Modulation of excitatory amino acid responses by tachykinins and selective tachykinin receptor agonists in the rat spinal cord.
1. The effects of tachykinins and agonists selective for the three subtypes of neurokinin (NK) receptor have been tested on spinal neuronal responses both to the excitatory amino acids (EAAs) NMDA, AMPA and kainate, and to noxious heat stimuli. The agonists were applied by microiontophoresis in in vivo experiments in alpha-chloralose-anaesthetized, spinalized rats. 2. The NK1-selective agonist, GR 73632, enhanced responses to all three EAAs similarly, whilst the NK2-selective agonist, GR64349, reduced responses to AMPA and kainate without affecting those to NMDA, and the NK3 selective agonist, senktide, enhanced responses to AMPA and kainate. 3. The endogenous ligands substance P (SP) and neurokinin A (NKA) both enhanced responses to NMDA with little effect on responses to kainate, whereas neurokinin B (NKB) selectively enhanced responses to kainate without affecting those to NMDA. 4. The effects of GR73632 on EAA responses showed some differences between the dorsal and ventral horn, with more selectivity towards enhancement of NMDA responses in the ventral horn, but a smaller maximum effect. 5. Background activity was significantly enhanced by GR73632, GR64349, SP and NKA but not by senktide or NKB. GR73632 had the greatest effect on background firing, but this action was variable between cells and was related both to the location within the spinal cord and to the degree of spontaneous activity prior to GR73632 administration. 6. Responses to noxious heat were enhanced consistently only by NKA. 7. These data show that selective agonists for the tachykinin receptors are capable of modulating EAA responses differentially. SP, NKA and NKB appear to act via more than one receptor type when modulating EAA responses in vivo. This indicates that NK-EAA interactions can be more specific than suggested hitherto, with the combined actions at NKI and NK2 receptors biasing EAA responsiveness towards NMDA receptor mediated functions, whereas NK3 receptor activation would have the opposite effect. The physiological role of such interactions is likely to be complex.
Cumberbatch
M J
MJ
Department of Physiology, University of Bristol, School of Medical Sciences.
Chizh
B A
BA
Headley
P M
PM
D000818:Animals; D004594:Electrophysiology; D018846:Excitatory Amino Acids / Q000378:metabolism*; D008297:Male; D016202:N-Methylaspartate / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D018040:Receptors, Neurokinin-1 / Q000145:classification / Q000187:drug effects*; D018039:Receptors, Tachykinin / Q000819:agonists* / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects*; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D015320:Tachykinins / Q000494:pharmacology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
D018846:Excitatory Amino Acids; D010446:Peptide Fragments; D018040:Receptors, Neurokinin-1; D018039:Receptors, Tachykinin; D015320:Tachykinins; C054724:senktide; C068032:GR 73632; D013373:Substance P; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid