Substance P Explained

tachykinin, precursor 1
Caption:Spacefilling model of substance P
Width:180
Hgncid:11517
Symbol:TAC1
Altsymbols:TAC2, NKNA
Entrezgene:6863
Omim:162320
Refseq:NM_003182
Uniprot:P20366
Chromosome:7
Arm:q
Band:21
Locussupplementarydata:-q22

Substance P (SP) is an undecapeptide (a peptide composed of a chain of 11 amino acid residues)[1] and a type of neuropeptide, belonging to the tachykinin family of neuropeptides. It acts as a neurotransmitter and a neuromodulator.[2] [3] Substance P and the closely related neurokinin A (NKA) are produced from a polyprotein precursor after alternative splicing of the preprotachykinin A gene. The deduced amino acid sequence of substance P is as follows:[4]

with an amide group at the C-terminus.[5] 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.

Discovery

The original discovery of Substance P (SP) was in 1931 by Ulf von Euler and John H. Gaddum as a tissue extract that caused intestinal contraction in vitro.[6] Its tissue distribution and biologic actions were further investigated over the following decades.[2] The eleven-amino-acid structure of the peptide was determined by Chang, et. al in 1971.[7]

In 1983, Neurokinin A (previously known as substance K or neuromedin L) was isolated from porcine spinal cord and was also found to stimulate intestinal contraction.[8]

Receptor

The endogenous receptor for substance P is neurokinin 1 receptor (NK1-receptor, NK1R).[9] It belongs to the tachykinin receptor sub-family of GPCRs.[10] Other neurokinin subtypes and neurokinin receptors that interact with SP have been reported as well. 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-1R results in internalization by the clathrin-dependent mechanism to the acidified endosomes where the complex disassociates. Subsequently, SP is degraded and NK-1R is re-expressed on the cell surface.[11]

Substance P and the NK1-receptor are widely distributed in the brain and are found in brain regions that are specific to regulating emotion (hypothalamus, amygdala, and the periaqueductal gray).[12] They are found in close association with serotonin (5-HT) and neurons containing norepinephrine that are targeted by the currently used antidepressant drugs.[13] The SP receptor promoter contains regions that are sensitive to cAMP, AP-1, AP-4, CEBPB,[14] 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. Also, SP can induce the cytokines that are capable of inducing NK-1 transcription factors.[15]

Function

Overview

Substance P ("P" standing for "Preparation" or "Powder") is a neuropeptide – but only nominally so, as it is ubiquitous. Its receptor – the neurokinin type 1 – is distributed over cytoplasmic membranes of many cell types (neurons, glia, endothelia of capillaries and lymphatics, fibroblasts, stem cells, white blood cells) in many tissues and organs. SP amplifies or excites most cellular processes.[16] [17]

Substance P is a key first responder to most noxious/extreme stimuli (stressors), i.e., those with a potential to compromise an organism's biological integrity. SP is thus regarded as an immediate defense, stress, repair, survival system. The molecule, which is rapidly inactivated (or at times further activated by peptidases) is rapidly released – repetitively and chronically, as warranted, in the presence of a stressor. Unique among biological processes, SP release (and expression of its NK1 Receptor (through autocrine, paracrine, and endocrine-like processes)) may not naturally subside in diseases marked by chronic inflammation (including cancer). The SP or its NK1R, as well as similar neuropeptides, appear to be vital targets capable of satisfying many unmet medical needs. The failure of clinical proof of concept studies, designed to confirm various preclinical predictions of efficacy, is currently a source of frustration and confusion among biomedical researchers.

Vasodilation

Substance P is a potent vasodilator. Substance P-induced vasodilation is dependent on nitric oxide release.[18] Substance P is involved in the axon reflex-mediated vasodilation to local heating and wheal and flare reaction. It has been shown that vasodilation 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 vasodilation has been found to decline during continuous infusion. This possibly suggests an internalization of neurokinin-1 (NK1).[19] 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).

Inflammation

SP initiates expression of almost all known immunological chemical messengers (cytokines).[20] [21] [22] Also, most of the cytokines, in turn, induce SP and the NK1 receptor.[23] [24] SP is particularly excitatory to cell growth and multiplication,[25] via usual,[26] as well as oncogenic drivers.[27] SP is a trigger for nausea and emesis.[28] 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 injury.[29]

Pain

Preclinical data support the notion that 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.[30] 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 injury.[29] Unfortunately, the reasons why NK1 receptor antagonists have failed as efficacious analgesics in well-conducted clinical proof of concept studies have not yet been persuasively elucidated.

