Biochemistry, Substance P


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]


(Click Image to Enlarge)
Substance P molecular structure
Substance P molecular structure
Wikipedia Commons titled "Skeletal formula of substance P." Created using ACD/ChemSketch 10.0 and Inkscape. by Author Fvasconcellos 22:22, 13 June 2007 (UTC), who released it on public domain.
Details

Author

Nader Rahimi

Author

Steven B. Graefe

Editor:

Shamim S. Mohiuddin

Updated:

7/30/2023 12:59:06 PM

Feedback:

Send Us Your Comments

References

[1]

Steinhoff MS, von Mentzer B, Geppetti P, Pothoulakis C, Bunnett NW. Tachykinins and their receptors: contributions to physiological control and the mechanisms of disease. Physiological reviews. 2014 Jan:94(1):265-301. doi: 10.1152/physrev.00031.2013. Epub     [PubMed PMID: 24382888]

[2]

O'Connor TM, O'Connell J, O'Brien DI, Goode T, Bredin CP, Shanahan F. The role of substance P in inflammatory disease. Journal of cellular physiology. 2004 Nov:201(2):167-80     [PubMed PMID: 15334652]

[3]

Gerard NP, Garraway LA, Eddy RL Jr, Shows TB, Iijima H, Paquet JL, Gerard C. Human substance P receptor (NK-1): organization of the gene, chromosome localization, and functional expression of cDNA clones. Biochemistry. 1991 Nov 5:30(44):10640-6     [PubMed PMID: 1657150]

[4]

Derocq JM, Ségui M, Blazy C, Emonds-Alt X, Le Fur G, Brelire JC, Casellas P. Effect of substance P on cytokine production by human astrocytic cells and blood mononuclear cells: characterization of novel tachykinin receptor antagonists. FEBS letters. 1996 Dec 16:399(3):321-5     [PubMed PMID: 8985172]

Level 3 (low-level) evidence

[5]

Mistrova E, Kruzliak P, Chottova Dvorakova M. Role of substance P in the cardiovascular system. Neuropeptides. 2016 Aug:58():41-51. doi: 10.1016/j.npep.2015.12.005. Epub 2015 Dec 8     [PubMed PMID: 26706184]

[6]

Fiebich BL, Schleicher S, Butcher RD, Craig A, Lieb K. The neuropeptide substance P activates p38 mitogen-activated protein kinase resulting in IL-6 expression independently from NF-kappa B. Journal of immunology (Baltimore, Md. : 1950). 2000 Nov 15:165(10):5606-11     [PubMed PMID: 11067916]

[7]

Guo CJ, Lai JP, Luo HM, Douglas SD, Ho WZ. Substance P up-regulates macrophage inflammatory protein-1beta expression in human T lymphocytes. Journal of neuroimmunology. 2002 Oct:131(1-2):160-7     [PubMed PMID: 12458047]

[8]

Koizumi H, Yasui C, Fukaya T, Ueda T, Ohkawara A. Substance P induces inositol 1,4,5-trisphosphate and intracellular free calcium increase in cultured normal human epidermal keratinocytes. Experimental dermatology. 1994 Feb:3(1):40-4     [PubMed PMID: 7520337]

[9]

Koon HW, Zhao D, Zhan Y, Simeonidis S, Moyer MP, Pothoulakis C. Substance P-stimulated interleukin-8 expression in human colonic epithelial cells involves protein kinase Cdelta activation. The Journal of pharmacology and experimental therapeutics. 2005 Sep:314(3):1393-400     [PubMed PMID: 15917399]

[10]

Lieb K, Fiebich BL, Berger M, Bauer J, Schulze-Osthoff K. The neuropeptide substance P activates transcription factor NF-kappa B and kappa B-dependent gene expression in human astrocytoma cells. Journal of immunology (Baltimore, Md. : 1950). 1997 Nov 15:159(10):4952-8     [PubMed PMID: 9366421]

[11]

