Pharmacological characterization of N-methyl-D-aspartate receptors in spinal cord of rats with a chronic peripheral mononeuropathy.
N-Methyl-D-aspartate (NMDA) receptor antagonists, acting in the spinal cord, are analgesic. However, the clinical utility of these antagonists is diminished by their adverse effects on cognition and behavior. To facilitate the development of spinal cord-selective NMDA receptor antagonists, we characterized ligand interactions at NMDA receptors in spinal cord of normal rats and rats with a chronic peripheral neuropathy. NMDA receptors in spinal cord were distinguished from those in cerebral cortex on the basis of differences in the potencies of competitive and noncompetitive antagonists and on the basis of differences in their response to spermidine. D(-)-2-Amino-5-phosphonopentanoic acid (AP-5) and (+)-(1-hydroxy-3-aminopyrrolidine-2-one) (HA-966) were more potent in inhibiting NMDA-dependent [3H]TCP binding in spinal cord while, conversely, MK-801 was more potent in inhibiting [3H]TCP binding to NMDA receptors in cerebral cortex. Spermidine increased [3H]TCP binding to NMDA receptors in cerebral cortex (39+/-8%) but not spinal cord (2+/-1%). Based on these properties, NMDA receptors in spinal cord more closely resembled those in cerebellum than those in cerebral cortex. Generation of a chronic neuropathy had no effect on the density of NMDA receptors in lumbar spinal cord. There were also no major changes in the potencies of competitive antagonists or channel blocking ligands, although there was a trend for kynurenic acid and D-CPP to be more potent in the spinal cords of neuropathic animals. These findings indicate that, in both normal and neuropathic pain states, NMDA receptors in spinal cord can be distinguished pharmacologically from those in cerebral cortex. These findings underscore the feasibility of developing spinal cord-selective NMDA receptor antagonists as novel analgesics.
Wei
H B
HB
Department of Molecular Pharmacology, Institute of Pharmacology, Roche Bioscience, Palo Alto, CA 94304, USA.
Jakeman
L B
LB
Hunter
J C
JC
Bonhaus
D W
DW
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002908:Chronic Disease; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000494:pharmacology; D066298:In Vitro Techniques; D010523:Peripheral Nervous System Diseases / Q000473:pathology*; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D012044:Regression Analysis; D012584:Sciatic Nerve / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects*
D018691:Excitatory Amino Acid Antagonists; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; C012058:tenocyclidine; D010622:Phencyclidine; D005998:Glycine