Introduction

Substance P (SP) is an 11-amino acid-long neuropeptide expressed by the central nervous system (CNS), the peripheral nervous system, and immune cells. SP is a member of the tachykinin (TAC) family of neuropeptides encoded by the TAC1 gene. SP elicits its activity via interacting with the G protein-coupled neurokinin receptors (NKRs), including NK1R, NK2R, and NK3R. NKRs are expressed on the surface of various cell types, including the blood vessels and lymphatics endothelial cells, immune cells, fibroblasts, and neurons.

Activation of NKRs stimulates inositol trisphosphate/diacylglycerol (IP3/DAG) and cyclic adenosine monophosphate (cAMP) second messenger in a cell context-dependent manner. Activation of NKRs mediates complex neuronal signaling pathways linked to sensations and emotional responses. Emerging evidence suggests that substance P plays other vital roles in inflammation, wound healing, and angiogenesis. Agents that inhibit substance P activity are currently being investigated as potential drugs for pain relief and other clinical conditions.

Fundamentals

The biological activity of substance P is mediated through NK receptors. The NK receptors belong to the G protein–coupled receptors (GPCRs). Activation of NK receptors stimulates inositol trisphosphate/diacylglycerol (IP3/DAG) and cyclic adenosine monophosphate (cAMP), leading to complex signaling events in a context-dependent manner. 

NK receptor activation involves phosphorylation of the C-terminal of the domain of the NK receptor by G protein–coupled receptor kinases, which results in the recruitment of with b-arrestin adapter to the NK receptor. β-Arrestin plays a key role in the desensitization of cells to SP signaling. 

Issues of Concern

Current strategies to target SP in human diseases such as gastrointestinal, respiratory inflammation, and other conditions are heavily concentrated upon blocking its high-affinity receptor NK1R via small peptide or non-peptide NK1R antagonists. However, none of the SP against have reached clinical use.  

Cellular Level

In mammals, there are three tachykinins (TAC) neuropeptides; substance P, neurokinin A (NKA), and neurokinin B (NKB). All TACs are derived from alternate spicing of TAC genes that are widely expressed throughout the nervous and immune systems. The biological function of SP is mediated through the binding of SP with the tachykinin receptors (NK1R, NK2R, NK3R).[1] NK receptors are a member of the seven-transmembrane, G protein-coupled receptors (GPCRs).

Substance P displays a greater affinity toward NK1R than NK2R and NK3R. Similar to GPCRs, NK receptors are composed of seven hydrophobic transmembrane domains, three extracellular (EL1, EL2, and EL3) domains, and three intracellular loops (C1, C2, and C3). The N-terminus tail of NK receptors faces the extracellular space, and the C-terminal faces the intracellular space. SP binds to loop C3, located in the second and third transmembrane domains of the NK receptors.[2][1][3]

SP-induced activation of NK receptors often produces different cellular responses. For example, in astrocytes, SP binding leads to the activation of phospholipase C, which stimulates IP3 and DAG levels, whereas, in smooth muscle cells, it stimulates cAMP.[4][5] These processes ultimately control the release of cytokines and regulate ion channel activity. Yet, activation of the same pathway in immune cells regulates the release of inflammatory cytokines.[6][7][8][9][10][11][12] 

Upon binding of SP to NKRs, the receptor rapidly undergoes internalization and subsequent degradation or recycling, which is mediated through the interaction of beta-arrestin with NKRs.[13] This recycling appears to be controlled by inflammatory and anti-inflammatory cytokines and, in certain conditions, by SP.[14][15][16][17][18] 

Unbound SP becomes hydrolyzed by peptidases, specifically by p-endopeptidase in the extracellular fluid and angiotensin-converting hormone (ACE) in the blood plasma.[19] SP 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.[20][21]

Molecular Level

Substance P belongs to a large family of structurally related neuropeptides and was the first member of the tachykinin family of peptides to be discovered; it is often referred to as a pioneering neuropeptide. They are also called tachykinins because of their ability to rapidly stimulate the contraction of intestinal muscle in contrast to the slower-acting bradykinins. Tachykinins are produced from the alternative processing of TAC genes and interact with three NK receptors. They possess a conserved carboxy-terminal sequence (-Phe-X-Gly-Leu-Met-NH2, X hydrophobic), which is required for their ability to interact and activate NK receptors.

The major human tachykinins are SP, neurokinin A (NKA), and neurokinin B (NKB), along with the NH2-terminally extended forms of NKA, such as neuropeptide K (NPK) and neuropeptide gamma. TAC1 gene encodes SP, NKA, NPK, and NP-gamma; TAC3 encodes NKB; and TAC4 encodes HK-1 and EKA, EKB, EKC, and EKD.[22][23][24][25][26][27]

SP is an amphiphilic molecule that appears to interact with the phospholipid bilayer of plasma membranes. However, research has found no cellular process is associated with its amphiphilic nature.[28] SP works primarily through interaction with its receptors.[4][8][29][30][31][32]

Function

Substance P is expressed throughout the nervous and immune systems; it regulates diverse physiological processes and has been implicated in various pathological conditions. 

