Substance P is a neuropeptide made up of 11 amino acids—an undecapeptide—and is a part of the tachykinin neuropeptide family. Its receptor, neurokinin type 1 (NK-1R), is a transmembrane bound receptor on many cell types in the body including the endothelium of the blood vessels and lymphatics, white blood cells (WBCs), fibroblasts and neurons. Substance P's most well-known function is as a neurotransmitter and a modulator of pain perception by altering cellular signaling pathways. Additionally, substance P plays a role in gastrointestinal functioning, memory processing, angiogenesis, vasodilation, and cell growth and proliferation. Substance P works by altering cellular signaling pathways primarily through G-protein coupled receptors acting through both the IP3/DAG and cAMP second messenger systems, depending on the cell type.
Clinically, research into substance P has led to the development of antiemetic medications called NK-1R/substance P antagonists. These are primarily used to control chemotherapy-induced vomiting by preventing the binding of substance P to NK1 receptors in the area postrema--the area in the brain that controls emesis. Substance P is also a key molecule in the neurogenic inflammation response, a critical interaction between the nervous system and the immune system. Additionally, the function of substance P is involved in the pathogenesis of various diseases including but not limited to cancer, diabetes, rheumatoid arthritis, myocarditis, heart failure, epilepsy, migraine, thrombosis, pruritus, depression, and anxiety.
The NK-1 receptor—the receptor of substance P—is found on chromosome 2 in humans and is a cytoplasmic receptor (located on the cell’s surface). It contains seven hydrophobic transmembrane domains (spans across the cell membrane seven times) and has three extracellular (EL1, EL2, and EL3) and three intracellular loops (C1, C2, and C3). The amino tail is facing the extracellular space, and the carboxyl-terminal is facing the intracellular space. Between the second and third transmembrane domains of the NK-1 receptor, the binding site for substance P and NK-1 receptor agonists/antagonists is found. Notably, loop C3 contains the G protein system. The NK-1 receptor has different G protein subtypes in different cell types. For example, in astrocytes, substance P binding leads to G protein activation of phospholipase C, which increases IP3/DAG levels in the cell. In smooth muscle cells, when substance P binds to the NK1-R, this leads to an increase in cyclic adenosine monophosphate levels. These processes ultimately control the release of cytokines and regulate ion channel activity. For immune cells, the activation of this pathway regulates the release of inflammatory cytokines.
The G protein-coupled receptor and the bound substance P molecule are internalized, degraded through the beta-arrestin pathway, and are eventually recycled. This recycling appears to be controlled by inflammatory and anti-inflammatory cytokines but may be autoregulated by substance P in certain tissues. Unbound substance P becomes hydrolyzed by peptidases, specifically p-endopeptidase in the extracellular fluid and angiotensin-converting hormone (ACE) in the blood plasma. Substance P has a longer half-life in the plasma than in the tissues, lasting from seconds to minutes in the extracellular fluid of tissue cells to hours in the plasma.
Substance P is a neuropeptide in the tachykinin peptide family and contains 11 amino acids, H-Arg1-Pro2-Lys3-Pro4-Gln5-Gln6-Phe7-Phe8-Gly9-Leu10-Met11-NH2. It is encoded by the TAC1/PPT, a gene on chromosome 7 in humans. The TAC 1 gene also encodes neuropeptide K and neuropeptide-gamma, which are peptides that assist in normal sensation in the body. The TAC1 gene contains seven exons (coding regions) and six introns (non-coding regions) with four different mRNA variants due to alternative splicing. The coding sequence for substance P is on exon 3 and is included in all four variants of mRNA, so regardless of the mRNA variant, a substance P molecule can be translated. After the transcription of the mRNA molecule, the translation of substance P occurs by ribosomes.
Substance P is an amphiphilic molecule that appears to interact with the phospholipid bilayer of plasma membranes. However, research has found no cellular process linked to its amphiphilic nature. Substance P works primarily through neurokinin receptors (NK receptors), which are G protein-coupled receptors activating second messenger systems such as diacyl-glycerol (DAG), inositol triphosphate (IP3) and cyclic adenosine monophosphate (cAMP). Substance P can bind to NK-1, NK-2, NK-3 receptors but has a higher specificity for NK-1 receptors.
Substance P is involved in various processes throughout the body, including pain perception, immune cell proliferation, chemotaxis, inflammation, and plays a role in the cardiovascular, respiratory, and gastrointestinal systems.
Substance P's earliest and most document role is of pain perception. Free nerve endings (C-fibers) in the skin contain nociceptors and thermoreceptors that sense pain and temperature, respectively. The pain signal from the free nerve ending travels along small, unmyelinated axons to synapse in the spinal cord. Contained in the presynaptic axon terminal are vesicles containing substance P and glutamate, which are released into synaptic cleft of the dorsal horn. The hypothesis is that substance P helps sensitize the postsynaptic neurons to glutamate, aiding in the transmission of pain signals to the somatosensory area of the brain.
While pain signals travel along axons of the somatosensory area of the brain, sensory neurons also release neurosecretory products in the area of the damaged tissue. These neurosecretory products include substance P and calcitonin-gene-related peptide (CGRP). The release of these chemicals leads to the degranulation of mast cells, vasodilation through relaxation of vascular smooth muscle, and chemotaxis of immune system cells. These events collectively lead to a process called the wheel & flare response. This process is one of the ways the nervous system can direct the immune system to the site of damage/infection. This interaction between the immune system and the nervous system is termed neurogenic inflammation. Neurogenic inflammation is involved in the pathogenesis of many disease processes, including eczema, dermatitis, psoriasis, migraines, asthma, fibromyalgia, and rosacea.