Mood, anxiety, learning

Substance P has been associated with the regulation of mood disorders, anxiety, stress,[31] reinforcement,[32] neurogenesis,[33] synaptic growth and dendritic arborisation,[34] respiratory rhythm,[35] neurotoxicity, pain, and nociception.[36] In 2014, it was found that substance P played a role in male fruit fly aggression.[37] Recently, it has been shown that substance P may play a critical role in long-term potentiation of aversive stimuli.[38]

Vomiting

The vomiting center in the medulla, called the area postrema, contains high concentrations of substance P and its receptor, in addition to other neurotransmitters such as choline, histamine, dopamine, serotonin, and endogenous 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 vomiting.[39]

Cell growth, proliferation, angiogenesis, and migration

The above processes are part and parcel to tissue integrity and repair. Substance P has been known to stimulate cell growth in normal and cancer cell line cultures,[40] and it was shown that substance P could promote wound healing of non-healing ulcers in humans.[41] SP and its induced cytokines promote multiplication of cells required for repair or replacement, growth of new blood vessels,[42] and "leg-like pods" on cells (including cancer cells) bestowing upon them mobility,[43] and metastasis.[44] It has been suggested that cancer exploits the SP-NK1R to progress and metastasize, and that NK1RAs may be useful in the treatment of several cancer types.[45] [46] [47] [48]

Clinical significance

Quantification in disease

Elevation of serum, plasma, or tissue SP and/or its receptor (NK1R) has been associated with many diseases: sickle cell crisis;[49] inflammatory bowel disease;[50] [51] major depression and related disorders;[52] [53] [54] fibromyalgia;[55] rheumatological;[56] and infections such as HIV/AIDS and respiratory syncytial virus,[57] as well as in cancer.[58] [59] When assayed in the human, the observed variability of the SP concentrations are large, and in some cases the assay methodology is questionable.[60] SP concentrations cannot yet be used to diagnose disease clinically or gauge disease severity. It is not yet known whether changes in concentration of SP or density of its receptors is the cause of any given disease, or an effect.

Blockade for diseases with a chronic immunological component

As increasingly documented, the SP-NK1R system induces or modulates many aspects of the immune response, including WBC production and activation, and cytokine expression,[61] Reciprocally, cytokines may induce expression of SP and its NK1R.[62] [63] In this sense, for diseases in which a pro-inflammatory component has been identified or strongly suspected, and for which current treatments are absent or in need of improvement, abrogation of the SP-NK1 system continues to receive focus as a treatment strategy. Currently, the only completely developed method available in that regard is antagonism (blockade, inhibition) of the SP preferring receptor, i.e., by drugs known as neurokinin type 1 antagonists (also termed: SP antagonists, or tachykinin antagonists.) One such drug is aprepitant to prevent the nausea and vomiting that accompanies chemotherapy, typically for cancer. With the exception of chemotherapy-induced nausea and vomiting, the patho-physiological basis of many of the disease groups listed below, for which NK1RAs have been studied as a therapeutic intervention, are to varying extents hypothesized to be initiated or advanced by a chronic non-homeostatic inflammatory response.[17] [64] [65] [66]

Dermatological disorders: eczema/psoriasis, chronic pruritus

High levels of BDNF and substance P have been found associated with increased itching in eczema.[67] [68]

Infections: HIV-AIDS, measles, RSV, others

The role of SP in HIV-AIDS has been well-documented.[61] Doses of aprepitant greater than those tested to date are required for demonstration of full efficacy. Respiratory syncytial and related viruses appear to upregulate SP receptors, and rat studies suggest that NK1RAs may be useful in treating or limiting long term sequelae from such infections.[69] [70]

Entamoeba histolytica is a unicellular parasitic protozoan that infects the lower gastrointestinal tract of humans. The symptoms of infection are diarrhea, constipation, and abdominal pain.[71] [72] This protozoan was found to secrete serotonin[73] as well as substance P and neurotensin.[74]

Inflammatory bowel disease (IBD)/cystitis

Despite strong preclinical rationale,[75] efforts to demonstrate efficacy of SP antagonists in inflammatory disease have been unproductive. A study in women with IBS confirmed that an NK1RAs antagonist was anxiolytic.[76]

Chemotherapy induced nausea and vomiting

In line with its role as a first line defense system, SP is released when toxicants or poisons come into contact with a range of receptors on cellular elements in the chemoreceptor trigger zone, located in the floor of the fourth ventricle of the brain (area postrema). Presumably, SP is released in or around the nucleus of the solitary tract upon integrated activity of dopamine, serotonin, opioid, and/or acetylcholine receptor signaling. NK1Rs are stimulated. In turn, a fairly complex reflex is triggered involving cranial nerves responsible for respiration, retroperistalsis, and general autonomic discharge. The actions of aprepitant are said to be entirely central, thus requiring passage of the drug into the central nervous system.[77] However, given that NK1Rs are unprotected by a blood brain barrier in the area postrema just adjacent to neuronal structures in the medulla, and the activity of sendide (the peptide based NK1RA) against cisplatin-induced emesis in the ferret,[78] it is likely that some peripheral exposure contributes to antiemetic effects, even if through vagal terminals in the clinical setting.