Quinlan KL, Naik SM, Cannon G, Armstrong CA, Bunnett NW, Ansel JC, Caughman SW. Substance P activates coincident NF-AT- and NF-kappa B-dependent adhesion molecule gene expression in microvascular endothelial cells through intracellular calcium mobilization. Journal of immunology (Baltimore, Md. : 1950). 1999 Nov 15:163(10):5656-65     [PubMed PMID: 10553096]

[12]

Sun J, Ramnath RD, Zhi L, Tamizhselvi R, Bhatia M. Substance P enhances NF-kappaB transactivation and chemokine response in murine macrophages via ERK1/2 and p38 MAPK signaling pathways. American journal of physiology. Cell physiology. 2008 Jun:294(6):C1586-96. doi: 10.1152/ajpcell.00129.2008. Epub 2008 Apr 23     [PubMed PMID: 18434625]

[13]

McConalogue K, Corvera CU, Gamp PD, Grady EF, Bunnett NW. Desensitization of the neurokinin-1 receptor (NK1-R) in neurons: effects of substance P on the distribution of NK1-R, Galphaq/11, G-protein receptor kinase-2/3, and beta-arrestin-1/2. Molecular biology of the cell. 1998 Aug:9(8):2305-24     [PubMed PMID: 9693383]

[14]

Beinborn M, Blum A, Hang L, Setiawan T, Schroeder JC, Stoyanoff K, Leung J, Weinstock JV. TGF-beta regulates T-cell neurokinin-1 receptor internalization and function. Proceedings of the National Academy of Sciences of the United States of America. 2010 Mar 2:107(9):4293-8. doi: 10.1073/pnas.0905877107. Epub 2010 Feb 16     [PubMed PMID: 20160079]

[15]

Weinstock JV. Substance P and the regulation of inflammation in infections and inflammatory bowel disease. Acta physiologica (Oxford, England). 2015 Feb:213(2):453-61. doi: 10.1111/apha.12428. Epub 2015 Jan 1     [PubMed PMID: 25424746]

[16]

Weinstock JV, Blum A, Metwali A, Elliott D, Arsenescu R. IL-18 and IL-12 signal through the NF-kappa B pathway to induce NK-1R expression on T cells. Journal of immunology (Baltimore, Md. : 1950). 2003 May 15:170(10):5003-7     [PubMed PMID: 12734344]

[17]

Malcangio M, Bowery NG. Peptide autoreceptors: does an autoreceptor for substance P exist? Trends in pharmacological sciences. 1999 Oct:20(10):405-7     [PubMed PMID: 10577252]

[18]

Patacchini R, Maggi CA, Holzer P. Tachykinin autoreceptors in the gut. Trends in pharmacological sciences. 2000 May:21(5):166     [PubMed PMID: 10785646]

[19]

Nyberg F, Le Greves P, Sundqvist C, Terenius L. Characterization of substance P(1-7) and (1-8) generating enzyme in human cerebrospinal fluid. Biochemical and biophysical research communications. 1984 Nov 30:125(1):244-50     [PubMed PMID: 6210084]

[20]

Skidgel RA, Engelbrecht S, Johnson AR, Erdös EG. Hydrolysis of substance p and neurotensin by converting enzyme and neutral endopeptidase. Peptides. 1984 Jul-Aug:5(4):769-76     [PubMed PMID: 6208535]

[21]

Suvas S. Role of Substance P Neuropeptide in Inflammation, Wound Healing, and Tissue Homeostasis. Journal of immunology (Baltimore, Md. : 1950). 2017 Sep 1:199(5):1543-1552. doi: 10.4049/jimmunol.1601751. Epub     [PubMed PMID: 28827386]

[22]

Severini C, Improta G, Falconieri-Erspamer G, Salvadori S, Erspamer V. The tachykinin peptide family. Pharmacological reviews. 2002 Jun:54(2):285-322     [PubMed PMID: 12037144]

[23]

