|tachykinin, precursor 1|
Spacefilling model of substance P
|Alt. symbols||TAC2, NKNA|
|Locus||Chr. 7 q21-q22|
|Molar mass||1347.63 g/mol|
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
|what is ?)(|
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. Substance P and its closely related neurokinin A (NKA) are produced from a polyprotein precursor after differential splicing of the preprotachykinin A gene. The deduced amino acid sequence of substance P is as follows:
with an amidation at the C-terminus. 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.
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. Its tissue distribution and biologic actions were further investigated over the following decades. The eleven-amino-acid structure of the peptide was determined by Chang, et. al in 1971.
The endogenous receptor for substance P is neurokinin 1 receptor (NK1-receptor, NK1R). It belongs to the tachykinin receptor sub-family of GPCRs. 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-1 results in internalization by the clathrin-dependent mechanism to the acidified endosomes where the complex disassociates. Subsequently, SP is degraded and NK-1 is re-expressed on the cell surface.
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). They are found in close association with serotonin (5-HT) and neurons containing norepinephrine that are targeted by the currently used antidepressant drugs. The SP receptor promoter contains regions that are sensitive to cAMP, AP-1, AP-4, CEBPB, 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.
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.
Substance P is a key first responder to most noxious/extreme stimuli (stressors), i.e., those with a potential to compromise 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.
Substance P is a potent vasodilator. Substance P-induced vasodilation is dependent on nitric oxide release. 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). 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).
SP initiates expression of almost all known immunological chemical messengers (cytokines). Also, most of the cytokines, in turn, induce SP and the NK1 receptor. SP is particularly excitatory to cell growth and multiplication, via usual, as well as oncogenic driver. SP is a trigger for nausea and emesis, 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.
Preclinical data support \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. 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. Unfortunately, why NK1RAs have failed as effective analgesics in clinical proof-of-concept studies is still unclear.
Mood, anxiety, learning
Substance P has been associated with the regulation of mood disorders, anxiety, stress, reinforcement, neurogenesis, respiratory rhythm, neurotoxicity, pain, and nociception. In 2014, it was found that substance P played a role in male fruit fly aggression.
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 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.
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, and it was shown that substance P could promote wound healing of non-healing ulcers in humans. SP and its induced cytokines promote multiplication of cells required for repair or replacement, growth of new blood vessels, and "leg-like pods" on cells (including cancer cells) bestowing upon them mobility, and metastasis. 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.
Clinical significance of the SP-NK1R
Quantification in disease
Elevation of serum, plasma, or tissue SP and/or its receptor (NK1R) has been associated with many diseases: sickle cell crisis; inflammatory bowel disease; major depression and related disorders; fibromyalgia; rheumatological; and infections such as HIV/AIDS and respiratory syncytial virus, as well as in cancer. When assayed in the human, the observed variability of the SP concentrations are large, and in some cases the assay methodology is questionable. 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, Reciprocally, cytokines may induce expression of SP and its NK1R. 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.
Dermatological disorders: eczema/psoriasis, chronic pruritus
Infections: HIV-AIDS, Measles, RSV, others
The role of SP in HIV-AIDS has been well-documented. 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.
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. This protozoan was found to secrete serotonin as well as substance P and neurotensin.
Inflammatory bowel disease (IBD)/cystitis
Despite strong preclinical rationale, 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.
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, 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. The actions of aprepitant are said to be entirely central, thus requiring passage of the drug into the central nervous system. 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. It is likely that some peripheral exposure contributes to antiemetic effects, even if through vagal terminals in the clinical setting.
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.
A suggestion of a link to male aggression was made in 2014. One research team found a correlation in male fruit flies and discussed it as a possibility in other species, even humans. Clues found in the brains of fruit flies might lead to further research that reveals the role of substance P in similar behaviour in those other species.
- Harrison S, Geppetti P (Jun 2001). "Substance p". The International Journal of Biochemistry & Cell Biology. 33 (6): 555–76. doi:10.1016/S1357-2725(01)00031-0. PMID 11378438.
- Datar P, Srivastava S, Coutinho E, Govil G (2004). "Substance P: structure, function, and therapeutics". Current Topics in Medicinal Chemistry. 4 (1): 75–103. doi:10.2174/1568026043451636. PMID 14754378.
- Campbell NA, Reece JB (2005). Biology (7th ed.). San Francisco: Pearson Benjamin Cummings. ISBN 9780805371468.
- Wong M, Jeng AY (Jan 1994). "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. doi:10.1002/jnr.490370113. PMID 7511706.
