「Substance P」の版間の差分

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{{infobox protein
#転送 [[サブスタンスP]]
| Name = tachykinin, precursor 1
| caption = Spacefilling [[Molecular model|model]] of substance P
| image = Substance_P.png
| width = 180
| HGNCid = 11517
| Symbol = TAC1
| AltSymbols = TAC2, NKNA
| EntrezGene = 6863
| OMIM = 162320
| RefSeq = NM_003182
| UniProt = P20366
| PDB =
| ECnumber =
| Chromosome = 7
| Arm = q
| Band = 21
| LocusSupplementaryData = -q22
}}
{{chembox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 414512791
| ImageFile=Substance P.svg
| ImageSize=275px
| IUPACName=
| OtherNames=
|Section1={{Chembox Identifiers
| IUPHAR_ligand = 2098
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 33558
| InChI = <div style="max-width: 22em; overflow: auto;">1/C63H98N18O13S/c1-37(2)33-45(57(89)74-41(53(68)85)27-32-95-3)73-52(84)36-72-54(86)46(34-38-15-6-4-7-16-38)78-58(90)47(35-39-17-8-5-9-18-39)79-56(88)42(23-25-50(66)82)75-55(87)43(24-26-51(67)83)76-59(91)49-22-14-31-81(49)62(94)44(20-10-11-28-64)77-60(92)48-21-13-30-80(48)61(93)40(65)19-12-29-71-63(69)70/h4-9,15-18,37,40-49H,10-14,19-36,64-65H2,1-3H3,(H2,66,82)(H2,67,83)(H2,68,85)(H,72,86)(H,73,84)(H,74,89)(H,75,87)(H,76,91)(H,77,92)(H,78,90)(H,79,88)(H4,69,70,71)/t40-,41-,42-,43-,44-,45-,46-,47-,48-,49-/m0/s1</div>
| InChIKey = ADNPLDHMAVUMIW-CUZNLEPHBU
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 235363
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = <div style="max-width: 22em; overflow: auto;">1S/C63H98N18O13S/c1-37(2)33-45(57(89)74-41(53(68)85)27-32-95-3)73-52(84)36-72-54(86)46(34-38-15-6-4-7-16-38)78-58(90)47(35-39-17-8-5-9-18-39)79-56(88)42(23-25-50(66)82)75-55(87)43(24-26-51(67)83)76-59(91)49-22-14-31-81(49)62(94)44(20-10-11-28-64)77-60(92)48-21-13-30-80(48)61(93)40(65)19-12-29-71-63(69)70/h4-9,15-18,37,40-49H,10-14,19-36,64-65H2,1-3H3,(H2,66,82)(H2,67,83)(H2,68,85)(H,72,86)(H,73,84)(H,74,89)(H,75,87)(H,76,91)(H,77,92)(H,78,90)(H,79,88)(H4,69,70,71)/t40-,41-,42-,43-,44-,45-,46-,47-,48-,49-/m0/s1</div>
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = ADNPLDHMAVUMIW-CUZNLEPHSA-N
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo=33507-63-0
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII =675VGV5J1D
| PubChem=36511
| SMILES=
| MeSHName=Substance+P
  }}
|Section2={{Chembox Properties
| Formula=C<sub>63</sub>H<sub>98</sub>N<sub>18</sub>O<sub>13</sub>S
| MolarMass=1347.63 g/mol
| Appearance=
| Density=
| MeltingPt=
| BoilingPt=
| Solubility=
  }}
|Section3={{Chembox Hazards
| MainHazards=
| FlashPt=
| AutoignitionPt =
  }}
}}
'''Substance P''' (SP) is an [[undecapeptide]] (a peptide composed of a chain of 11 amino acid residues) member of the [[tachykinin]] neuropeptide family. It is a [[neuropeptide]], acting as a [[neurotransmitter]] and as a [[neuromodulator]].<ref name="pmid11378438">{{cite journal | vauthors = Harrison S, Geppetti P | title = Substance p | journal = The International Journal of Biochemistry & Cell Biology | volume = 33 | issue = 6 | pages = 555–76 | date = Jun 2001 | pmid = 11378438 | doi = 10.1016/S1357-2725(01)00031-0 }}</ref><ref name="pmid14754378">{{cite journal | vauthors = Datar P, Srivastava S, Coutinho E, Govil G | title = Substance P: structure, function, and therapeutics | journal = Current Topics in Medicinal Chemistry | volume = 4 | issue = 1 | pages = 75–103 | year = 2004 | pmid = 14754378 | doi = 10.2174/1568026043451636 | url = http://www.bentham-direct.org/pages/content.php?CTMC/2004/00000004/00000001/0009R.SGM }}</ref> Substance P and its closely related  [[neurokinin A]] (NKA) are produced from a polyprotein precursor after differential splicing of the [[preprotachykinin| preprotachykinin A gene]]. The deduced amino acid sequence of substance P is as follows:<ref>{{ cite book | author = Campbell NA, Reece JB | title = Biology | edition = 7th | location = San Francisco | publisher = Pearson Benjamin Cummings | year = 2005 | isbn = 9780805371468 }}</ref>
* [[Arginine|Arg]] [[Proline|Pro]] [[Lysine|Lys]] [[Proline|Pro]] [[Glutamine|Gln]] [[Glutamine|Gln]] [[Phenylalanine|Phe]] [[Phenylalanine|Phe]] [[Glycine|Gly]] [[Leucine|Leu]] [[Methionine|Met]] (RPKPQQFFGLM)
with an amidation at the C-terminus.<ref name="pmid7511706">{{cite journal | vauthors = Wong M, Jeng AY | title = Posttranslational modification of glycine-extended substance P by an alpha-amidating enzyme in cultured sensory neurons of dorsal root ganglia | journal = Journal of Neuroscience Research | volume = 37 | issue = 1 | pages = 97–102 | date = Jan 1994 | pmid = 7511706 | pmc =  | doi = 10.1002/jnr.490370113 | url = http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7511706 }}</ref>
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==
Substance P (SP) was originally discovered in 1931 by [[Ulf von Euler]] and [[John H. Gaddum]] as a tissue extract that caused intestinal contraction ''in vitro''.<ref name="pmid16994201">{{cite journal | vauthors = V Euler US, Gaddum JH | title = An unidentified depressor substance in certain tissue extracts | journal = The Journal of Physiology | volume = 72 | issue = 1 | pages = 74–87 | date = Jun 1931 | pmid = 16994201 | pmc = 1403098 | url = http://jp.physoc.org/content/72/1/74.long }}</ref> Its tissue distribution and biologic actions were further investigated over the following decades.<ref name="pmid11378438"/> The eleven-amino-acid structure of the peptide was determined by [[Susan Leeman]] in 1971.<ref>{{cite book |url= http://books.google.co.uk/books?id=egeRx2hNQywC&lpg=PT82&dq=Susan%20Leeman&pg=PT82#v=onepage&q=Susan%20Leeman&f=false |title= Molecules Of Emotion: Why You Feel The Way You Feel |author= Pert CB |year= 2012 |isbn= 1471109704 |publisher= Simon and Schuster |accessdate= 31 July 2014}}</ref>
 