Nawa H, Hirose T, Takashima H, Inayama S, Nakanishi S. Nucleotide sequences of cloned cDNAs for two types of bovine brain substance P precursor. Nature. 1983 Nov 3-9:306(5938):32-6     [PubMed PMID: 6195531]

[24]

Carter MS, Krause JE. Structure, expression, and some regulatory mechanisms of the rat preprotachykinin gene encoding substance P, neurokinin A, neuropeptide K, and neuropeptide gamma. The Journal of neuroscience : the official journal of the Society for Neuroscience. 1990 Jul:10(7):2203-14     [PubMed PMID: 1695945]

[25]

Pennefather JN, Lecci A, Candenas ML, Patak E, Pinto FM, Maggi CA. Tachykinins and tachykinin receptors: a growing family. Life sciences. 2004 Feb 6:74(12):1445-63     [PubMed PMID: 14729395]

[26]

Page NM. Hemokinins and endokinins. Cellular and molecular life sciences : CMLS. 2004 Jul:61(13):1652-63     [PubMed PMID: 15224188]

[27]

Harmar A, Keen P. Synthesis, and central and peripheral axonal transport of substance P in a dorsal root ganglion-nerve preparation in vitro. Brain research. 1982 Jan 14:231(2):379-85     [PubMed PMID: 6173094]

[28]

McGregor GP, Bloom SR. Radioimmunoassay of substance P and its stability in tissue. Life sciences. 1983 Feb 7:32(6):655-62     [PubMed PMID: 6188020]

[29]

Christian C, Gilbert M, Payan DG. Stimulation of transcriptional regulatory activity by substance P. Neuroimmunomodulation. 1994 May-Jun:1(3):159-64     [PubMed PMID: 7489329]

[30]

Guard S, Watson SP. Tachykinin receptor types: Classification and membrane signalling mechanisms. Neurochemistry international. 1991:18(2):149-65     [PubMed PMID: 20504688]

[31]

Mantyh PW. Neurobiology of substance P and the NK1 receptor. The Journal of clinical psychiatry. 2002:63 Suppl 11():6-10     [PubMed PMID: 12562137]

[32]

Maggi CA. The mammalian tachykinin receptors. General pharmacology. 1995 Sep:26(5):911-44     [PubMed PMID: 7557266]

[33]

Conti F, De Biasi S, Giuffrida R, Rustioni A. Substance P-containing projections in the dorsal columns of rats and cats. Neuroscience. 1990:34(3):607-21     [PubMed PMID: 1693760]

[34]

Nishiyama K, Kwak S, Murayama S, Kanazawa I. Substance P is a possible neurotransmitter in the rat spinothalamic tract. Neuroscience research. 1995 Jan:21(3):261-6     [PubMed PMID: 7538653]

[35]

Dum RP, Levinthal DJ, Strick PL. The spinothalamic system targets motor and sensory areas in the cerebral cortex of monkeys. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2009 Nov 11:29(45):14223-35. doi: 10.1523/JNEUROSCI.3398-09.2009. Epub     [PubMed PMID: 19906970]

[36]

De Koninck Y, Henry JL. Substance P-mediated slow excitatory postsynaptic potential elicited in dorsal horn neurons in vivo by noxious stimulation. Proceedings of the National Academy of Sciences of the United States of America. 1991 Dec 15:88(24):11344-8     [PubMed PMID: 1722327]

[37]

Gouin O, L'Herondelle K, Lebonvallet N, Le Gall-Ianotto C, Sakka M, Buhé V, Plée-Gautier E, Carré JL, Lefeuvre L, Misery L, Le Garrec R. TRPV1 and TRPA1 in cutaneous neurogenic and chronic inflammation: pro-inflammatory response induced by their activation and their sensitization. Protein & cell. 2017 Sep:8(9):644-661. doi: 10.1007/s13238-017-0395-5. Epub 2017 Mar 31     [PubMed PMID: 28364279]

[38]

