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In the field of neuroscience, substance P
(SP) is a neuropeptide: an undecapeptide that
functions as a neurotransmitter and as a neuromodulator.
It belongs to the tachykinin neuropeptide family. Substance P
and its closely related neuropeptide neurokinin A (NKA) are produced from a
polyprotein precursor after differential splicing of the
preprotachykinin A gene. The deduced amino acid sequence of
substance P is as follows:
- Arg Pro Lys Pro Gln Gln Phe Phe Gly Leu Met
Substance P is released from the terminals of specific sensory
nerves, it is found in the brain and spinal cord, and is associated
with inflammatory processes and pain.
Substance P was originally discovered in 1931 by Ulf von Euler and
John H. Gaddum as a tissue extract that
caused intestinal contraction in vitro.
Its tissue distribution and biologic actions were further
investigated over the following decades.
In 1983, NKA (previously known as substance K or neuromedin L) was
isolated from porcine spinal cord and was
also found to stimulate intestinal contraction.
The endogenous receptor for Substance P is neurokinin 1 receptor
It belongs to the tachykinin receptor sub-family of
Other neurokinin subtypes and neurokinin receptors that interact
with SP have also been reported. Amino acid residues that are
responsible for the binding of SP and its antagonists are present in the
extracellular loops and transmembrane regions of NK-1. Binding of
SP to NK-1 results in internalization by the clathrin-dependant mechanism to the acidified
endosomes where the
complex disassociates. SP is subsequently degraded and NK-1 is
re-expressed on the cell surface.
Substance P and the NK1 receptor are widely distributed in the
brain and are specifically found in brain regions that regulate
emotion (hypothalamus, amygdala, and the periaqueductal gray).
They are also found in close association with 5-hydroxytryptamine (5-HT) and neurons
containing norepinephrine that are targeted by the currently used
The SP receptor promoter contains regions that are sensitive to cAMP, AP-1,
and epidermal growth factor.
Because these regions are related to complexed signal
transduction pathways mediated by cytokines, it has been
proposed that cytokines and neurotropic factors can induce NK-1. SP
can also induce the cytokines that are capable of inducing NK-1
Substance P is an important element in pain perception. The
sensory function of substance P is thought to be related to the
transmission of pain information into the central nervous system.
Substance P coexists with the excitatory
neurotransmitter glutamate in primary afferents that respond
to painful stimulation.
SP has been associated with the regulation of mood disorders, anxiety, stress,
pain and nociception.
Substance P and other sensory neuropeptides can be released from
the peripheral terminals of sensory nerve fibers in the skin,
muscle and joints. It is proposed that this release is involved in
neurogenic inflammation which
is a local inflammatory response to certain types of infection or
The regulatory function of SP also involves the regulation of its
high-affinity receptor, NK-1. Substance P receptor antagonists may
have important therapeutic applications in the treatment of a
variety of stress-related illnesses, in addition to their potential
The vomiting center in
the brainstem contains
high concentrations of substance P and its receptor, in addition to
other neurotransmitters such as choline, histamine, dopamine, serotonin, and opioids. Their activation stimulates the
vomiting reflex. Different emetic pathways exist, and substance
P/NK1R appears to be within the final common pathway to regulate
Substance P antagonist (SPA) aprepitant is available in the market in the
treatment of chemotherapy-induced nausea / emesis.
Substance P is involved in nociception, transmitting information about
tissue damage from peripheral receptors to the central nervous system to be
converted to the sensation of pain. It has been theorized that it plays a part
Capsaicin has been shown
to reduce the levels of Substance P probably by reducing the number
of C-fibre nerves or causing these nerves to
be more tolerant. Thus, Capsaicin is clinically used as an
analgesic and anti-inflammatory agent to relieve pain associated
with arthritis and many types of neuralgia. A role of substance P
and NKA in nociception is suggested by the reduction in response
thresholds to noxious stimuli by central administration of NK1 and
NK2 agonists. Based on recent studies, it was
proposed that NK1, and possibly the NK2 receptor
antagonists could be developed as analgesic drugs. It has been
studied that the mice carrying a disruption of the gene encoding
SP/NKA, show severely reduced nociceptive pain responses when the
stimuli are moderate to intense. Pain behaviors induced by
mechanical, thermal and chemical stimulation of somatic and
visceral tissues were reduced in the mutant mice lacking SP/NKA.
However, it has been proposed that the importance of SP and NKA in
animal's pain response apply only to a certain 'window' of pain
intensities and when the intensity of the pain stimuli is further
increased, the responses of the knockout mice is not severely different from
the wild-type mice.
Substance P has been known to stimulate cell growth in
and it was shown that Substance P could promote wound healing of
non-healing ulcers in humans.
It has also been shown to reverse diabetes in mice.
Substance P also has effects as a potent vasodilator. Substance
P-induced vasodilatation is dependent on nitric oxide release.
Substance P is involved in the axon reflex-mediated vasodilatation
to local heating and wheal and
flare reaction. It has been shown that vasodilatation to substance
P is dependent on the NK1 receptor located on the endothelium. In
contrast to other neuropeptides studied in human skin, substance
P-induced vasodilatation has been found to decline during
continuous infusion. This possibly suggest an internalization of
As is typical with many vasodilators, it also has bronchoconstrictive properties, administered
through the non-adrenergic, non-cholinergic nervous system (branch
of the vagal system).
High levels of BDNF and Substance P have been found
associated with increased itching in eczema.
Entamoeba histolytica is a
single-celled parasitic protozoan that infects the lower
gastrointestinal tract of humans. The symptoms of infection are diarrhea, constipation, and abdominal
This protozoan was found to secrete serotonin as
well as substance P and neurotensin.
rats lack Substance P and do not feel pain when painful stimuli are administered to the
studies have shown that when the function of SP is genetically
disrupted in the mice, the animals demonstrated reduced responses
to painful stimuli. Moreover, the response to capsaicin was absent
or severely reduced in knockout mice.
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