Other findings

Denervation supersensitivity

When the innervation to substance P nerve terminals is lost, post-synaptic cells compensate for the loss of adequate neurotransmitter by increasing the expression of post-synaptic receptors. This, ultimately, leads to a condition known as denervation supersensitivity as the post-synaptic nerves will become hypersensitive to any release of substance P into the synaptic cleft.

Aggression

Tachykinin / Substance P plays an evolutionarily conserved role in inducing aggressive behaviors.[79] In rodents and cats, activation of hypothalamic neurons which release Substance P induces aggressive behaviors (defensive biting and predatory attack).[80] [81] [82] Similarly, in fruit flies, tachykinin-releasing neurons have been implicated in aggressive behaviors (lunging).[83] [84] In this context, male-specific tachykinin neurons control lunging behaviors that can be modulated by the amount of tachykinin release.[85]

External links

Notes and References

  1. Web site: Undecapeptide Definition & Meaning . . 17 November 2022.
  2. Harrison S, Geppetti P . Substance p . The International Journal of Biochemistry & Cell Biology . 33 . 6 . 555–76 . Jun 2001 . 11378438 . 10.1016/S1357-2725(01)00031-0 .
  3. Datar P, Srivastava S, Coutinho E, Govil G . Substance P: structure, function, and therapeutics . Current Topics in Medicinal Chemistry . 4 . 1 . 75–103 . 2004 . 14754378 . 10.2174/1568026043451636 . 2008-11-01 . 2009-08-17 . https://web.archive.org/web/20090817115536/http://www.bentham-direct.org/pages/content.php?CTMC%2F2004%2F00000004%2F00000001%2F0009R.SGM . dead . subscription .
  4. Book: Reece . Jane B. . Campbell . Neil A. . Biology, 7th Edition . 2005 . 57368924 . Pearson, Benjamin Cummings . San Francisco . 9780805371468.
  5. Wong M, Jeng AY . Posttranslational modification of glycine-extended substance P by an alpha-amidating enzyme in cultured sensory neurons of dorsal root ganglia . Journal of Neuroscience Research . 37 . 1 . 97–102 . Jan 1994 . 7511706 . 10.1002/jnr.490370113 . 31252390 .
  6. V Euler US, Gaddum JH . An unidentified depressor substance in certain tissue extracts . The Journal of Physiology . 72 . 1 . 74–87 . June 1931 . 16994201 . 1403098 . 10.1113/jphysiol.1931.sp002763 .
  7. Chang MM, Leeman SE, Niall HD . Amino-acid sequence of substance P . Nature . 232 . 29 . 86–87 . July 1971 . 5285346 . 10.1038/newbio232086a0 .
  8. Panula P, Hadjiconstantinou M, Yang HY, Costa E . Immunohistochemical localization of bombesin/gastrin-releasing peptide and substance P in primary sensory neurons . The Journal of Neuroscience . 3 . 10 . 2021–9 . Oct 1983 . 6194276 . 6564571 . 10.1523/JNEUROSCI.03-10-02021.1983 .
  9. Gerard NP, Garraway LA, Eddy RL, 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 . 30 . 44 . 10640–6 . Nov 1991 . 1657150 . 10.1021/bi00108a006 .
  10. Maggi CA . The mammalian tachykinin receptors . General Pharmacology . 26 . 5 . 911–44 . Sep 1995 . 7557266 . 10.1016/0306-3623(94)00292-U .
  11. Grady EF, Garland AM, Gamp PD, Lovett M, Payan DG, Bunnett NW . Delineation of the endocytic pathway of substance P and its seven-transmembrane domain NK1 receptor . Molecular Biology of the Cell . 6 . 5 . 509–24 . May 1995 . 7545030 . 301212 . 10.1091/mbc.6.5.509 .
  12. Yip J, Chahl LA . Localization of NK1 and NK3 receptors in guinea-pig brain . Regulatory Peptides . 98 . 1–2 . 55–62 . Apr 2001 . 11179779 . 10.1016/S0167-0115(00)00228-7 . 33205594 .
  13. Gabriella Gobbi . Gobbi G, Cassano T, Radja F, Morgese MG, Cuomo V, Santarelli L, Hen R, Blier P . Neurokinin 1 receptor antagonism requires norepinephrine to increase serotonin function . European Neuropsychopharmacology . 17 . 5 . 328–38 . Apr 2007 . 16950604 . 10.1016/j.euroneuro.2006.07.004 . 24350120 .