Substance P also appears to contribute to the attraction of immune cells to the site of inflammation. Research with NK1-R knockout mice showed impaired migration of neutrophils to the site of inflammation, showing the substance P is involved in the response of neutrophils to IL-1beta. Substance P is also involved in the movement of immune cells through indirect mechanisms that induce cytokines that lead to the recruitment of macrophages and dendritic cells and helps stimulate the expression of interleukin-8 (IL-8), which is involved in neutrophil recruitment. Additionally, research has shown substance P to increase the expression of endothelial-leukocyte adhesion molecules (ELAM-1) on microvascular endothelial cells leading to the movement (diapedesis) of leukocytes.
Substance P and NK1-R are involved in the regulation of heart rate, blood pressure, ischemia, reperfusion, cardiac response to stress, and angiogenesis. Substance P is best known as a potent vasodilator. The vasodilatory effects of substance P are dependent on the nitric oxide production of endothelium cells, which leads to smooth muscle relaxation and, ultimately, the dilation of the blood vessel. As a result, intravenous administration of substance P results in decreased blood pressure.
Substance P and NK1 receptors are found in cardiac muscle and may factor into the pathogenesis of myocardial infarction, myocarditis, and reperfusion injury. Interestingly, in a study using a capsaicin-treated heart (a substance that depletes substance P and calcitonin gene-related peptide), acute infarction resulted in more irreversible injury to myocardial tissue than a non-capsaicin treated heart. Therefore, the hypothesis is that substance P and calcitonin gene-related peptide are involved in the reduction of reperfusion injury through the vasodilation of coronary arteries acutely. However, in the long term, substance P also plays a role in cardiac remodeling and fibrosis through the activation of cardiac mast cells and upregulation of endothelium-1 in cardiomyocytes.
Substance P is implicated in the pathogenesis of asthma and chronic bronchitis. Substance P induces constriction of bronchial smooth muscle cells, which reduces the airway diameter and triggers mast cell degranulation in lung tissue. Additionally, intravenous injection of substance P leads to tachypnea in healthy individuals.
The gastrointestinal system also contains substance P and NK1 receptors. A well-known function of substance P is its role in the vomiting reflex. In the CNS, there are areas in the medulla called the area postrema and the nucleus solitarius. These two areas control the vomiting reflex and contain high levels of substance P. Emetogenic chemotherapies such as cisplatin, and other systemic chemotherapies cause the release of substance P, which binds to NK1 receptors triggering emesis. NK1R antagonists, such as aprepitant and its pro-drug fosaprepitant, block substance P from binding to the NK-1 receptor. This blockade prevents the signaling of the vomiting reflex, hopefully lessening the severity of chemotherapy-induced emesis.
Additionally, enteric motor neurons of the GI tract release acetylcholine and substance P onto smooth muscle, regulating gastric motility. It appears that substance P increases the sensitivity of GI tract smooth muscle to acetylcholine, which is the major neurotransmitter for GI smooth muscle contractions.
NK1 receptors are found on the surface of mast cells and contribute to the pathogenesis of eczema and psoriasis. Through neurogenic inflammation, substance P is released from sensory neurons of damaged tissue. Substance P leads to the production of inflammatory cytokines and the degranulation of mast cells. The release of histamine from granules causes increased capillary permeability and edema. These events lead to the five cardinal signs of inflammation: redness (rubor), heat (calor), swelling (tumor), pain (dolor), and loss of function.
As previously described above, substance P works through a G protein-coupled receptor, either through the IP3/DAG pathway or the cAMP pathway depending on cell type. In the dorsal horn, substance P assists in the transmission of pain signals to the central nervous system. In the gastrointestinal tract, substance P assists in potentiating smooth muscle contraction in response to acetylcholine and serotonin from post-synaptic neurons. Additionally, in response to skin damage, substance P and CGRP are products released from afferent nerve terminals that are involved in neurogenic inflammation. After its release, substance P acts on the endothelium indirectly through mast cells by increasing its permeability (through the degranulation of mast cells) and directly upregulating cell adhesion molecules, assisting in cell chemotaxis and diapedesis.
While novel therapies involving substance P and NK-1R antagonists are currently undergoing clinical testing, the biggest clinical impact of Substance P research is as NK-1 receptor antagonists. NK-1 receptor antagonists were originally tested as antidepressants, but research revealed them to have antiemetic effects. Aprepitant and its prodrug fosaprepitant are NK-1 receptor antagonists used as antiemetic agents. Aprepitant is available by oral and intravenous (IV) administration and fosaprepitant are only available intravenously (IV). Both of these drugs are useful for the prevention of nausea and vomiting associated with chemotherapy agents. Netupitant, an NK-1 receptor antagonist only available by oral administration, is also used as an antiemetic agent and is combined with palonosetron. These drugs are administered prophylactically before chemotherapy treatment for the reduction of nausea and vomiting. Aprepitant may be used for the treatment of chronic refractory pruritus. Fosaprepitant, a prodrug of aprepitant, is converted by hepatic enzymes in the body into aprepitant, the biologically active molecule. Substance P/NK1R antagonists are currently being researched as antidepressants, anxiolytics, and anti-inflammatory drugs. These drugs are all moderate inhibitors of the CYP3A4 metabolic pathway, and dose reductions of certain drugs may be needed.
Capsaicin, a molecule found in chili peppers, has been shown to decrease the amount of substance P at the terminal and peripheral nerve endings of afferent nerves. Due to substance P's role in pain transmission, capsaicin decreases the awareness of painful stimuli. Capsaicin interferes with a molecule called nerve growth factor (NGF), which is necessary for the synthesis of substance P. Capsaicin cream is used for pain relief, especially in arthritis, post-herpetic neuralgia, shingles, fibromyalgia, and peripheral diabetic neuropathy.
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