Regulation of sigma activity by the amino-terminus of substance P in the mouse spinal cord: involvement of phencyclidine (PCP) sites not linked to N-methyl-D-aspartate (NMDA) activity.
Behavioral responses to kainic acid (KA) injected intrathecally in mice are enhanced by N-but not C-terminal fragments of substance P (SP). Repeated injections of KA result in sensitization to KA-induced activity, an effect that appears to be mediated by SP N-terminal activity and inhibited by PCP ligands. The present study was initiated to determine whether the ability of SP N-terminal fragments to enhance KA activity is also sensitive to PCP ligands. We compared the effect of a PCP ligand, dizocilpine (MK-801), to that of haloperidol, a sigma ligand and dopamine antagonist. MK-801 (1 nmol) failed to alter the enhancement of behavioral responses to KA (25 pmol) produced by SP(1-7) (22.5 pmol, 30 min). However, pretreatment with 1 nmol of either haloperidol or the N-terminal SP antagonist, [D-Pro2-D-Phe7]SP(1-7) [D-SP(1-7)], prevented potentiation of KA by SP(1-7). Like SP(1-7), 5 nmol of the sigma ligand 1,3-di(2-tolyl)guanidine (DTG) also enhanced behaviors elicited by KA, and this effect was also blocked by haloperidol or D-SP(1-7), but not spiperone (2.5 nmol), a dopamine antagonist. Together these data suggest that sigma receptors are involved in the potentiation of KA. A large dose of SP(1-7) (10 nmol) or DTG (20 nmol) did not alter the response to KA 24 hr later, yet further potentiated responses to KA 30 min after SP(1-7) (22.5 pmol) or DTG (5 nmol), suggesting sensitization to the effects of these compounds.(ABSTRACT TRUNCATED AT 250 WORDS)
Larson
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Department of Veterinary Pathobiology, University of Minnesota, St Paul 55108.
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D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004357:Drug Synergism; D006146:Guanidines / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D007278:Injections, Spinal; D007608:Kainic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D017478:Receptors, Phencyclidine / Q000037:antagonists & inhibitors / Q000187:drug effects*; D017480:Receptors, sigma / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects*; D013373:Substance P / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D006146:Guanidines; D010446:Peptide Fragments; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D017478:Receptors, Phencyclidine; D017480:Receptors, sigma; D013373:Substance P; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; C036877:substance P (1-7); C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D006220:Haloperidol; C050232:1,3-ditolylguanidine; D007608:Kainic Acid