  14. Kovács KA, Steinmann M, Magistretti PJ, Halfon O, Cardinaux JR . C/EBPbeta couples dopamine signalling to substance P precursor gene expression in striatal neurones . Journal of Neurochemistry . 98 . 5 . 1390–9 . Sep 2006 . 16771829 . 10.1111/j.1471-4159.2006.03957.x . 36225447 .
  15. Rameshwar P . Substance P: a regulatory neuropeptide for hematopoiesis and immune functions . Clinical Immunology and Immunopathology . 85 . 2 . 129–33 . Nov 1997 . 9344694 . 10.1006/clin.1997.4446 .
  16. Pinto FM, Almeida TA, Hernandez M, Devillier P, Advenier C, Candenas ML . mRNA expression of tachykinins and tachykinin receptors in different human tissues . European Journal of Pharmacology . 494 . 2–3 . 233–9 . Jun 2004 . 15212980 . 10.1016/j.ejphar.2004.05.016 .
  17. 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 . 201 . 2 . 167–80 . Nov 2004 . 15334652 . 10.1002/jcp.20061 . 30899555 . free .
  18. Bossaller C, Reither K, Hehlert-Friedrich C, Auch-Schwelk W, Graf K, Gräfe M, Fleck E . In vivo measurement of endothelium-dependent vasodilation with substance P in man . Herz . 17 . 5 . 284–90 . Oct 1992 . 1282120 .
  19. Wong BJ, Tublitz NJ, Minson CT . Neurokinin-1 receptor desensitization to consecutive microdialysis infusions of substance P in human skin . The Journal of Physiology . 568 . Pt 3 . 1047–56 . Nov 2005 . 16123103 . 1464169 . 10.1113/jphysiol.2005.095372 .
  20. Rameshwar P, Gascon P, Ganea D . Immunoregulatory effects of neuropeptides. Stimulation of interleukin-2 production by substance p . Journal of Neuroimmunology . 37 . 1–2 . 65–74 . Mar 1992 . 1372331 . 10.1016/0165-5728(92)90156-f. 45933685 .
  21. Palma C, Manzini S . Substance P induces secretion of immunomodulatory cytokines by human astrocytoma cells . Journal of Neuroimmunology . 81 . 1–2 . 127–37 . Jan 1998 . 9521614 . 10.1016/s0165-5728(97)00167-7. 6114230 .
  22. Garza A, Weinstock J, Robinson P . Absence of the SP/SP receptor circuitry in the substance P-precursor knockout mice or SP receptor, neurokinin (NK)1 knockout mice leads to an inhibited cytokine response in granulomas associated with murine Taenia crassiceps infection . The Journal of Parasitology . 94 . 6 . 1253–8 . Dec 2008 . 18576810 . 10.1645/GE-1481.1 . 2647574.
  23. Freidin M, Kessler JA . Cytokine regulation of substance P expression in sympathetic neurons . Proceedings of the National Academy of Sciences of the United States of America . 88 . 8 . 3200–3 . Apr 1991 . 1707535 . 51413 . 10.1073/pnas.88.8.3200. 1991PNAS...88.3200F . free .
  24. 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 . 399 . 3 . 321–5 . Dec 1996 . 8985172 . 10.1016/s0014-5793(96)01346-4. 84912440 .
  25. Mary Pat Moyer . Koon HW, Zhao D, Na X, Moyer MP, Pothoulakis C . Metalloproteinases and transforming growth factor-alpha mediate substance P-induced mitogen-activated protein kinase activation and proliferation in human colonocytes . The Journal of Biological Chemistry . 279 . 44 . 45519–27 . Oct 2004 . 15319441 . 10.1074/jbc.M408523200 . free .
  26. 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 . 165 . 10 . 5606–11 . Nov 2000 . 11067916 . 10.4049/jimmunol.165.10.5606. free .
  27. Kearney CJ, Sheridan C, Cullen SP, Tynan GA, Logue SE, Afonina IS, Vucic D, Lavelle EC, Martin SJ . Inhibitor of apoptosis proteins (IAPs) and their antagonists regulate spontaneous and tumor necrosis factor (TNF)-induced proinflammatory cytokine and chemokine production . The Journal of Biological Chemistry . 288 . 7 . 4878–90 . Feb 2013 . 23275336 . 10.1074/jbc.M112.422410 . 3576092. free .
