Amino Acids

, Volume 46, Issue 7, pp 1727–1750 | Cite as

Involvement of substance P and the NK-1 receptor in human pathology

  • Miguel MuñozEmail author
  • Rafael Coveñas
Original Article


The peptide substance P (SP) shows a widespread distribution in both the central and peripheral nervous systems, but it is also present in cells not belonging to the nervous system (immune cells, liver, lung, placenta, etc.). SP is located in all body fluids, such as blood, cerebrospinal fluid, breast milk, etc. i.e. it is ubiquitous in human body. After binding to the neurokinin-1 (NK-1) receptor, SP regulates many pathophysiological functions in the central nervous system, such as emotional behavior, stress, depression, anxiety, emesis, vomiting, migraine, alcohol addiction, seizures and neurodegeneration. SP has been also implicated in pain, inflammation, hepatitis, hepatotoxicity, cholestasis, pruritus, myocarditis, bronchiolitis, abortus, bacteria and viral infection (e.g., HIV infection) and it plays an important role in cancer (e.g., tumor cell proliferation, antiapoptotic effects in tumor cells, angiogenesis, migration of tumor cells for invasion, infiltration and metastasis). This means that the SP/NK-1 receptor system is involved in the molecular bases of many human pathologies. Thus, knowledge of this system is the key for a better understanding and hence a better management of many human diseases. In this review, we update the involvement of the SP/NK-1 receptor system in the physiopathology of the above-mentioned pathologies and we suggest valuable future therapeutic interventions involving the use of NK-1 receptor antagonists, particularly in the treatment of emesis, depression, cancer, neural degeneration, inflammatory bowel disease, viral infection and pruritus, in which that system is upregulated.


Substance P NK-1 receptor NK-1 receptor antagonists Molecular bases Human pathology 



The authors thank N. Skinner (University of Salamanca, Spain) for stylistic revision of the English text. The technical assistance of Dr. Miguel E. Muñoz (Virgen del Rocío University Hospital, Sevilla, Spain) and Mr. Javier Muñoz (University of Sevilla, Spain) is gratefully acknowledged.

Conflict of interest

USPTO Application no. 20090012086 “Use of non-peptide NK-1 receptor antagonists for the production of apoptosis in tumor cells” (Miguel Muñoz).


