Endogenous modulation of excitatory amino acid responsiveness by tachykinin NK1 and NK2 receptors in the rat spinal cord.
1. The effects of selective tachykinin (neurokinin, NK) NK1 and NK2 receptor antagonists have been examined on spinal neurones in alpha-chloralose anaesthetized, spinalized rats. They were tested for effects on responses both to excitatory amino acids (EAA) and to noxious heat stimuli. They were also tested for their ability to reverse the actions of selective NK agonists. 2. The NK1-selective antagonists GR82334 (peptide) and CP-99,994 (non-peptide), when applied by microiontophoresis, both reduced responses to kainate > AMPA > NMDA. Intravenous CP-99,994 (3 mg kg-1) also reduced responses to kainate but had inconsistent effects on nociceptive responses. 3. GR82334, applied microiontophoretically, reduced the enhancement by the selective NK1 agonist, GR73632 of both responses to EAAs and background activity. Systemic CP-99,994 (< or = 10 mg kg-1) failed to reverse the effects of GR73632. 4. The selective peptide NK2 antagonist, GR103537, had no consistent effects on responses to EAAs when applied by iontophoresis. In contrast, the non-peptide NK2 antagonist, GR159897, administered systemically (0.5-2 mg kg-1, i.v.) enhanced responses to kainate (but not NMDA); responses to noxious heat were enhanced only weakly. 5. Iontophoretically-administered GR103537 attenuated the effects of the NK2 agonist GR64349, which selectively reduced responses to kainate compared to those to NMDA. Systemically administered GR159897 (< or = 2 mg kg-1, i.v.) caused little antagonism of the effects of GR64349. 6. The data indicate that under these conditions the non-peptide antagonists are not reliable at reversing the actions of selective NK agonists. 7. These results suggest that there is a tonic release of endogenous tachykinins that can modulate glutamatergic neurotransmission in the spinal cord. They provide further support for the hypothesis that release of endogenous NKs acting on NK1 and NK2 receptors can promote NMDA receptor mediated glutamatergic transmission.
Chizh
B A
BA
Department of Physiology, University of Bristol, School of Medical Sciences.
Cumberbatch
M J
MJ
Birch
P J
PJ
Headley
P M
PM
D000818:Animals; D004305:Dose-Response Relationship, Drug; D018846:Excitatory Amino Acids / Q000378:metabolism*; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010803:Physalaemin / Q000031:analogs & derivatives / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D018040:Receptors, Neurokinin-1 / Q000187:drug effects*; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors* / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism
D018846:Excitatory Amino Acids; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; C079014:GR 82334; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D010803:Physalaemin