  28. Hesketh PJ . Potential role of the NK1 receptor antagonists in chemotherapy-induced nausea and vomiting . Supportive Care in Cancer . 9 . 5 . 350–4 . Jul 2001 . 11497388 . 10.1007/s005200000199 . 34636170 .
  29. Book: Donkin JJ, Turner RJ, Hassan I, Vink R . Neurotrauma: New Insights into Pathology and Treatment . Substance P in traumatic brain injury . Progress in Brain Research . 161 . 97–109 . 2007 . 17618972 . 10.1016/S0079-6123(06)61007-8 . 9780444530172 .
  30. De Felipe C, Herrero JF, O'Brien JA, Palmer JA, Doyle CA, Smith AJ, Laird JM, Belmonte C, Cervero F, Hunt SP . Altered nociception, analgesia and aggression in mice lacking the receptor for substance P . Nature . 392 . 6674 . 394–7 . Mar 1998 . 9537323 . 10.1038/32904 . 1998Natur.392..394D . 4324247 .
  31. Ebner K, Singewald N . The role of substance P in stress and anxiety responses . Amino Acids . 31 . 3 . 251–72 . Oct 2006 . 16820980 . 10.1007/s00726-006-0335-9 . 23380355 .
  32. Huston JP, Hasenöhrl RU, Boix F, Gerhardt P, Schwarting RK . Sequence-specific effects of neurokinin substance P on memory, reinforcement, and brain dopamine activity . Psychopharmacology . 112 . 2–3 . 147–62 . 1993 . 7532865 . 10.1007/BF02244906 . 21680843 .
  33. Park SW, Yan YP, Satriotomo I, Vemuganti R, Dempsey RJ . Substance P is a promoter of adult neural progenitor cell proliferation under normal and ischemic conditions . Journal of Neurosurgery . 107 . 3 . 593–9 . Sep 2007 . 17886560 . 10.3171/JNS-07/09/0593 . free .
  34. Baloyannis S, Costa V, Deretzi G, Michmizos D. 1999. Intraventricular Administration of Substance P Increases the Dendritic Arborisation and the Synaptic Surfaces of Purkinje Cells in Rat's Cerebellum. International Journal of Neuroscience, 101(1-4):89-107. https://www.tandfonline.com/doi/abs/10.3109/00207450008986495
  35. Bonham AC . Neurotransmitters in the CNS control of breathing . Respiration Physiology . 101 . 3 . 219–30 . Sep 1995 . 8606995 . 10.1016/0034-5687(95)00045-F .
  36. Zubrzycka M, Janecka A . Substance P: transmitter of nociception (Minireview) . Endocrine Regulations . 34 . 4 . 195–201 . Dec 2000 . 11137976 .
  37. Gorman, James, To Study Aggression, a Fight Club for Flies, The New York Times, February 4, 2014, page D5 of the New York edition
  38. Belilos . Andrew . Gray . Cortez . Sanders . Christie . Black . Destiny . Mays . Elizabeth . Richie . Christopher . Sengupta . Ayesha . Hake . Holly . Francis . T. Chase . Nucleus accumbens local circuit for cue-dependent aversive learning . Cell Reports . December 2023 . 42 . 12 . 113488 . 10.1016/j.celrep.2023.113488 . 37995189 . free . 10795009 .
  39. Hornby PJ . Central neurocircuitry associated with emesis . The American Journal of Medicine . 111 . 8 Suppl 8A . 106S–112S . Dec 2001 . 11749934 . 10.1016/S0002-9343(01)00849-X .
  40. Reid TW, Murphy CJ, Iwahashi CK, Foster BA, Mannis MJ . Stimulation of epithelial cell growth by the neuropeptide substance P . Journal of Cellular Biochemistry . 52 . 4 . 476–85 . Aug 1993 . 7693729 . 10.1002/jcb.240520411 . 45018815 .
  41. Brown SM, Lamberts DW, Reid TW, Nishida T, Murphy CJ . Neurotrophic and anhidrotic keratopathy treated with substance P and insulinlike growth factor 1 . Archives of Ophthalmology . 115 . 7 . 926–7 . Jul 1997 . 9230840 . 10.1001/archopht.1997.01100160096021 .
  42. Katsanos GS, Anogeianaki A, Orso C, Tete S, Salini V, Antinolfi PL, Sabatino G . Impact of substance P on cellular immunity . Journal of Biological Regulators and Homeostatic Agents . 22 . 2 . 93–8 . 2008 . 18597700 .
  43. Meshki J, Douglas SD, Hu M, Leeman SE, Tuluc F . 2011 . Substance P induces rapid and transient membrane blebbing in U373MG cells in a p21-activated kinase-dependent manner . PLOS ONE . 6 . 9. e25332 . 10.1371/journal.pone.0025332 . 21966499 . 3179504. 2011PLoSO...625332M . free .
