The role of substance P in stress and anxiety responses

Amino Acids. 2006 Oct;31(3):251-72. doi: 10.1007/s00726-006-0335-9. Epub 2006 Jul 6.


Substance P (SP) is one of the most abundant peptides in the central nervous system and has been implicated in a variety of physiological and pathophysiological processes including stress regulation, as well as affective and anxiety-related behaviour. Consistent with these functions, SP and its preferred neurokinin 1 (NK1) receptor has been found within brain areas known to be involved in the regulation of stress and anxiety responses. Aversive and stressful stimuli have been shown repeatedly to change SP brain tissue content, as well as NK1 receptor binding. More recently it has been demonstrated that emotional stressors increase SP efflux in specific limbic structures such as amygdala and septum and that the magnitude of this effect depends on the severity of the stressor. Depending on the brain area, an increase in intracerebral SP concentration (mimicked by SP microinjection) produces mainly anxiogenic-like responses in various behavioural tasks. Based on findings that SP transmission is stimulated under stressful or anxiety-provoking situations it was hypothesised that blockade of NK1 receptors may attenuate stress responses and exert anxiolytic-like effects. Preclinical and clinical studies have found evidence in favour of such an assumption. The status of this research is reviewed here.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Anti-Anxiety Agents / pharmacology
  • Antidepressive Agents / pharmacology
  • Anxiety / drug therapy
  • Anxiety / metabolism
  • Anxiety / physiopathology*
  • Brain / drug effects
  • Brain / metabolism*
  • Depression / metabolism
  • Depression / physiopathology
  • Humans
  • Hypothalamo-Hypophyseal System / physiology
  • Mood Disorders / drug therapy
  • Neurokinin-1 Receptor Antagonists*
  • Pituitary-Adrenal System / physiology
  • Psychotropic Drugs / pharmacology
  • Receptors, Neurokinin-1 / metabolism*
  • Serotonin / metabolism
  • Stress, Physiological / metabolism
  • Stress, Physiological / physiopathology*
  • Substance P / metabolism
  • Substance P / physiology*
  • Synaptic Transmission / drug effects


  • Anti-Anxiety Agents
  • Antidepressive Agents
  • Neurokinin-1 Receptor Antagonists
  • Psychotropic Drugs
  • Receptors, Neurokinin-1
  • Serotonin
  • Substance P