In 1983, NKA (previously known as substance K or neuromedin L) was isolated from [[pig|porcine]] [[spinal cord]] and was also found to stimulate intestinal contraction.<ref name="pmid6194276">{{cite journal | vauthors = Panula P, Hadjiconstantinou M, Yang HY, Costa E | title = Immunohistochemical localization of bombesin/gastrin-releasing peptide and substance P in primary sensory neurons | journal = The Journal of Neuroscience | volume = 3 | issue = 10 | pages = 2021–9 | date = Oct 1983 | pmid = 6194276 | url = http://www.jneurosci.org/content/3/10/2021.long }}</ref>
 
==Receptor==
The [[endogenous]] [[receptor (biochemistry)|receptor]] for substance P is [[tachykinin receptor 1|neurokinin 1]] receptor (NK1-receptor, NK1R).<ref name="pmid1657150">{{cite journal | vauthors = Gerard NP, Garraway LA, Eddy RL, Shows TB, Iijima H, Paquet JL, Gerard C | title = Human substance P receptor (NK-1): organization of the gene, chromosome localization, and functional expression of cDNA clones | journal = Biochemistry | volume = 30 | issue = 44 | pages = 10640–6 | date = Nov 1991 | pmid = 1657150 | doi = 10.1021/bi00108a006 }}</ref> It belongs to the [[tachykinin receptor]] sub-family of [[G protein-coupled receptor|GPCR]]s.<ref name="pmid7557266">{{cite journal | vauthors = Maggi CA | title = The mammalian tachykinin receptors | journal = General Pharmacology | volume = 26 | issue = 5 | pages = 911–44 | date = Sep 1995 | pmid = 7557266 | doi = 10.1016/0306-3623(94)00292-U }}</ref> Other neurokinin subtypes and neurokinin receptors that interact with SP have also been reported. Amino acid residues that are responsible for the binding of SP and its [[Receptor antagonist|antagonists]] are present in the extracellular loops and transmembrane regions of NK-1. Binding of SP to NK-1 results in internalization by the [[clathrin]]-dependent mechanism to the acidified [[endosome]]s where the complex disassociates. SP is subsequently  degraded and NK-1 is re-expressed on the cell surface.<ref name="pmid7545030">{{cite journal | vauthors = Grady EF, Garland AM, Gamp PD, Lovett M, Payan DG, Bunnett NW | title = Delineation of the endocytic pathway of substance P and its seven-transmembrane domain NK1 receptor | journal = Molecular Biology of the Cell | volume = 6 | issue = 5 | pages = 509–24 | date = May 1995 | pmid = 7545030 | pmc = 301212 | doi = 10.1091/mbc.6.5.509 | url = http://www.molbiolcell.org/cgi/content/abstract/6/5/509 }}</ref> 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]]).<ref name="pmid11179779">{{cite journal | vauthors = Yip J, Chahl LA | title = Localization of NK1 and NK3 receptors in guinea-pig brain | journal = Regulatory Peptides | volume = 98 | issue = 1-2 | pages = 55–62 | date = Apr 2001 | pmid = 11179779 | doi = 10.1016/S0167-0115(00)00228-7 }}</ref> They are also found in close association with [[serotonin]] (5-HT) and neurons containing norepinephrine that are targeted by the currently used antidepressant drugs.<ref name="pmid16950604">{{cite journal | vauthors = Gobbi G, Cassano T, Radja F, Morgese MG, Cuomo V, Santarelli L, Hen R, Blier P | title = Neurokinin 1 receptor antagonism requires norepinephrine to increase serotonin function | journal = European Neuropsychopharmacology | volume = 17 | issue = 5 | pages = 328–38 | date = Apr 2007 | pmid = 16950604 | doi = 10.1016/j.euroneuro.2006.07.004 }}</ref> The SP receptor promoter contains regions that are sensitive to [[Cyclic adenosine monophosphate|cAMP]], [[AP-1 (transcription factor)|AP-1]], [[TFAP4|AP-4]], [[CEBPB]],<ref name="pmid16771829">{{cite journal | vauthors = Kovács KA, Steinmann M, Magistretti PJ, Halfon O, Cardinaux JR | title = C/EBPbeta couples dopamine signalling to substance P precursor gene expression in striatal neurones | journal = Journal of Neurochemistry | volume = 98 | issue = 5 | pages = 1390–9 | date = Sep 2006 | pmid = 16771829 | doi = 10.1111/j.1471-4159.2006.03957.x }}</ref> and [[epidermal growth factor]]. Because these regions are related to complexed [[signal transduction pathways]] mediated by [[cytokines]], it has been proposed that cytokines and neurotropic factors can induce NK-1. SP can also induce the cytokines that are capable of inducing NK-1 transcription factors.