MK-801 and phencyclidine act at phencyclidine sites that are not linked to N-methyl-D-aspartate activity to inhibit behavioral sensitization to kainate.
Sensitization to the behavioral effects of intrathecal kainate in mice depends on an accumulation of the N-terminus of substance P in the spinal cord and may reflect similar synaptic activity as that underlying pain transmission. The purpose of this study was to determine whether kainate sensitization, like pain, is sensitive to inhibition by phencyclidine ligands. Doses that selectively inhibit the behavioral response to a single injection of N-methyl-D-aspartate, but not kainate, were established for two non-competitive antagonists, dizocilpine (MK-801) and phencyclidine, as well as two competitive antagonists, D-amino-5-phosphonovaleric acid and (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, of N-methyl-D-aspartate. Using these doses, we found that 1 nmol of MK-801 or 3 nmol of phencyclidine blocked sensitization to four injections of 25 pmol of kainate administered at 2 min intervals. In contrast, 1.48 nmol of D-amino-5-phosphonovaleric acid and 0.5 nmol of (+/-)-3)2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid failed to alter sensitization to kainate, indicating that activation of N-methyl-D-aspartate receptors is not necessary for kainate sensitization. Haloperidol (1 nmol), a sigma receptor ligand, also failed to inhibit sensitization to kainate, suggesting that the actions of MK-801 and phencyclidine were not produced by a non-selective effect at sigma sites. Together, these data suggest that MK-801 and phencyclidine inhibit behavioral sensitization to kainate via phencyclidine receptors that are not linked to the N-methyl-D-aspartate receptor complex.(ABSTRACT TRUNCATED AT 250 WORDS)
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Department of Veterinary Pathobiology, University of Minnesota, St. Paul 55108.
Larson
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D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002211:Capsaicin / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology; D007608:Kainic Acid / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000502:physiology*; D009619:Nociceptors / Q000187:drug effects; D010622:Phencyclidine / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D017478:Receptors, Phencyclidine / Q000187:drug effects*; D017480:Receptors, sigma / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects
D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D017478:Receptors, Phencyclidine; D017480:Receptors, sigma; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D010622:Phencyclidine; D006220:Haloperidol; D002211:Capsaicin; D007608:Kainic Acid