  44. Muñoz M, Rosso M, Coveñas R . The NK-1 receptor: a new target in cancer therapy . Current Drug Targets . 12 . 6 . 909–21 . Jun 2011 . 21226668 . 10.2174/138945011795528796.
  45. Seckl MJ, Higgins T, Widmer F, Rozengurt E . [D-Arg1,D-Trp5,7,9,Leu11]substance P: a novel potent inhibitor of signal transduction and growth in vitro and in vivo in small cell lung cancer cells . Cancer Research . 57 . 1 . 51–4 . Jan 1997 . 8988040 .
  46. Muñoz M, Rosso M, Coveñas R . A new frontier in the treatment of cancer: NK-1 receptor antagonists . Current Medicinal Chemistry . 17 . 6 . 504–16 . 20015033 . 2010 . 10.2174/092986710790416308.
  47. Muñoz M, Coveñas R . Involvement of substance P and the NK-1 receptor in cancer progression . Peptides . 48 . 1–9 . Oct 2013 . 23933301 . 10.1016/j.peptides.2013.07.024 . 34038324 .
  48. Berger M, Neth O, Ilmer M, Garnier A, Salinas-Martín MV, de Agustín Asencio JC, von Schweinitz D, Kappler R, Muñoz M . Hepatoblastoma cells express truncated neurokinin-1 receptor and can be growth inhibited by aprepitant in vitro and in vivo . Journal of Hepatology . 60 . 5 . 985–94 . May 2014 . 24412605 . 10.1016/j.jhep.2013.12.024 .
  49. Michaels LA, Ohene-Frempong K, Zhao H, Douglas SD . Serum levels of substance P are elevated in patients with sickle cell disease and increase further during vaso-occlusive crisis . Blood . 92 . 9 . 3148–51 . Nov 1998 . 9787150 . 10.1182/blood.V92.9.3148.
  50. Mantyh CR, Gates TS, Zimmerman RP, Welton ML, Passaro EP, Vigna SR, Maggio JE, Kruger L, Mantyh PW . Receptor binding sites for substance P, but not substance K or neuromedin K, are expressed in high concentrations by arterioles, venules, and lymph nodules in surgical specimens obtained from patients with ulcerative colitis and Crohn disease . Proceedings of the National Academy of Sciences of the United States of America . 85 . 9 . 3235–9 . May 1988 . 2834738 . 280179 . 10.1073/pnas.85.9.3235 . 1988PNAS...85.3235M . free .
  51. Fehder WP, Sachs J, Uvaydova M, Douglas SD . Substance P as an immune modulator of anxiety . Neuroimmunomodulation . 4 . 1 . 42–8 . 1997 . 9326744 . 10.1159/000097314.
  52. Geracioti TD, Carpenter LL, Owens MJ, Baker DG, Ekhator NN, Horn PS, Strawn JR, Sanacora G, Kinkead B, Price LH, Nemeroff CB. Gerard Sanacora . Elevated cerebrospinal fluid substance p concentrations in posttraumatic stress disorder and major depression . The American Journal of Psychiatry . 163 . 4 . 637–43 . Apr 2006 . 16585438 . 10.1176/appi.ajp.163.4.637 .
  53. Schwarz MJ, Ackenheil M . The role of substance P in depression: therapeutic implications . Dialogues in Clinical Neuroscience . 4 . 1 . 21–9 . Mar 2002 . 10.31887/DCNS.2002.4.1/mschwarz . 22033776 . 3181667.
  54. Rupniak NM . New insights into the antidepressant actions of substance P (NK1 receptor) antagonists . Canadian Journal of Physiology and Pharmacology . 80 . 5 . 489–94 . May 2002 . 12056558 . 10.1139/y02-048 .
  55. Vaerøy H, Helle R, Førre O, Kåss E, Terenius L . Elevated CSF levels of substance P and high incidence of Raynaud phenomenon in patients with fibromyalgia: new features for diagnosis . Pain . 32 . 1 . 21–6 . Jan 1988 . 2448729 . 10.1016/0304-3959(88)90019-X . 41455803 .
  56. Anichini M, Cesaretti S, Lepori M, Maddali Bongi S, Maresca M, Zoppi M . Substance P in the serum of patients with rheumatoid arthritis . Revue du Rhumatisme . 64 . 1 . 18–21 . Jan 1997 . 9051855 .
  57. Douglas SD, Ho WZ, Gettes DR, Cnaan A, Zhao H, Leserman J, Petitto JM, Golden RN, Evans DL . Elevated substance P levels in HIV-infected men . AIDS . 15 . 15 . 2043–5 . Oct 2001 . 11600835 . 10.1097/00002030-200110190-00019 . free .
