Substance P and its transglutaminase-synthesized spermine derivative elicit yawning behavior via nitric oxide in rats

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.