Neurobiology of substance P and the NK1 receptor

J Clin Psychiatry. 2002;63 Suppl 11:6-10.


Substance P belongs to a group of neurokinins (NKs), small peptides that are broadly distributed in the central nervous system (CNS) and peripheral nervous system (PNS). The biological effects of substance P in the CNS, namely regulation of affective behavior and emesis in the brain and nociception in the spinal cord, are mediated by its binding to the NK1 receptor. The substance P-NK1 (SP-NK1) receptor system is the most extensively studied NK pathway, and in contrast to receptors for other neurotransmitters, such as glutamate, which have high expression throughout the CNS, only a minority of neurons (5% to 7%) in certain CNS areas express the NK1 receptor. The NK1 receptor is distributed in the plasma membrane of cell bodies and dendrites of unstimulated neurons, but upon substance P binding, the NK1 receptor undergoes rapid internalization, followed by rapid recycling to the plasma membrane. Release of substance P is induced by stressful stimuli, and the magnitude of its release is proportional to the intensity and frequency of stimulation. More potent and more frequent stimuli allow diffusion of substance P farther from the site of release, allowing activation of an approximately 3- to 5-times greater number of NK1 receptor-expressing neurons. Recent studies employing pharmacologic or genetic inactivation of NK1 receptors demonstrate the important role of the SP-NK1 receptor system in the regulation of affective behavior and suggest that inhibition of this pathway may be a useful approach to treatment of depression and associated anxiety.

Publication types

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

MeSH terms

  • Affect / drug effects
  • Affect / physiology
  • Animals
  • Antidepressive Agents / pharmacology
  • Anxiety Disorders / drug therapy
  • Anxiety Disorders / physiopathology
  • Brain / cytology
  • Brain / physiology
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cells, Cultured
  • Depressive Disorder / drug therapy
  • Depressive Disorder / physiopathology
  • Humans
  • Immunotoxins / immunology
  • Immunotoxins / pharmacology
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / physiology*
  • Mice
  • Models, Animal
  • Rats
  • Receptors, Immunologic / drug effects
  • Receptors, Immunologic / immunology
  • Receptors, Immunologic / physiology*
  • Receptors, Neurokinin-1 / drug effects
  • Receptors, Neurokinin-1 / immunology*
  • Receptors, Neurokinin-1 / physiology
  • Ribosome Inactivating Proteins, Type 1
  • Saporins
  • Spinal Cord / cytology
  • Spinal Cord / physiology
  • Substance P / analogs & derivatives
  • Substance P / drug effects
  • Substance P / immunology
  • Substance P / pharmacology
  • Substance P / physiology*


  • Antidepressive Agents
  • Immunotoxins
  • Receptors, Immunologic
  • Receptors, Neurokinin-1
  • Ribosome Inactivating Proteins, Type 1
  • substance P-saporin
  • Substance P
  • Saporins