<ref name="pmid9344694">{{cite journal | vauthors = Rameshwar P | title = Substance P: a regulatory neuropeptide for hematopoiesis and immune functions | journal = Clinical Immunology and Immunopathology | volume = 85 | issue = 2 | pages = 129–33 | date = Nov 1997 | pmid = 9344694 | doi = 10.1006/clin.1997.4446 }}</ref>
 
== Function ==
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.<ref name="pmid9537323"/> Substance P has been associated with the regulation of [[mood disorders]], [[anxiety]], [[stress (medicine)|stress]],<ref name="pmid16820980">{{cite journal | vauthors = Ebner K, Singewald N | title = The role of substance P in stress and anxiety responses | journal = Amino Acids | volume = 31 | issue = 3 | pages = 251–72 | date = Oct 2006 | pmid = 16820980 | doi = 10.1007/s00726-006-0335-9 }}</ref> [[reinforcement]],<ref name="pmid7532865">{{cite journal | vauthors = Huston JP, Hasenöhrl RU, Boix F, Gerhardt P, Schwarting RK | title = Sequence-specific effects of neurokinin substance P on memory, reinforcement, and brain dopamine activity | journal = Psychopharmacology | volume = 112 | issue = 2-3 | pages = 147–62 | year = 1993 | pmid = 7532865 | doi = 10.1007/BF02244906 }}</ref> [[neurogenesis]],<ref name="pmid17886560">{{cite journal | vauthors = Park SW, Yan YP, Satriotomo I, Vemuganti R, Dempsey RJ | title = Substance P is a promoter of adult neural progenitor cell proliferation under normal and ischemic conditions | journal = Journal of Neurosurgery | volume = 107 | issue = 3 | pages = 593–9 | date = Sep 2007 | pmid = 17886560 | doi = 10.3171/JNS-07/09/0593 }}</ref> respiratory rhythm,<ref name="pmid8606995">{{cite journal | vauthors = Bonham AC | title = Neurotransmitters in the CNS control of breathing | journal = Respiration Physiology | volume = 101 | issue = 3 | pages = 219–30 | date = Sep 1995 | pmid = 8606995 | doi = 10.1016/0034-5687(95)00045-F }}</ref> [[neurotoxicity]], [[nausea]]/[[emesis]],<ref name="pmid11497388">{{cite journal | vauthors = Hesketh PJ | title = Potential role of the NK1 receptor antagonists in chemotherapy-induced nausea and vomiting | journal = Supportive Care in Cancer | volume = 9 | issue = 5 | pages = 350–4 | date = Jul 2001 | pmid = 11497388 | doi = 10.1007/s005200000199 }}</ref> [[pain]] and [[nociception]].<ref name="pmid11137976">{{cite journal | vauthors = Zubrzycka M, Janecka A | title = Substance P: transmitter of nociception (Minireview) | journal = Endocrine Regulations | volume = 34 | issue = 4 | pages = 195–201 | date = Dec 2000 | pmid = 11137976 | doi =  }}</ref> 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.<ref name="pmid17618972">{{cite journal | vauthors = Donkin JJ, Turner RJ, Hassan I, Vink R | title = Substance P in traumatic brain injury | journal = Progress in Brain Research | volume = 161 | pages = 97–109 | year = 2007 | pmid = 17618972 | doi = 10.1016/S0079-6123(06)61007-8 }}</ref> The regulatory function of SP also involves the regulation of its high-affinity receptor, NK-1. Substance P receptor antagonists may have important therapeutic applications in the treatment of a variety of stress-related illnesses, in addition to their potential as analgesics.
 