  58. Palma C, Maggi CA . The role of tachykinins via NK1 receptors in progression of human gliomas . Life Sciences . 67 . 9 . 985–1001 . 2000 . 10954033 . 10.1016/s0024-3205(00)00692-5 .
  59. Singh D, Joshi DD, Hameed M, Qian J, Gascón P, Maloof PB, Mosenthal A, Rameshwar P . Increased expression of preprotachykinin-I and neurokinin receptors in human breast cancer cells: implications for bone marrow metastasis . Proceedings of the National Academy of Sciences of the United States of America . 97 . 1 . 388–93 . Jan 2000 . 10618428 . 26673 . 10.1073/pnas.97.1.388 . 2000PNAS...97..388S . free .
  60. Campbell DE, Raftery N, Tustin R, Tustin NB, Desilvio ML, Cnaan A, Aye PP, Lackner AA, Douglas SD . Measurement of plasma-derived substance P: biological, methodological, and statistical considerations . Clinical and Vaccine Immunology . 13 . 11 . 1197–203 . Nov 2006 . 16971517 . 10.1128/CVI.00174-06 . 1656550.
  61. Ho WZ, Douglas SD . Substance P and neurokinin-1 receptor modulation of HIV . Journal of Neuroimmunology . 157 . 1–2 . 48–55 . Dec 2004 . 15579279 . 10.1016/j.jneuroim.2004.08.022 . 14975995 .
  62. Lambert N, Lescoulié PL, Yassine-Diab B, Enault G, Mazières B, De Préval C, Cantagrel A . Substance P enhances cytokine-induced vascular cell adhesion molecule-1 (VCAM-1) expression on cultured rheumatoid fibroblast-like synoviocytes . Clinical and Experimental Immunology . 113 . 2 . 269–75 . Aug 1998 . 9717978 . 10.1046/j.1365-2249.1998.00621.x . 1905034.
  63. Azzolina A, Bongiovanni A, Lampiasi N . Substance P induces TNF-alpha and IL-6 production through NF kappa B in peritoneal mast cells . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1643 . 1–3 . 75–83 . Dec 2003 . 14654230 . 10.1016/j.bbamcr.2003.09.003 .
  64. Douglas SD, Leeman SE . Neurokinin-1 receptor: functional significance in the immune system in reference to selected infections and inflammation . Annals of the New York Academy of Sciences . 1217 . 83–95 . Jan 2011 . 1 . 21091716 . 10.1111/j.1749-6632.2010.05826.x . 3058850. 2011NYASA1217...83D .
  65. Łazarczyk M, Matyja E, Lipkowski A . Substance P and its receptors -- a potential target for novel medicines in malignant brain tumour therapies (mini-review) . Folia Neuropathologica . 45 . 3 . 99–107 . 2007 . 17849359 .
  66. van der Hart . Maria Geertrudis Cornelia . Substance P and the Neurokinin 1 receptor: From behavior to bioanalysis . Ph.D. . 2009 . University of Groningen . 978-90-367-3874-3 .
  67. Web site: 'Blood chemicals link' to eczema . 2007-08-26 . Health . BBC News . 2008-11-01.
  68. Hon KL, Lam MC, Wong KY, Leung TF, Ng PC . Pathophysiology of nocturnal scratching in childhood atopic dermatitis: the role of brain-derived neurotrophic factor and substance P . The British Journal of Dermatology . 157 . 5 . 922–5 . Nov 2007 . 17725670 . 10.1111/j.1365-2133.2007.08149.x . 38031193 .
  69. King KA, Hu C, Rodriguez MM, Romaguera R, Jiang X, Piedimonte G . Exaggerated neurogenic inflammation and substance P receptor upregulation in RSV-infected weanling rats . American Journal of Respiratory Cell and Molecular Biology . 24 . 2 . 101–7 . Feb 2001 . 11159042 . 10.1165/ajrcmb.24.2.4264 .
  70. Piedimonte G . Neural mechanisms of respiratory syncytial virus-induced inflammation and prevention of respiratory syncytial virus sequelae . American Journal of Respiratory and Critical Care Medicine . 163 . 3 Pt 2 . S18-21 . Mar 2001 . 11254547 . 10.1164/ajrccm.163.supplement_1.2011113 .
  71. Steinitz H . [Chronic recurrent intestinal amebiasis in Israel (author's transl)] . de . Leber, Magen, Darm . 9 . 4 . 175–9 . Aug 1979 . 491812 .
