science Ltd. All rights reserved.