===Vomiting===
The [[vomiting]] center in the [[Medulla oblongata|medulla]] contains high concentrations of substance P and its receptor, in addition to other neurotransmitters such as [[choline]], [[histamine]], [[dopamine]], [[serotonin]], and [[opioid]]s. 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.<ref name="pmid11749934">{{cite journal | vauthors = Hornby PJ | title = Central neurocircuitry associated with emesis | journal = The American Journal of Medicine | volume = 111 Suppl 8A | issue = 8 | pages = 106S–112S | date = Dec 2001 | pmid = 11749934 | doi = 10.1016/S0002-9343(01)00849-X }}</ref> Substance P antagonist (SPA) [[aprepitant]] is available in the market in the treatment of [[chemotherapy]]-induced nausea/emesis.
 
===Pain===
Substance P is involved in [[nociception]], transmitting information about tissue damage from peripheral receptors to the [[central nervous system]] to be converted to the sensation of [[pain]]. It has been theorized that it plays a part in [[fibromyalgia]]. [[Capsaicin]] has been shown to reduce the levels of substance P, it is presumed, by reducing the number of [[C-fibre]] nerves or causing these nerves to be more tolerant. Thus, capsaicin is clinically used as an analgesic and an [[anti-inflammatory]] agent to reduce pain associated with arthritis and many types of neuralgia.  A role of  substance P and NKA in nociception is suggested by the reduction in response thresholds to noxious stimuli by central administration of K2 and K3 [[agonists]]. Based on recent studies, it was proposed that NK1, and possibly NK2 [[receptor antagonist]]s, could be developed as analgesic drugs.
It has been studied that the mice carrying a disruption of the gene encoding SP/NKA show severely reduced nociceptive pain responses when the stimuli are moderate to intense. Pain behaviors induced by mechanical, thermal, and chemical stimulation of somatic and visceral tissues were reduced in the mutant mice lacking SP/NKA. However, it has been proposed that the importance of SP and NKA in animal's  pain response apply only to a certain 'window' of pain intensities, and, when the intensity of the pain stimuli is further increased, the responses of the [[knockout mouse|knockout mice]] is not severely different from the wild-type mice.<ref name="pmid9537323">{{cite journal | vauthors = De Felipe C, Herrero JF, O'Brien JA, Palmer JA, Doyle CA, Smith AJ, Laird JM, Belmonte C, Cervero F, Hunt SP | title = Altered nociception, analgesia and aggression in mice lacking the receptor for substance P | journal = Nature | volume = 392 | issue = 6674 | pages = 394–7 | date = Mar 1998 | pmid = 9537323 | doi = 10.1038/32904 }}</ref>
 
Substance P increases glutamate activity (NMDA) in central nervous system, and it is associated with the development of [[brain edema]] and functional deficits after traumatic brain injury.<ref name="pmid19436311">{{cite journal | vauthors = Donkin JJ, Nimmo AJ, Cernak I, Blumbergs PC, Vink R | title = Substance P is associated with the development of brain edema and functional deficits after traumatic brain injury | journal = Journal of Cerebral Blood Flow and Metabolism | volume = 29 | issue = 8 | pages = 1388–98 | date = Aug 2009 | pmid = 19436311 | doi = 10.1038/jcbfm.2009.63 }}</ref>
 