  72. Stark D, van Hal S, Marriott D, Ellis J, Harkness J . Irritable bowel syndrome: a review on the role of intestinal protozoa and the importance of their detection and diagnosis . International Journal for Parasitology . 37 . 1 . 11–20 . Jan 2007 . 17070814 . 10.1016/j.ijpara.2006.09.009 .
  73. McGowan K, Kane A, Asarkof N, Wicks J, Guerina V, Kellum J, Baron S, Gintzler AR, Donowitz M . Entamoeba histolytica causes intestinal secretion: role of serotonin . Science . 221 . 4612 . 762–4 . Aug 1983 . 6308760 . 10.1126/science.6308760 . 1983Sci...221..762M .
  74. Book: McGowan K, Guerina V, Wicks J, Donowitz M . D. Evered . J. Whelan . Chapter 8: Secretory Hormones of Entamoeba histolytica . Ciba Found. Symp. . 112 . Microbial Toxins and Diarrhoeal Disease . 139–54 . 1985 . 2861068 . 10.1002/9780470720936.ch8 .
  75. Steinhoff MS, von Mentzer B, Geppetti P, Pothoulakis C, Bunnett NW . 2014 . Tachykinins and their receptors: contributions to physiological control and the mechanisms of disease . Physiol. Rev. . 94 . 1. 265–301 . 10.1152/physrev.00031.2013 . 24382888 . 3929113 .
  76. Tillisch K, Labus J, Nam B et al . 2012 . Neurokinin-1-receptor antagonism decreases anxiety and emotional arousal circuit response to noxious visceral distension in women with irritable bowel syndrome: a pilot study . Aliment. Pharmacol. Ther. . 35 . 3. 360–367 . 10.1111/j.1365-2036.2011.04958.x . 22221140 . 4073664 .
  77. Huskey SE, Dean BJ, Bakhtiar R, Sanchez RI, Tattersall FD, Rycroft W, Hargreaves R, Watt AP, Chicchi GG, Keohane C, Hora DF, Chiu SH . Brain penetration of aprepitant, a substance P receptor antagonist, in ferrets . Drug Metabolism and Disposition . 31 . 6 . 785–91 . Jun 2003 . 12756213 . 10.1124/dmd.31.6.785 . 5350781 .
  78. Diemunsch P, Joshi GP, Brichant JF . Neurokinin-1 receptor antagonists in the prevention of postoperative nausea and vomiting . British Journal of Anaesthesia . 103 . 1 . 7–13 . Jul 2009 . 19454547 . 10.1093/bja/aep125 . free .
  79. Nässel DR, Zandawala M, Kawada T, Satake H . Tachykinins: Neuropeptides That Are Ancient, Diverse, Widespread and Functionally Pleiotropic . Frontiers in Neuroscience . 13 . 1262 . 2019-11-20 . 31824255 . 6880623 . 10.3389/fnins.2019.01262 . free .
  80. Siegel A, Schubert KL, Shaikh MB . Neurotransmitters regulating defensive rage behavior in the cat . Neuroscience and Biobehavioral Reviews . 21 . 6 . 733–742 . November 1997 . 9415898 . 10.1016/S0149-7634(96)00056-5 . The neurobiology of defensive behavior in animals . 38166332 .
  81. Halasz J, Zelena D, Toth M, Tulogdi A, Mikics E, Haller J . Substance P neurotransmission and violent aggression: the role of tachykinin NK(1) receptors in the hypothalamic attack area . European Journal of Pharmacology . 611 . 1–3 . 35–43 . June 2009 . 19344710 . 10.1016/j.ejphar.2009.03.050 .
  82. Katsouni E, Sakkas P, Zarros A, Skandali N, Liapi C . The involvement of substance P in the induction of aggressive behavior . Peptides . 30 . 8 . 1586–1591 . August 2009 . 19442694 . 10.1016/j.peptides.2009.05.001 . 207357396 .
  83. Asahina K . Neuromodulation and Strategic Action Choice in Drosophila Aggression . Annual Review of Neuroscience . 40 . 1 . 51–75 . July 2017 . 28375770 . 10.1146/annurev-neuro-072116-031240 . 207745183 . free .
  84. News: Gorman . James . 2014-02-03 . To Study Aggression, a Fight Club for Flies-US . The New York Times . 2022-03-24 . 0362-4331.
  85. Asahina K, Watanabe K, Duistermars BJ, Hoopfer E, González CR, Eyjólfsdóttir EA, Perona P, Anderson DJ . Tachykinin-expressing neurons control male-specific aggressive arousal in Drosophila . English . Cell . 156 . 1–2 . 221–235 . January 2014 . 24439378 . 10.1016/j.cell.2013.11.045 . 3978814 .

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Substance P".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.