Pain

The most studied role of SP is its role in 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. In the presynaptic axon terminal are vesicles containing SP and glutamate, which are released into the synaptic cleft of the dorsal horn. The hypothesis is that SP helps sensitize the postsynaptic neurons to glutamate, aiding in transmitting pain signals to the somatosensory area of the brain.[33][34][35][36]

Neurogenic Inflammation

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.[37] These neurosecretory products include SP 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.[38]

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.[39]

Immune Cells/Proliferation/Chemotaxis

SP also appears to contribute to the attraction of immune cells to the site of inflammation.[40][7][9] Research with NK1-R knockout mice showed impaired migration of neutrophils to the site of inflammation, showing the SP is involved in the response of neutrophils to IL-1bet and 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.[12][41][42][43][44][45] Additionally, research has shown SP to increase the expression of endothelial-leukocyte adhesion molecules (ELAM-1) on microvascular endothelial cells leading to the movement (diapedesis) of leukocytes.[46][47][48][49]

Cardiovascular

SP, along with its NK1R, is involved in regulating heart rate, blood pressure, ischemia, reperfusion, cardiac response to stress, and angiogenesis. SP is best known as a potent vasodilator.[5] The vasodilatory effects of SP 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 SP results in decreased blood pressure.[50]

SP 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 SP 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 SP and calcitonin gene-related peptide are involved in the reduction of reperfusion injury through the acute vasodilation of coronary arteries.[51][52][53] However, in the long term, SP also plays a role in cardiac remodeling and fibrosis by activating cardiac mast cells and upregulating endothelium-1 in cardiomyocytes.[54]

Respiratory

SP is implicated in the pathogenesis of asthma and chronic bronchitis. SP induces constriction of bronchial smooth muscle cells, which reduces the airway diameter and triggers mast cell degranulation in lung tissue.[55][56] Additionally, intravenous injection of SP leads to tachypnea in healthy individuals.[57]

Gastrointestinal

The gastrointestinal system also contains SP and NK1 receptors. A well-known function of SP is its role in the vomiting reflex. In the CNS 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 SP. Emetogenic chemotherapies such as cisplatin and other systemic chemotherapies cause the release of SP, which binds to NK1 receptors triggering emesis. NK1R antagonists, such as aprepitant and its pro-drug fosaprepitant, block SP from binding to the NK-1 receptor. This blockade prevents the signaling of the vomiting reflex, hopefully lessening the severity of chemotherapy-induced emesis.[58][59]

Additionally, enteric motor neurons of the GI tract release acetylcholine and SP onto smooth muscle, regulating gastric motility; it appears that SP increases the sensitivity of GI tract smooth muscle to acetylcholine, the major neurotransmitter for GI smooth muscle contractions.[60]

Integument

NK1 receptors are found on the surface of mast cells and contribute to the pathogenesis of eczema and psoriasis. Through neurogenic inflammation, SP is released from the sensory neurons of damaged tissue. SP 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, heat, swelling, pain, and loss of function.[61]

Mechanism

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, SP assists in transmitting pain signals to the central nervous system. In the gastrointestinal tract, SP helps potentiate smooth muscle contraction in response to acetylcholine and serotonin from post-synaptic neurons.[60]

In response to skin damage, SP and CGRP are products released from afferent nerve terminals involved in neurogenic inflammation. After its release, SP 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.[49][61]

Pathophysiology

Substance P has been implicated in the pathogenesis of several diseases.[62][63][64][54] These include the following:

• Emesis
• Fibromyalgia
• Eczema
• Psoriasis
• Depression
• Anxiety
• Heart failure
• Myocardial infarction
• Myocardial reperfusion injury
• Asthma
• Chronic bronchitis
• Inflammatory bowel diseases
• Migraine
• Osteoarthritis
• Rheumatoid arthritis
• Bipolar disorder
• Epilepsy
• Alzheimer disease
• Cardiomyopathies

Clinical Significance

While novel therapies involving substance P and NK-1R antagonists are currently undergoing clinical testing, the most significant clinical impact of SP research is as NK-1 receptor antagonists. NK-1 receptor antagonists were initially tested as antidepressants, but research revealed an antiemetic effect. 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 drugs are useful for preventing 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.[65]

These drugs are administered prophylactically before chemotherapy treatment to reduce nausea and vomiting. Aprepitant may be used for the treatment of chronic refractory pruritus.[66] Fosaprepitant, a prodrug of aprepitant, is converted by hepatic enzymes in the body into aprepitant, the biologically active molecule.[67][68] SP/NK1R antagonists are currently being researched as antidepressants, anxiolytics, and anti-inflammatory drugs.[69] 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 SP at the terminal and peripheral nerve endings of afferent nerves. Due to SP's role in pain transmission, capsaicin decreases the awareness of painful stimuli.[70][71][72] Capsaicin interferes with a molecule called nerve growth factor (NGF), which is necessary for the synthesis of SP. Capsaicin cream is used for pain relief, especially in arthritis, post-herpetic neuralgia, shingles, fibromyalgia, and peripheral diabetic neuropathy.[73][74][75]

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Disclosure: Steven Graefe declares no relevant financial relationships with ineligible companies.

Disclosure: Nader Rahimi declares no relevant financial relationships with ineligible companies.

Disclosure: Shamim Mohiuddin declares no relevant financial relationships with ineligible companies.