===Cell growth===
Substance P has been known to stimulate cell growth in culture,<ref name="pmid7693729">{{cite journal | vauthors = Reid TW, Murphy CJ, Iwahashi CK, Foster BA, Mannis MJ | title = Stimulation of epithelial cell growth by the neuropeptide substance P | journal = Journal of Cellular Biochemistry | volume = 52 | issue = 4 | pages = 476–85 | date = Aug 1993 | pmid = 7693729 | doi = 10.1002/jcb.240520411 }}</ref> and it was shown that substance P could promote wound healing of non-healing [[ulcer (dermatology)|ulcer]]s in humans.<ref name="pmid9230840">{{cite journal | vauthors = Brown SM, Lamberts DW, Reid TW, Nishida T, Murphy CJ | title = Neurotrophic and anhidrotic keratopathy treated with substance P and insulinlike growth factor 1 | journal = Archives of Ophthalmology | volume = 115 | issue = 7 | pages = 926–7 | date = Jul 1997 | pmid = 9230840 | doi = 10.1001/archopht.1997.01100160096021 }}</ref>
 
===Diabetes===
Substance P injected into pancreatic nerves has been shown to reverse diabetes in mice<ref name="urlBreakthrough sheds light on cause of diabetes - health - 15 December 2006 - New Scientist">{{cite web | url = http://www.newscientist.com/article/dn10812-breakthrough-sheds-light-on-cause-of-diabetes.html | title = Breakthrough sheds light on cause of diabetes  | author = Motluk A,  Geddes  L | authorlink = | coauthors = | date = 2005-12-15 | work = Health | publisher = New Scientist | pages = | archiveurl = | archivedate = | quote = | accessdate = 2008-11-01}}</ref><ref name="pmid17900987">{{cite journal | vauthors = Tsui H, Razavi R, Chan Y, Yantha J, Dosch HM | title = 'Sensing' autoimmunity in type 1 diabetes | journal = Trends in Molecular Medicine | volume = 13 | issue = 10 | pages = 405–13 | date = Oct 2007 | pmid = 17900987 | doi = 10.1016/j.molmed.2007.07.006 }}</ref> but effects to insulin secretion seem to be species-dependent. In humans, substance P given intravenously seems to decrease insulin release and causes fluctuations in blood sugar levels.<ref name="insulin1">{{cite journal | vauthors = Brown M, Vale W | title = Effects of neurotensin and substance P on plasma insulin, glucagon and glucose levels | journal = Endocrinology | volume = 98 | issue = 3 | pages = 819–822 | date = Mar 1976 | pmid = 1261503 | doi = 10.1210/endo-98-3-819 }}</ref>
 
===Vasodilation===
Substance P also has effects as a potent [[vasodilator]]. Substance P-induced vasodilatation is dependent on [[nitric oxide]] release.<ref name="pmid1282120">{{cite journal | vauthors = Bossaller C, Reither K, Hehlert-Friedrich C, Auch-Schwelk W, Graf K, Gräfe M, Fleck E | title = In vivo measurement of endothelium-dependent vasodilation with substance P in man | journal = Herz | volume = 17 | issue = 5 | pages = 284–90 | date = Oct 1992 | pmid = 1282120 | doi =  }}</ref>  Substance P is involved in the axon reflex-mediated vasodilatation to local heating and [[wikt:wheal|wheal]] and flare reaction. It has been shown that vasodilatation to substance P is dependent on the NK1 receptor located on the endothelium.  In contrast to other neuropeptides studied in human skin, substance P-induced vasodilatation has been found to decline during continuous infusion. This possibly suggests an internalization of neurokinin-1 (NK1).<ref name="pmid16123103">{{cite journal | vauthors = Wong BJ, Tublitz NJ, Minson CT | title = Neurokinin-1 receptor desensitization to consecutive microdialysis infusions of substance P in human skin | journal = The Journal of Physiology | volume = 568 | issue = Pt 3 | pages = 1047–56 | date = Nov 2005 | pmid = 16123103 | pmc = 1464169 | doi = 10.1113/jphysiol.2005.095372 }}</ref>  As is typical with many vasodilators, it also has [[Bronchoconstriction|bronchoconstrictive]] properties, administered through the non-adrenergic, non-cholinergic nervous system (branch of the vagal system).
 