- V Euler US, Gaddum JH (Jun 1931). "An unidentified depressor substance in certain tissue extracts". The Journal of Physiology. 72 (1): 74–87. doi:10.1113/jphysiol.1931.sp002763. PMC 1403098. PMID 16994201.
- Niall, Hugh D.; Leeman, Susan E.; Chang, Michael M. (1971-07-21). "Amino-acid Sequence of Substance P". Nature New Biology. 232 (29): 86–87. doi:10.1038/newbio232086a0. ISSN 2058-1092. PMID 5285346.
- Panula P, Hadjiconstantinou M, Yang HY, Costa E (Oct 1983). "Immunohistochemical localization of bombesin/gastrin-releasing peptide and substance P in primary sensory neurons". The Journal of Neuroscience. 3 (10): 2021–9. doi:10.1523/JNEUROSCI.03-10-02021.1983. PMC 6564571. PMID 6194276.
- Gerard NP, Garraway LA, Eddy RL, Shows TB, Iijima H, Paquet JL, Gerard C (Nov 1991). "Human substance P receptor (NK-1): organization of the gene, chromosome localization, and functional expression of cDNA clones". Biochemistry. 30 (44): 10640–6. doi:10.1021/bi00108a006. PMID 1657150.
- Maggi CA (Sep 1995). "The mammalian tachykinin receptors". General Pharmacology. 26 (5): 911–44. doi:10.1016/0306-3623(94)00292-U. PMID 7557266.
- Grady EF, Garland AM, Gamp PD, Lovett M, Payan DG, Bunnett NW (May 1995). "Delineation of the endocytic pathway of substance P and its seven-transmembrane domain NK1 receptor". Molecular Biology of the Cell. 6 (5): 509–24. doi:10.1091/mbc.6.5.509. PMC 301212. PMID 7545030.
- Yip J, Chahl LA (Apr 2001). "Localization of NK1 and NK3 receptors in guinea-pig brain". Regulatory Peptides. 98 (1–2): 55–62. doi:10.1016/S0167-0115(00)00228-7. PMID 11179779.
- Gobbi G, Cassano T, Radja F, Morgese MG, Cuomo V, Santarelli L, Hen R, Blier P (Apr 2007). "Neurokinin 1 receptor antagonism requires norepinephrine to increase serotonin function". European Neuropsychopharmacology. 17 (5): 328–38. doi:10.1016/j.euroneuro.2006.07.004. PMID 16950604.
- Kovács KA, Steinmann M, Magistretti PJ, Halfon O, Cardinaux JR (Sep 2006). "C/EBPbeta couples dopamine signalling to substance P precursor gene expression in striatal neurones". Journal of Neurochemistry. 98 (5): 1390–9. doi:10.1111/j.1471-4159.2006.03957.x. PMID 16771829.
- Rameshwar P (Nov 1997). "Substance P: a regulatory neuropeptide for hematopoiesis and immune functions". Clinical Immunology and Immunopathology. 85 (2): 129–33. doi:10.1006/clin.1997.4446. PMID 9344694.
- Pinto FM, Almeida TA, Hernandez M, Devillier P, Advenier C, Candenas ML (Jun 2004). "mRNA expression of tachykinins and tachykinin receptors in different human tissues". European Journal of Pharmacology. 494 (2–3): 233–9. doi:10.1016/j.ejphar.2004.05.016. PMID 15212980.
- O'Connor TM, O'Connell J, O'Brien DI, Goode T, Bredin CP, Shanahan F (Nov 2004). "The role of substance P in inflammatory disease". Journal of Cellular Physiology. 201 (2): 167–80. doi:10.1002/jcp.20061. PMID 15334652.
- Bossaller C, Reither K, Hehlert-Friedrich C, Auch-Schwelk W, Graf K, Gräfe M, Fleck E (Oct 1992). "In vivo measurement of endothelium-dependent vasodilation with substance P in man". Herz. 17 (5): 284–90. PMID 1282120.
- Wong BJ, Tublitz NJ, Minson CT (Nov 2005). "Neurokinin-1 receptor desensitization to consecutive microdialysis infusions of substance P in human skin". The Journal of Physiology. 568 (Pt 3): 1047–56. doi:10.1113/jphysiol.2005.095372. PMC 1464169. PMID 16123103.
- Rameshwar P, Gascon P, Ganea D (Mar 1992). "Immunoregulatory effects of neuropeptides. Stimulation of interleukin-2 production by substance p". Journal of Neuroimmunology. 37 (1–2): 65–74. doi:10.1016/0165-5728(92)90156-f. PMID 1372331.
