Neurobiology of Substance P and the NK1 Receptor

Substance P belongs to a group of neurokinins (NKs), small peptides that are broadly distributedin the central nervous system (CNS) and peripheral nervous system (PNS). The biological effects ofsubstance P in the CNS, namely regulation of affective behavior and emesis in the brain andnociception 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 aminority 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 uponsubstance P binding, the NK₁ receptor undergoes rapid internalization, followed by rapid recycling tothe plasma membrane. Release of substance P is induced by stressful stimuli, and the magnitude of itsrelease is proportional to the intensity and frequency of stimulation. More potent and more frequentstimuli allow diffusion of substance P farther from the site of release, allowing activation of anapproximately 3- to 5-times greater number of NK₁ receptor-expressing neurons. Recent studies employingpharmacologic or genetic inactivation of NK₁ receptors demonstrate the important role of theSP-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.