== Clinical significance ==
 
Elevation of serum, plasma, or tissue SP and/or its receptor (NK1R) has been associated with many diseases: sickle cell crisis;<ref name="pmid9787150">{{cite journal | vauthors = Michaels LA, Ohene-Frempong K, Zhao H, Douglas SD | title = Serum levels of substance P are elevated in patients with sickle cell disease and increase further during vaso-occlusive crisis | journal = Blood | volume = 92 | issue = 9 | pages = 3148–51 | date = Nov 1998 | pmid = 9787150 | doi =  }}</ref> inflammatory bowel disease;<ref name="pmid2834738">{{cite journal | vauthors = Mantyh CR, Gates TS, Zimmerman RP, Welton ML, Passaro EP, Vigna SR, Maggio JE, Kruger L, Mantyh PW | title = 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 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 85 | issue = 9 | pages = 3235–9 | date = May 1988 | pmid = 2834738 | pmc = 280179 | doi =  10.1073/pnas.85.9.3235}}</ref><ref name="pmid9326744">{{cite journal | vauthors = Fehder WP, Sachs J, Uvaydova M, Douglas SD | title = Substance P as an immune modulator of anxiety | journal = Neuroimmunomodulation | volume = 4 | issue = 1 | pages = 42–8 | year = 1997 | pmid = 9326744 | doi =  }}</ref> major depression and related disorders;<ref>{{cite journal | vauthors = Geracioti TD, Carpenter LL, Owens MJ, Baker DG, Ekhator NN, Horn PS, Strawn JR, Sanacora G, Kinkead B, Price LH, Nemeroff CB | title = Elevated cerebrospinal fluid substance p concentrations in posttraumatic stress disorder and major depression | journal = The American Journal of Psychiatry | volume = 163 | issue = 4 | date = Apr 2006 | pmid = 16585438 | doi = 10.1176/appi.ajp.163.4.637 }}</ref><ref>{{cite journal | vauthors = Schwarz MJ, Ackenheil M | title = The role of substance P in depression: therapeutic implications | journal = Dialogues in Clinical Neuroscience | volume = 4 | issue = 1 | date = Mar 2002 | pmid = 22033776 }}</ref><ref name="pmid12056558">{{cite journal | vauthors = Rupniak NM | title = New insights into the antidepressant actions of substance P (NK1 receptor) antagonists | journal = Canadian Journal of Physiology and Pharmacology | volume = 80 | issue = 5 | pages = 489–94 | date = May 2002 | pmid = 12056558 | doi =  10.1139/y02-048}}</ref> fibromyalgia;<ref>{{cite journal | vauthors = Vaerøy H, Helle R, Førre O, Kåss E, Terenius L | title = Elevated CSF levels of substance P and high incidence of Raynaud phenomenon in patients with fibromyalgia: new features for diagnosis | journal = Pain | volume = 32 | issue = 1 | date = Jan 1988 | pmid = 2448729 }}</ref> rheumatological;<ref name="pmid9051855">{{cite journal | vauthors = Anichini M, Cesaretti S, Lepori M, Maddali Bongi S, Maresca M, Zoppi M | title = Substance P in the serum of patients with rheumatoid arthritis | journal = Revue Du Rhumatisme | volume = 64 | issue = 1 | pages = 18–21 | date = Jan 1997 | pmid = 9051855 | doi =  }}</ref> and infections such as HIV/AIDS and respiratory syncytial virus,<ref name="pmid11600835">{{cite journal | vauthors = Douglas SD, Ho WZ, Gettes DR, Cnaan A, Zhao H, Leserman J, Petitto JM, Golden RN, Evans DL | title = Elevated substance P levels in HIV-infected men | journal = Aids | volume = 15 | issue = 15 | pages = 2043–5 | date = Oct 2001 | pmid = 11600835 | doi =  10.1097/00002030-200110190-00019}}</ref> as well as in cancer.<ref name="pmid10954033">{{cite journal | vauthors = Palma C, Maggi CA | title = The role of tachykinins via NK1 receptors in progression of human gliomas | journal = Life Sciences | volume = 67 | issue = 9 | pages = 985–1001 | year = 2000 | pmid = 10954033 | doi =  10.1016/s0024-3205(00)00692-5}}</ref><ref name="pmid10618428">{{cite journal | vauthors = Singh D, Joshi DD, Hameed M, Qian J, Gascón P, Maloof PB, Mosenthal A, Rameshwar P | title = Increased expression of preprotachykinin-I and neurokinin receptors in human breast cancer cells: implications for bone marrow metastasis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 1 | pages = 388–93 | date = Jan 2000 | pmid = 10618428 | pmc = 26673 | doi =  10.1073/pnas.97.1.388}}</ref>
 
When assayed in the intact human, the observed variability of the SP concentrations are large, and in some cases the assay methodology is questionable.<ref>{{cite journal | vauthors = Campbell DE, Raftery N, Tustin R, Tustin NB, Desilvio ML, Cnaan A, Aye PP, Lackner AA, Douglas SD | title = Measurement of plasma-derived substance P: biological, methodological, and statistical considerations | journal = Clinical and Vaccine Immunology | volume = 13 | issue = 11 | date = Nov 2006 | pmid = 16971517 | doi = 10.1128/CVI.00174-06 }}</ref> SP concentrations cannot yet be used to clinically diagnose disease 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 its effect.
 