Herbert MK, Holzer P. [Neurogenic inflammation. I. Basic mechanisms, physiology and pharmacology]. Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie : AINS. 2002 Jun:37(6):314-25     [PubMed PMID: 12063584]

[39]

Choi JE, Di Nardo A. Skin neurogenic inflammation. Seminars in immunopathology. 2018 May:40(3):249-259. doi: 10.1007/s00281-018-0675-z. Epub 2018 Apr 30     [PubMed PMID: 29713744]

[40]

Ahluwalia A, De Felipe C, O'Brien J, Hunt SP, Perretti M. Impaired IL-1beta-induced neutrophil accumulation in tachykinin NK1 receptor knockout mice. British journal of pharmacology. 1998 Jul:124(6):1013-5     [PubMed PMID: 9720767]

[41]

Zhao D, Kuhnt-Moore S, Zeng H, Pan A, Wu JS, Simeonidis S, Moyer MP, Pothoulakis C. Substance P-stimulated interleukin-8 expression in human colonic epithelial cells involves Rho family small GTPases. The Biochemical journal. 2002 Dec 1:368(Pt 2):665-72     [PubMed PMID: 12169092]

[42]

Tran MT, Lausch RN, Oakes JE. Substance P differentially stimulates IL-8 synthesis in human corneal epithelial cells. Investigative ophthalmology & visual science. 2000 Nov:41(12):3871-7     [PubMed PMID: 11053288]

[43]

Castellani ML, Vecchiet J, Salini V, Conti P, Theoharides TC, Caraffa A, Antinolfi P, Teté S, Ciampoli C, Cuccurullo C, Cerulli G, Felaco M, Boscolo P. Stimulation of CCL2 (MCP-1) and CCL2 mRNA by substance P in LAD2 human mast cells. Translational research : the journal of laboratory and clinical medicine. 2009 Jul:154(1):27-33. doi: 10.1016/j.trsl.2009.03.006. Epub 2009 Apr 22     [PubMed PMID: 19524871]

[44]

Chernova I, Lai JP, Li H, Schwartz L, Tuluc F, Korchak HM, Douglas SD, Kilpatrick LE. Substance P (SP) enhances CCL5-induced chemotaxis and intracellular signaling in human monocytes, which express the truncated neurokinin-1 receptor (NK1R). Journal of leukocyte biology. 2009 Jan:85(1):154-64. doi: 10.1189/jlb.0408260. Epub 2008 Oct 3     [PubMed PMID: 18835883]

[45]

Okayama Y, Ono Y, Nakazawa T, Church MK, Mori M. Human skin mast cells produce TNF-alpha by substance P. International archives of allergy and immunology. 1998 Sep:117 Suppl 1():48-51     [PubMed PMID: 9758897]

[46]

Takashima A. Harnessing DCs by substance P. Blood. 2013 Apr 11:121(15):2815-6. doi: 10.1182/blood-2013-02-483354. Epub     [PubMed PMID: 23580632]

[47]

Janelsins BM, Sumpter TL, Tkacheva OA, Rojas-Canales DM, Erdos G, Mathers AR, Shufesky WJ, Storkus WJ, Falo LD Jr, Morelli AE, Larregina AT. Neurokinin-1 receptor agonists bias therapeutic dendritic cells to induce type 1 immunity by licensing host dendritic cells to produce IL-12. Blood. 2013 Apr 11:121(15):2923-33. doi: 10.1182/blood-2012-07-446054. Epub 2013 Jan 30     [PubMed PMID: 23365459]

[48]

Mathers AR, Tckacheva OA, Janelsins BM, Shufesky WJ, Morelli AE, Larregina AT. In vivo signaling through the neurokinin 1 receptor favors transgene expression by Langerhans cells and promotes the generation of Th1- and Tc1-biased immune responses. Journal of immunology (Baltimore, Md. : 1950). 2007 Jun 1:178(11):7006-17     [PubMed PMID: 17513750]

[49]