- Palma C, Manzini S (Jan 1998). "Substance P induces secretion of immunomodulatory cytokines by human astrocytoma cells". Journal of Neuroimmunology. 81 (1–2): 127–37. doi:10.1016/s0165-5728(97)00167-7. PMID 9521614.
- Garza A, Weinstock J, Robinson P (Dec 2008). "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. doi:10.1645/GE-1481.1. PMC 2647574. PMID 18576810.
- Freidin M, Kessler JA (Apr 1991). "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. Bibcode:1991PNAS...88.3200F. doi:10.1073/pnas.88.8.3200. PMC 51413. PMID 1707535.
- Derocq JM, Ségui M, Blazy C, Emonds-Alt X, Le Fur G, Brelire JC, Casellas P (Dec 1996). "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. doi:10.1016/s0014-5793(96)01346-4. PMID 8985172.
- Koon HW, Zhao D, Na X, Moyer MP, Pothoulakis C (Oct 2004). "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. doi:10.1074/jbc.M408523200. PMID 15319441.
- Fiebich BL, Schleicher S, Butcher RD, Craig A, Lieb K (Nov 2000). "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. doi:10.4049/jimmunol.165.10.5606. PMID 11067916.
- Kearney CJ, Sheridan C, Cullen SP, Tynan GA, Logue SE, Afonina IS, Vucic D, Lavelle EC, Martin SJ (Feb 2013). "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. doi:10.1074/jbc.M112.422410. PMC 3576092. PMID 23275336.
- Hesketh PJ (Jul 2001). "Potential role of the NK1 receptor antagonists in chemotherapy-induced nausea and vomiting". Supportive Care in Cancer. 9 (5): 350–4. doi:10.1007/s005200000199. PMID 11497388.
- Donkin JJ, Turner RJ, Hassan I, Vink R (2007). "Substance P in traumatic brain injury". Progress in Brain Research. 161: 97–109. doi:10.1016/S0079-6123(06)61007-8. ISBN 9780444530172. PMID 17618972.
- De Felipe C, Herrero JF, O'Brien JA, Palmer JA, Doyle CA, Smith AJ, Laird JM, Belmonte C, Cervero F, Hunt SP (Mar 1998). "Altered nociception, analgesia and aggression in mice lacking the receptor for substance P". Nature. 392 (6674): 394–7. Bibcode:1998Natur.392..394D. doi:10.1038/32904. PMID 9537323.
- Ebner K, Singewald N (Oct 2006). "The role of substance P in stress and anxiety responses". Amino Acids. 31 (3): 251–72. doi:10.1007/s00726-006-0335-9. PMID 16820980.
- Huston JP, Hasenöhrl RU, Boix F, Gerhardt P, Schwarting RK (1993). "Sequence-specific effects of neurokinin substance P on memory, reinforcement, and brain dopamine activity". Psychopharmacology. 112 (2–3): 147–62. doi:10.1007/BF02244906. PMID 7532865.
- Park SW, Yan YP, Satriotomo I, Vemuganti R, Dempsey RJ (Sep 2007). "Substance P is a promoter of adult neural progenitor cell proliferation under normal and ischemic conditions". Journal of Neurosurgery. 107 (3): 593–9. doi:10.3171/JNS-07/09/0593. PMID 17886560.
- Bonham AC (Sep 1995). "Neurotransmitters in the CNS control of breathing". Respiration Physiology. 101 (3): 219–30. doi:10.1016/0034-5687(95)00045-F. PMID 8606995.
- Zubrzycka M, Janecka A (Dec 2000). "Substance P: transmitter of nociception (Minireview)". Endocrine Regulations. 34 (4): 195–201. PMID 11137976.
- Gorman, James, To Study Aggression, a Fight Club for Flies, The New York Times, February 4, 2014, page D5 of the New York edition
- Hornby PJ (Dec 2001). "Central neurocircuitry associated with emesis". The American Journal of Medicine. 111 Suppl 8A (8): 106S–112S. doi:10.1016/S0002-9343(01)00849-X. PMID 11749934.
- Reid TW, Murphy CJ, Iwahashi CK, Foster BA, Mannis MJ (Aug 1993). "Stimulation of epithelial cell growth by the neuropeptide substance P". Journal of Cellular Biochemistry. 52 (4): 476–85. doi:10.1002/jcb.240520411. PMID 7693729.
- Brown SM, Lamberts DW, Reid TW, Nishida T, Murphy CJ (Jul 1997). "Neurotrophic and anhidrotic keratopathy treated with substance P and insulinlike growth factor 1". Archives of Ophthalmology. 115 (7): 926–7. doi:10.1001/archopht.1997.01100160096021. PMID 9230840.