As increasingly documented,  the SP-NK1R system induces or modulates many aspects of the immune response, including WBC production and activation,  and cytokine expression.<ref name="ReferenceA">{{cite journal | vauthors = Ho WZ, Douglas SD | title = Substance P and neurokinin-1 receptor modulation of HIV | journal = Journal of Neuroimmunology | volume = 157 | issue = 1-2 | date = Dec 2004 | pmid = 15579279 | doi = 10.1016/j.jneuroim.2004.08.022 }}</ref> Reciprocally, cytokines  may induce expression of SP and its NK1R.<ref>{{cite journal | vauthors = Lambert N, Lescoulié PL, Yassine-Diab B, Enault G, Mazières B, De Préval C, Cantagrel A | title = Substance P enhances cytokine-induced vascular cell adhesion molecule-1 (VCAM-1) expression on cultured rheumatoid fibroblast-like synoviocytes | journal = Clinical and Experimental Immunology | volume = 113 | issue = 2 | date = Aug 1998 | pmid = 9717978 }}</ref><ref>{{cite journal | vauthors = Azzolina A, Bongiovanni A, Lampiasi N | title = Substance P induces TNF-alpha and IL-6 production through NF kappa B in peritoneal mast cells | journal = Biochimica Et Biophysica Acta | volume = 1643 | issue = 1-3 | date = Dec 2003 | pmid = 14654230 }}</ref> 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 which accompanies chemotherapy, typically of 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.<ref name="ReferenceA"/><ref>{{cite journal | vauthors = Douglas SD, Leeman SE | title = Neurokinin-1 receptor: functional significance in the immune system in reference to selected infections and inflammation | journal = Annals of the New York Academy of Sciences | volume = 1217 | date = Jan 2011 | pmid = 21091716 | doi = 10.1111/j.1749-6632.2010.05826.x }}</ref><ref>{{cite journal | vauthors = Łazarczyk M, Matyja E, Lipkowski A | title = Substance P and its receptors -- a potential target for novel medicines in malignant brain tumour therapies (mini-review) | journal = Folia Neuropathologica / Association of Polish Neuropathologists and Medical Research Centre, Polish Academy of Sciences | volume = 45 | issue = 3 | pmid = 17849359 }}</ref><ref>{{cite journal | vauthors = O'Connor TM, O'Connell J, O'Brien DI, Goode T, Bredin CP, Shanahan F | title = The role of substance P in inflammatory disease | journal = Journal of Cellular Physiology | volume = 201 | issue = 2 | date = Nov 2004 | pmid = 15334652 | doi = 10.1002/jcp.20061 }}</ref><ref>{{cite thesis | last = van der Hart | first = Maria Geertrudis Cornelia | title = Substance P and the Neurokinin 1 receptor: From behavior to bioanalysis | type = Ph.D. | url = https://www.rug.nl/research/portal/publications/pub(0cba2451-8fcd-4b9b-b020-c397aa828e95).html  | date = | year = 2009 | publisher = University of Groningen | isbn = 978-90-367-3874-3 | name-list-format = vanc }}</ref>
 
=== Chemotherapy Induced Nausea and Vomiting===
see: [[Chemotherapy-induced nausea and vomiting]] and [[Aprepitant]]
 
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, the ([[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 sub-serving respiration, retroperistalsis, and general autonomic discharge.
 
=== Major Depressive Disorder and other psychiatric disorders ===
 
=== Inflammatory Pain ===
 
=== Cancer ===
 
=== Infection ===
 
=== Chronic Pruritis ===
 
=== Chronic Cough ===
 
=== Inflammatory Skin Diseases ===
 
====Eczema====
High levels of [[BDNF]] and substance P have been found associated with increased itching in [[eczema]].<ref name="urlBBC NEWS | Health | Blood chemicals link to eczema">{{cite web | url =http://news.bbc.co.uk/2/hi/health/6962450.stm | title =  'Blood chemicals link' to eczema | author = | authorlink = | coauthors = | date = 2007-08-26 | format = | work = Health | publisher = BBC NEWS | pages = | archiveurl = | archivedate = | quote = | accessdate = 2008-11-01}}</ref><ref name="pmid17725670">{{cite journal | vauthors = Hon KL, Lam MC, Wong KY, Leung TF, Ng PC | title = Pathophysiology of nocturnal scratching in childhood atopic dermatitis: the role of brain-derived neurotrophic factor and substance P | journal = The British Journal of Dermatology | volume = 157 | issue = 5 | pages = 922–5 | date = Nov 2007 | pmid = 17725670 | doi = 10.1111/j.1365-2133.2007.08149.x }}</ref>
 
