Neurobiology of Substance P and the NK1 Receptor
J Clin Psychiatry 2002;63(suppl 11):6-10
© Copyright 2015 Physicians Postgraduate Press, Inc.
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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.