- Katsanos GS, Anogeianaki A, Orso C, Tete S, Salini V, Antinolfi PL, Sabatino G (2008). "Impact of substance P on cellular immunity" (PDF). Journal of Biological Regulators and Homeostatic Agents. 22 (2): 93–8. PMID 18597700.
- 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. Bibcode:2011PLoSO...625332M. doi:10.1371/journal.pone.0025332. PMC 3179504. PMID 21966499.
- Muñoz M, Rosso M, Coveñas R (Jun 2011). "The NK-1 receptor: a new target in cancer therapy". Current Drug Targets. 12 (6): 909–21. doi:10.2174/138945011795528796. PMID 21226668.
- Seckl MJ, Higgins T, Widmer F, Rozengurt E (Jan 1997). "[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. PMID 8988040.
- Muñoz M, Rosso M, Coveñas R (2010). "A new frontier in the treatment of cancer: NK-1 receptor antagonists". Current Medicinal Chemistry. 17 (6): 504–16. doi:10.2174/092986710790416308. PMID 20015033.
- Muñoz M, Coveñas R (Oct 2013). "Involvement of substance P and the NK-1 receptor in cancer progression". Peptides. 48: 1–9. doi:10.1016/j.peptides.2013.07.024. PMID 23933301.
- Berger M, Neth O, Ilmer M, Garnier A, Salinas-Martín MV, de Agustín Asencio JC, von Schweinitz D, Kappler R, Muñoz M (May 2014). "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. doi:10.1016/j.jhep.2013.12.024. PMID 24412605.
- Michaels LA, Ohene-Frempong K, Zhao H, Douglas SD (Nov 1998). "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. doi:10.1182/blood.V92.9.3148. PMID 9787150.
- Mantyh CR, Gates TS, Zimmerman RP, Welton ML, Passaro EP, Vigna SR, Maggio JE, Kruger L, Mantyh PW (May 1988). "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. Bibcode:1988PNAS...85.3235M. doi:10.1073/pnas.85.9.3235. PMC 280179. PMID 2834738.
- Fehder WP, Sachs J, Uvaydova M, Douglas SD (1997). "Substance P as an immune modulator of anxiety". Neuroimmunomodulation. 4 (1): 42–8. doi:10.1159/000097314. PMID 9326744.
- Geracioti TD, Carpenter LL, Owens MJ, Baker DG, Ekhator NN, Horn PS, Strawn JR, Sanacora G, Kinkead B, Price LH, Nemeroff CB (Apr 2006). "Elevated cerebrospinal fluid substance p concentrations in posttraumatic stress disorder and major depression". The American Journal of Psychiatry. 163 (4): 637–43. doi:10.1176/appi.ajp.163.4.637. PMID 16585438.
- Schwarz MJ, Ackenheil M (Mar 2002). "The role of substance P in depression: therapeutic implications". Dialogues in Clinical Neuroscience. 4 (1): 21–9. PMC 3181667. PMID 22033776.
- Rupniak NM (May 2002). "New insights into the antidepressant actions of substance P (NK1 receptor) antagonists". Canadian Journal of Physiology and Pharmacology. 80 (5): 489–94. doi:10.1139/y02-048. PMID 12056558.
- Vaerøy H, Helle R, Førre O, Kåss E, Terenius L (Jan 1988). "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. doi:10.1016/0304-3959(88)90019-X. PMID 2448729.
- Anichini M, Cesaretti S, Lepori M, Maddali Bongi S, Maresca M, Zoppi M (Jan 1997). "Substance P in the serum of patients with rheumatoid arthritis". Revue du Rhumatisme. 64 (1): 18–21. PMID 9051855.
- Douglas SD, Ho WZ, Gettes DR, Cnaan A, Zhao H, Leserman J, Petitto JM, Golden RN, Evans DL (Oct 2001). "Elevated substance P levels in HIV-infected men". AIDS. 15 (15): 2043–5. doi:10.1097/00002030-200110190-00019. PMID 11600835.
- Palma C, Maggi CA (2000). "The role of tachykinins via NK1 receptors in progression of human gliomas". Life Sciences. 67 (9): 985–1001. doi:10.1016/s0024-3205(00)00692-5. PMID 10954033.
- Singh D, Joshi DD, Hameed M, Qian J, Gascón P, Maloof PB, Mosenthal A, Rameshwar P (Jan 2000). "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. Bibcode:2000PNAS...97..388S. doi:10.1073/pnas.97.1.388. PMC 26673. PMID 10618428.
