ABSTRACT
Previously, we showed that intranigrostriatal injection of substance P (SP) cause behavioral changes in rats. Those effects, such as locomotion and food intake, resulted related to catecholamines release modulated by nitric oxide [18]. Here we report that intranigrostriatal injection of SP elicited yawning in rats. Moreover, since in previous studies we demonstrated that transglutaminase-synthesized gamma-(glutamyl5)spermine derivative of SP (Spm-SP) could be a useful tool in differentiating NK1 receptors [5,19,26], we reports the effects of injecting the selective septide-sensitive NK1 receptor agonist Spm-SP into the nigrostriatal region of the rat brain on yawning. The administration of L-N(omega)-nitroarginine methyl ester, a NO-synthase inhibitor, stereospecifically reduced in a dose related manner both SP and Spm-SP-induced yawning. In contrast, L-arginine pretreatment prevented the effect of NO-synthase inhibitor. Moreover, the NK1 antagonist RP,67580 blocked yawning behavior induced by both SP and Spm-SP, whereas the pretreatment with systemic reserpine determined its increase. The administration of NO-synthase inhibitor resulted ineffective in reducing SP and Spm-SP-induced yawns in reserpinized rats. Finally, yawns elicited by SP or Spm-SP were blocked when rats were treated with scopolamine but not with methylscopolamine. These results indicate that yawning induced in rats by SP injection is dependent upon endogenous dopamine levels in brain nigrostriatal area. Moreover, we demonstrate, by using Spm-SP, that septide-sensitive NK1 receptor are specifically involved in yawning behavior.
Subject(s)
Nitric Oxide/physiology , Receptors, Neurokinin-1/drug effects , Substance P/analogs & derivatives , Substance P/pharmacology , Substantia Nigra/drug effects , Yawning/drug effects , Animals , Arginine/analogs & derivatives , Arginine/pharmacology , Behavior, Animal/drug effects , Catheterization , Dose-Response Relationship, Drug , Drug Interactions , Indoles/pharmacology , Injections, Intraperitoneal , Isoindoles , Male , N-Methylscopolamine/pharmacology , NG-Nitroarginine Methyl Ester/pharmacology , Neurokinin-1 Receptor Antagonists , Nitric Oxide Synthase/antagonists & inhibitors , Rats , Receptors, Neurokinin-1/agonists , Scopolamine/pharmacology , Stereoisomerism , Structure-Activity Relationship , Substance P/administration & dosage , Substance P/chemical synthesis , Substantia Nigra/anatomy & histology , Time FactorsABSTRACT
The in vitro metabolism of transglutaminase-synthesized substance P analogs has been characterized comparing their stability to that of the parent peptide. The major metabolites have been purified and their structures elucidated by mass spectrometry. Our results demonstrated that gln5 spermidine and spermine analogs of substance P possess an enhanced resistance to the action of proteases. Moreover spermine, a large size hydrophilic compound, specifically prevented the hydrolysis at Phe7-Phe8 bond.