Substance P: A neuropeptide involved in the psychopathology of anxiety disorders

Substance P (SP) is the most widely distributed neuropeptide in central nervous system (CNS) where it participates in numerous physiological and pathophysiological processes including stress and anxiety related behaviors. In line with this notion, brain areas that are thought to be involved in anxiety regulation contains SP and its specific NK1 receptors. SP concentration in different brain regions alters with the exposure of stressful stimulus and affected NK1 receptor binding is observed. SP is released in response to a stressor, which produces anxiogenic effects via activation of hypothalamic-pituitary-adrenal (HPA) axis, resulting in the liberation of cortisol. Moreover, SP is also involved in the activation of the sympathetic nervous system via stimulation of locus coeruleus (LC). This sympathetic surge initiates cortisol discharge by activation of HPA axis, representing the indirect anxiogenic effect of SP. Besides the aforementioned regions, SP also has an impact on other brain regions known to be involved in stress and anxiety mechanisms, including amygdala, lateral septum (LS), periaqueductal gray (PAG), ventromedial nucleus of the hypothalamus (VMH), and bed nucleus of stria terminalis (BNST). Thus, SP acts as an important neuromodulator in various brain regions in stress and anxiety response. Consistent with the above statement, SP makes a robust link in the psychopathology of anxiety disorders. As SP concentration is found elevated in stressed conditions, several studies have reported that the pharmacological antagonism or genetic depletion of NK-1 receptors results in the anxiolytic response making them a suitable therapeutic target for the treatment of stress and anxiety related disorders.