Matis WL, Lavker RM, Murphy GF. Substance P induces the expression of an endothelial-leukocyte adhesion molecule by microvascular endothelium. The Journal of investigative dermatology. 1990 Apr:94(4):492-5     [PubMed PMID: 1690249]

[50]

Maxwell DL, Fuller RW, Dixon CM, Cuss FM, Barnes PJ. Ventilatory effects of substance P, vasoactive intestinal peptide, and nitroprusside in humans. Journal of applied physiology (Bethesda, Md. : 1985). 1990 Jan:68(1):295-301     [PubMed PMID: 1690202]

[51]

Ustinova EE, Bergren D, Schultz HD. Neuropeptide depletion impairs postischemic recovery of the isolated rat heart: role of substance P. Cardiovascular research. 1995 Jul:30(1):55-63     [PubMed PMID: 7553724]

[52]

Zhang RL, Guo Z, Wang LL, Wu J. Degeneration of capsaicin sensitive sensory nerves enhances myocardial injury in acute myocardial infarction in rats. International journal of cardiology. 2012 Sep 20:160(1):41-7. doi: 10.1016/j.ijcard.2011.03.025. Epub 2011 Apr 6     [PubMed PMID: 21470700]

[53]

Dehlin HM, Levick SP. Substance P in heart failure: the good and the bad. International journal of cardiology. 2014 Jan 1:170(3):270-7. doi: 10.1016/j.ijcard.2013.11.010. Epub 2013 Nov 12     [PubMed PMID: 24286592]

[54]

Feickert M, Burckhardt BB. Substance P in cardiovascular diseases - A bioanalytical review. Clinica chimica acta; international journal of clinical chemistry. 2019 Aug:495():501-506. doi: 10.1016/j.cca.2019.05.014. Epub 2019 May 16     [PubMed PMID: 31103623]

[55]

Heaney LG, Cross LJ, Stanford CF, Ennis M. Substance P induces histamine release from human pulmonary mast cells. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 1995 Feb:25(2):179-86     [PubMed PMID: 7538443]

[56]

Harrison S, Geppetti P. Substance p. The international journal of biochemistry & cell biology. 2001 Jun:33(6):555-76     [PubMed PMID: 11378438]

[57]

Fuller RW, Maxwell DL, Dixon CM, McGregor GP, Barnes VF, Bloom SR, Barnes PJ. Effect of substance P on cardiovascular and respiratory function in subjects. Journal of applied physiology (Bethesda, Md. : 1985). 1987 Apr:62(4):1473-9     [PubMed PMID: 2439484]

[58]

Darmani NA, Wang Y, Abad J, Ray AP, Thrush GR, Ramirez J. Utilization of the least shrew as a rapid and selective screening model for the antiemetic potential and brain penetration of substance P and NK1 receptor antagonists. Brain research. 2008 Jun 12:1214():58-72. doi: 10.1016/j.brainres.2008.03.077. Epub 2008 Apr 9     [PubMed PMID: 18471804]

[59]

Ray AP, Chebolu S, Ramirez J, Darmani NA. Ablation of least shrew central neurokinin NK1 receptors reduces GR73632-induced vomiting. Behavioral neuroscience. 2009 Jun:123(3):701-6. doi: 10.1037/a0015733. Epub     [PubMed PMID: 19485577]

[60]

Li C, Micci MA, Murthy KS, Pasricha PJ. Substance P is essential for maintaining gut muscle contractility: a novel role for coneurotransmission revealed by botulinum toxin. American journal of physiology. Gastrointestinal and liver physiology. 2014 May 15:306(10):G839-48. doi: 10.1152/ajpgi.00436.2012. Epub 2014 Apr 3     [PubMed PMID: 24699329]

[61]

Foreman JC. Substance P and calcitonin gene-related peptide: effects on mast cells and in human skin. International archives of allergy and applied immunology. 1987:82(3-4):366-71     [PubMed PMID: 2437050]

[62]

