Tachykinin induced regulation of excitatory amino acid responses in the rat spinal cord in vitro.
The interaction between neurokinin and excitatory amino acid receptors in the spinal cord have been characterised using the neonatal rat spinal cord in vitro preparation. Ventral root (VR) depolarization evoked by N-methyl-D-aspartate (NMDA) and quisqualate was reversibly enhanced in the presence of subthreshold concentrations of neurokinin A (NKA; 1.0-10 nM), but not by substance P (1.0-5.0 nM). When substance P (SP) was replaced by the metabolically stable substance P methyl ester (SPOMe), both NMDA and quisqualate responses were significantly enhanced. VR depolarization evoked by kainate was not altered by any of the neurokinin (NK) receptor agonists. In the presence of the endopeptidase inhibitors, bestatin, captopril and thiorphan (each 1.0 microM), SP significantly enhanced NMDA-evoked responses. The selective NK1 receptor antagonist (+/-) CP96 345 (100 nM) reversibly blocked the enhancement of NMDA-evoked depolarization by SPOMe. Furthermore, MEN10 376 (50 nM), a selective NK2 receptor antagonist blocked the enhancement of NMDA- and quisqualate-evoked depolarization by NKA. The protein kinase C and protein kinase A inhibitor staurosporine (1.0 microM) blocked the enhancement of excitatory amino acid-induced responses by NK-receptor activation. However, whilst NKA-evoked ventral root depolarization was completely abolished in the presence of staurosporine, SPOMe- and SP-induced depolarizations were unaffected. These data show that activation of NK1 or NK2 receptors enhances NMDA- and quisqualate-evoked ventral root depolarization in the neonatal rat spinal cord. The interaction between neurokinin and excitatory amino acid receptors involves protein kinase C activation.
Urban
L
L
Department of Pharmacology, Sandoz Institute for Medical Research, London, UK.
Naeem
S
S
Patel
I A
IA
Dray
A
A
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001920:Bradykinin / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004347:Drug Interactions; D066298:In Vitro Techniques; D007700:Kinetics; D016202:N-Methylaspartate / Q000494:pharmacology*; D015288:Neurokinin A / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D016318:Quisqualic Acid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*; D019311:Staurosporine; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology*; D013997:Time Factors
D000470:Alkaloids; D011480:Protease Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D018040:Receptors, Neurokinin-1; D013373:Substance P; D016202:N-Methylaspartate; C033611:substance P, methyl ester-; D015288:Neurokinin A; D016318:Quisqualic Acid; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D019311:Staurosporine; D001920:Bradykinin