=== Overactive Bladder ===
 
===Infections===
 
====HIV/AIDS====
 
====Measles====
 
====Entamoeba Histolytica====
 
''[[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]].<ref>{{cite journal | vauthors = Steinitz H | title = [Chronic recurrent intestinal amebiasis in Israel (author's transl)] | language = German | journal = Leber, Magen, Darm | volume = 9 | issue = 4 | pages = 175–9 | date = Aug 1979 | pmid = 491812 }}</ref><ref name="pmid17070814">{{cite journal | vauthors = Stark D, van Hal S, Marriott D, Ellis J, Harkness J | title = Irritable bowel syndrome: a review on the role of intestinal protozoa and the importance of their detection and diagnosis | journal = International Journal for Parasitology | volume = 37 | issue = 1 | pages = 11–20 | date = Jan 2007 | pmid = 17070814 | doi = 10.1016/j.ijpara.2006.09.009 }}</ref> This protozoan was found to secrete [[serotonin]]<ref>{{cite journal | vauthors = McGowan K, Kane A, Asarkof N, Wicks J, Guerina V, Kellum J, Baron S, Gintzler AR, Donowitz M | title = Entamoeba histolytica causes intestinal secretion: role of serotonin | journal = Science | volume = 221 | issue = 4612 | pages = 762–4 | date = Aug 1983 | pmid = 6308760 | doi = 10.1126/science.6308760 }}</ref> as well as substance P and [[neurotensin]].<ref>{{ cite book | author = McGowan K, Guerina V, Wicks J, Donowitz M | editor = D. Evered; J. Whelan | chapter = Chapter 8: Secretory Hormones of ''Entamoeba histolytica'' | series = Ciba Found. Symp. | volume = 112 | title = Microbial Toxins and Diarrhoeal Disease | pages = 139–54 | year = 1985 | pmid = 2861068 | doi = 10.1002/9780470720936.ch8 }}</ref>
 
===Other===
 
====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.
 
==Deficiency==
[[Naked mole-rat]]s (Heterocephalus glaber, NMR) lack cutaneous C fibers reactive to substance P (SP) and many small neurons that are normally SP-positive. Thus, these animals are insensitive to [[pain]] when painful stimuli are administered to the skin.<ref>{{cite journal | vauthors = Park TJ, Comer C, Carol A, Lu Y, Hong HS, Rice FL | title = Somatosensory organization and behavior in naked mole-rats: II. Peripheral structures, innervation, and selective lack of neuropeptides associated with thermoregulation and pain | journal = The Journal of Comparative Neurology | volume = 465 | issue = 1 | pages = 104–20 | date = Oct 2003 | pmid = 12926019 | doi = 10.1002/cne.10824 }}</ref><ref>{{ cite news | url  = http://pubs.acs.org/cen/critter/8202molerats.html | title =
Ugly Ducklings | date = 2004-01-07 | accessdate = 2007-08-14 | author = Pepling RS | newspaper = ''[[Chemical & Engineering News]]''}}</ref> New studies have shown that, when the function of SP is genetically disrupted in mice, the animals demonstrated reduced responses to painful stimuli. Moreover, the response to capsaicin was absent or severely reduced in [[knockout mouse|knockout mice]].<ref name="pmid9537323"/>
 
Two other features of the NMR are compelling: 1) with a lifespan up to 28 years,  it is the longest living of all rodents, and 2) it has marked resistance to cancer.<ref name="pmid19858485">{{cite journal | vauthors = Seluanov A, Hine C, Azpurua J, Feigenson M, Bozzella M, Mao Z, Catania KC, Gorbunova V | title = Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 46 | pages = 19352–7 | date = Nov 2009 | pmid = 19858485 | pmc = 2780760 | doi = 10.1073/pnas.0905252106 }}</ref> Although [[NK1R]]s are intact in the NMR, it is unclear whether SP is diminished system-wide or just in skin. This is a potentially important question for future studies on the mechanisms underlying the NMR's resistance to cancer beyond contact inhibition via [[p53]] and [[pRb]] tumor suppressor pathways in the animal.  Abundant preclinical data now support a potentially significant role of SP in promoting [[mitogenesis]], [[cell motility]] and [[neoangiogenesis]]. [[NK1 antagonism]] has been commended as a potential anticancer mechanism by several groups independent groups.<ref name="pmid22545017">{{cite journal | vauthors = Rosso M, Muñoz M, Berger M | title = The role of neurokinin-1 receptor in the microenvironment of inflammation and cancer | journal = TheScientificWorldJournal | volume = 2012 | issue =  | pages = 381434 | year = 2012 | pmid = 22545017 | pmc = 3322385 | doi = 10.1100/2012/381434 }}</ref>
 
== References ==
{{Reflist|33em}}
 
== External links ==
* {{cite web | url = http://www.fibromyalgiasupport.com/library/showarticle.cfm/id/3097 | title = Neurochemical Substance P is Key to Understanding Pain Process | author = Russell J | authorlink = | coauthors = | date = 2001-09-14 | format = | work = Fibromyalgia Library | publisher = ProHealth.com | pages = | archiveurl = | archivedate = | quote = | accessdate = 2008-11-01 }}
 
{{pain}}
{{Tachykinins}}
{{Obsessive–compulsive disorder}}
{{Neuropeptidergics}}
 
[[Category:Neuropeptides]]
[[Category:Neurotransmitters]]
[[Category:Depressogenics]]

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