- Campbell DE, Raftery N, Tustin R, Tustin NB, Desilvio ML, Cnaan A, Aye PP, Lackner AA, Douglas SD (Nov 2006). "Measurement of plasma-derived substance P: biological, methodological, and statistical considerations". Clinical and Vaccine Immunology. 13 (11): 1197–203. doi:10.1128/CVI.00174-06. PMC 1656550. PMID 16971517.
- Ho WZ, Douglas SD (Dec 2004). "Substance P and neurokinin-1 receptor modulation of HIV". Journal of Neuroimmunology. 157 (1–2): 48–55. doi:10.1016/j.jneuroim.2004.08.022. PMID 15579279.
- Lambert N, Lescoulié PL, Yassine-Diab B, Enault G, Mazières B, De Préval C, Cantagrel A (Aug 1998). "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. doi:10.1046/j.1365-2249.1998.00621.x. PMC 1905034. PMID 9717978.
- Azzolina A, Bongiovanni A, Lampiasi N (Dec 2003). "Substance P induces TNF-alpha and IL-6 production through NF kappa B in peritoneal mast cells". Biochimica et Biophysica Acta. 1643 (1–3): 75–83. doi:10.1016/j.bbamcr.2003.09.003. PMID 14654230.
- Douglas SD, Leeman SE (Jan 2011). "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 (1): 83–95. Bibcode:2011NYASA1217...83D. doi:10.1111/j.1749-6632.2010.05826.x. PMC 3058850. PMID 21091716.
- Łazarczyk M, Matyja E, Lipkowski A (2007). "Substance P and its receptors -- a potential target for novel medicines in malignant brain tumour therapies (mini-review)". Folia Neuropathologica. 45 (3): 99–107. PMID 17849359.
- van der Hart MG (2009). Substance P and the Neurokinin 1 receptor: From behavior to bioanalysis (Ph.D.). University of Groningen. ISBN 978-90-367-3874-3.
- Hon KL, Lam MC, Wong KY, Leung TF, Ng PC (Nov 2007). "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. doi:10.1111/j.1365-2133.2007.08149.x. PMID 17725670.
- King KA, Hu C, Rodriguez MM, Romaguera R, Jiang X, Piedimonte G (Feb 2001). "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. doi:10.1165/ajrcmb.24.2.4264. PMID 11159042.
- Piedimonte G (Mar 2001). "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. doi:10.1164/ajrccm.163.supplement_1.2011113. PMID 11254547.
- Steinitz H (Aug 1979). "[Chronic recurrent intestinal amebiasis in Israel (author's transl)]". Leber, Magen, Darm (in German). 9 (4): 175–9. PMID 491812.
- Stark D, van Hal S, Marriott D, Ellis J, Harkness J (Jan 2007). "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. doi:10.1016/j.ijpara.2006.09.009. PMID 17070814.
- McGowan K, Kane A, Asarkof N, Wicks J, Guerina V, Kellum J, Baron S, Gintzler AR, Donowitz M (Aug 1983). "Entamoeba histolytica causes intestinal secretion: role of serotonin". Science. 221 (4612): 762–4. Bibcode:1983Sci...221..762M. doi:10.1126/science.6308760. PMID 6308760.
- McGowan K, Guerina V, Wicks J, Donowitz M (1985). "Chapter 8: Secretory Hormones of Entamoeba histolytica". In D. Evered, J. Whelan (eds.). Microbial Toxins and Diarrhoeal Disease. Ciba Found. Symp. 112. pp. 139–54. doi:10.1002/9780470720936.ch8. PMID 2861068.
- 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. doi:10.1152/physrev.00031.2013. PMC 3929113. PMID 24382888.
- 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. doi:10.1111/j.1365-2036.2011.04958.x. PMC 4073664. PMID 22221140.
- Huskey SE, Dean BJ, Bakhtiar R, Sanchez RI, Tattersall FD, Rycroft W, Hargreaves R, Watt AP, Chicchi GG, Keohane C, Hora DF, Chiu SH (Jun 2003). "Brain penetration of aprepitant, a substance P receptor antagonist, in ferrets". Drug Metabolism and Disposition. 31 (6): 785–91. doi:10.1124/dmd.31.6.785. PMID 12756213.
- Diemunsch P, Joshi GP, Brichant JF (Jul 2009). "Neurokinin-1 receptor antagonists in the prevention of postoperative nausea and vomiting". British Journal of Anaesthesia. 103 (1): 7–13. doi:10.1093/bja/aep125. PMID 19454547.
- Russell J (2001-09-14). "Neurochemical Substance P is Key to Understanding Pain Process". Fibromyalgia Library. ProHealth.com. Retrieved 2008-11-01.
- Fight Club for Flies video, Science Take, New York Times, February 3, 2014