Perlis RH, Purcell S, Fagerness J, Kirby A, Petryshen TL, Fan J, Sklar P. Family-based association study of lithium-related and other candidate genes in bipolar disorder. Archives of general psychiatry. 2008 Jan:65(1):53-61. doi: 10.1001/archgenpsychiatry.2007.15. Epub     [PubMed PMID: 18180429]

[63]

Chi G, Huang Z, Li X, Zhang K, Li G. Substance P Regulation in Epilepsy. Current neuropharmacology. 2018:16(1):43-50. doi: 10.2174/1570159X15666170504122410. Epub     [PubMed PMID: 28474564]

[64]

Severini C, Petrella C, Calissano P. Substance P and Alzheimer's Disease: Emerging Novel Roles. Current Alzheimer research. 2016:13(9):964-72     [PubMed PMID: 27033058]

[65]

Keating GM. Netupitant/Palonosetron: A Review in the Prevention of Chemotherapy-Induced Nausea and Vomiting. Drugs. 2015 Dec:75(18):2131-41. doi: 10.1007/s40265-015-0512-9. Epub     [PubMed PMID: 26613606]

[66]

He A, Alhariri JM, Sweren RJ, Kwatra MM, Kwatra SG. Aprepitant for the Treatment of Chronic Refractory Pruritus. BioMed research international. 2017:2017():4790810. doi: 10.1155/2017/4790810. Epub 2017 Sep 19     [PubMed PMID: 29057261]

[67]

Candelario N, Lu ML. Fosaprepitant dimeglumine for the management of chemotherapy-induced nausea and vomiting: patient selection and perspectives. Cancer management and research. 2016:8():77-82. doi: 10.2147/CMAR.S93620. Epub 2016 Jun 22     [PubMed PMID: 27382332]

Level 3 (low-level) evidence

[68]

Jordan K. Neurokinin-1-receptor antagonists: a new approach in antiemetic therapy. Onkologie. 2006 Feb:29(1-2):39-43     [PubMed PMID: 16514255]

[69]

Wang SY, Yang ZJ, Zhang Z, Zhang H. Aprepitant in the prevention of vomiting induced by moderately and highly emetogenic chemotherapy. Asian Pacific journal of cancer prevention : APJCP. 2014:15(23):10045-51     [PubMed PMID: 25556423]

[70]

Anand P, Bley K. Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. British journal of anaesthesia. 2011 Oct:107(4):490-502. doi: 10.1093/bja/aer260. Epub 2011 Aug 17     [PubMed PMID: 21852280]

[71]

Sharma SK, Vij AS, Sharma M. Mechanisms and clinical uses of capsaicin. European journal of pharmacology. 2013 Nov 15:720(1-3):55-62. doi: 10.1016/j.ejphar.2013.10.053. Epub 2013 Nov 5     [PubMed PMID: 24211679]

[72]

Roosterman D, Goerge T, Schneider SW, Bunnett NW, Steinhoff M. Neuronal control of skin function: the skin as a neuroimmunoendocrine organ. Physiological reviews. 2006 Oct:86(4):1309-79     [PubMed PMID: 17015491]

[73]

Burks TF, Buck SH, Miller MS. Mechanisms of depletion of substance P by capsaicin. Federation proceedings. 1985 Jun:44(9):2531-4     [PubMed PMID: 2581820]

[74]

Fernandes ES, Cerqueira AR, Soares AG, Costa SK. Capsaicin and Its Role in Chronic Diseases. Advances in experimental medicine and biology. 2016:929():91-125     [PubMed PMID: 27771922]

Level 3 (low-level) evidence

[75]

Derry S, Rice AS, Cole P, Tan T, Moore RA. Topical capsaicin (high concentration) for chronic neuropathic pain in adults. The Cochrane database of systematic reviews. 2017 Jan 13:1(1):CD007393. doi: 10.1002/14651858.CD007393.pub4. Epub 2017 Jan 13     [PubMed PMID: 28085183]

Level 1 (high-level) evidence