  1. Abidi MH, Tageja N, Ayash L, Abrams J, Ratanatharathorn V, Al-Kadhimi Z, Lum L, Cronin S, Ventimiglia M, Uberti J (2012) Aprepitant for prevention of nausea and vomiting secondary to high-dose cyclophosphamide administered to patients undergoing autologous peripheral blood stem cells mobilization: a phase II trial. Support Care Cancer 20:2363–2369PubMedCentralPubMedGoogle Scholar
  2. Angulo JA, McEwen BS (1994) Molecular aspects of neuropeptide regulation and function in the corpus striatum and nucleus accumbens. Brain Res Brain Res Rev 19:1–28PubMedGoogle Scholar
  3. Annunziata P, Cioni C, Toneatto S, Paccagnini E (1998) HIV-1 gp120 increases the permeability of rat brain endothelium cultures by a mechanism involving substance P. AIDS 12:2377–2385PubMedGoogle Scholar
  4. Arck PC, Merali FS, Stanisz AM, Stead RH, Chaouat G, Manuel J, Clark DA (1995) Stress-induced murine abortion associated with substance P-dependent alteration in cytokines in maternal uterine decidua. Biol Reprod 53:814–819PubMedGoogle Scholar
  5. Armstrong DM, Pickel VM, Joh TH, Reis DJ, Miller RJ (1981) Immunocytochemical localization of catecholamine synthesizing enzymes and neuropeptides in the area postrema and medial nucleus tractus solitarius of rat brain. J Comp Neurol 196:505–517PubMedGoogle Scholar
  6. Azzari C, Rossi ME, Resti M, Caldini AL, Lega L, Galli L, Fico E, Vierucci A (1992) Changed levels of substance P and somatostatin in HIV-positive children. Pediatr Med Chir 14:577–581PubMedGoogle Scholar
  7. Baek MN, Jung KH, Halder D, Choi MR, Lee BH, Lee BC, Jung MH, Choi IG, Chung MK, Oh DY, Chai YG (2010) Artificial microRNA-based neurokinin-1 receptor gene silencing reduces alcohol consumption in mice. Neurosci Lett 475:124–128PubMedGoogle Scholar
  8. Bang R, Sass G, Kiemer AK, Vollmar AM, Neuhuber WL, Tiegs G (2003) Neurokinin-1 receptor antagonists CP-96,345 and L-733,060 protect mice from cytokine-mediated liver injury. J Pharmacol Exp Ther 305:31–39PubMedGoogle Scholar
  9. Bang R, Biburger M, Neuhuber WL, Tiegs G (2004) Neurokinin-1 receptor antagonists protect mice from CD95- and tumor necrosis factor-alpha-mediated apoptotic liver damage. J Pharmacol Exp Ther 308:1174–1180PubMedGoogle Scholar
  10. Bardelli C, Amoruso A, Manzetti E, Fresu LG, Valsesia R, Zeppegno P, Brunelleschi S (2013) Recurrent major depressive disorder: imbalance of neurokinin (NK)-1 and NK-2 receptor expression in monocytes. Pharmacol Res 68:24–30PubMedGoogle Scholar
  11. Berger M, Neth O, Ilmer M, Garnier A, Salinas-Martín MV, de Agustín Asencio JC, von Schweinitz D, Kappler R, Muñoz M (2014) Hepatoblastoma cells express truncated neurokinin-1 receptor and can be growth inhibited by aprepitant in vitro and in vivo. J Hepatol (in press)Google Scholar
  12. Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA, Moskowitz MA (2002) Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med 8:136–142PubMedGoogle Scholar
  13. Borsook D, Upadhyay J, Klimas M, Schwarz AJ, Coimbra A, Baumgartner R, George E, Potter WZ, Large T, Bleakman D, Evelhoch J, Iyengar S, Becerra L, Hargreaves RJ (2012) Decision-making using fMRI in clinical drug development: revisiting NK-1 receptor antagonists for pain. Drug Discov Today 17:964–973PubMedGoogle Scholar
  14. Bountra C, Bunce K, Dale K, Gardner C, Jordan C, Twissell D, Ward P (1993) Anti-emetic profile of a non-peptide neurokinin NK1 receptor antagonist, CP-99,994, in ferrets. Eur J Pharmacol 249:R3–R4PubMedGoogle Scholar
  15. Brener S, González-Moles MA, Tostes D, Esteban F, Gil-Montoya JA, Ruiz-Avila I, Bravo M, Muñoz M (2009) A role for the substance P/NK-1 receptor complex in cell proliferation in oral squamous cell carcinoma. Anticancer Res 29:2323–2329PubMedGoogle Scholar
  16. Carletti R, Corsi M, Melotto S, Caberlotto L (2005) Down-regulation of amygdala preprotachykinin A mRNA but not 3H-SP receptor binding sites in subjects affected by mood disorders and schizophrenia. Eur J Neurosci 21:1712–1718PubMedGoogle Scholar
  17. Castro-Obregón S, del Río G, Chen SF, Swanson RA, Frankowski H, Rao RV, Stoka V, Vesce S, Nicholls DG, Bredesen DE (2002) A ligand-receptor pair that triggers a non-apoptotic form of programmed cell death. Cell Death Differ 9:807–817PubMedGoogle Scholar
  18. Chauhan VS, Sterka DG Jr, Gray DL, Bost KL, Marriott I (2008) Neurogenic exacerbation of microglial and astrocyte responses to Neisseria meningitidis and Borrelia burgdorferi. J Immunol 180:8241–8249PubMedCentralPubMedGoogle Scholar
  19. Chauhan VS, Kluttz JM, Bost KL, Marriott I (2011) Prophylactic and therapeutic targeting of the neurokinin-1 receptor limits neuroinflammation in a murine model of pneumococcal meningitis. J Immunol 186:7255–7263PubMedCentralPubMedGoogle Scholar
  20. Connor HE (1998) Clinical evaluation of a novel, potent, CNS penetrating NK-1 receptor antagonist in the acute treatment of migraine. Cephalalgia 18:392Google Scholar
  21. Cuello AC, Kanazawa I (1978) The distribution of substance P immunoreactive fibres in the rat central nervous system. J Comp Neurol 178:129–156PubMedGoogle Scholar
  22. de Lanerolle NC, Brines M, Williamson A, Kim JH, Spencer DD (1992) Neurotransmitters and their receptors in human temporal lobe epilepsy. Epilepsy Res 7:235–250Google Scholar
  23. Diener HC (2003) RPR100893 Study Group. RPR100893, a substance-P antagonist, is not effective in the treatment of migraine attacks. Cephalalgia 23:183–185PubMedGoogle Scholar
  24. Dionne RA, Max MB, Gordon SM, Parada S, Sang C, Gracely RH, Sethna NF, MacLean DB (1998) The substance P receptor antagonist CP-99,994 reduces acute postoperative pain. Clin Pharmacol Ther 64:562–568PubMedGoogle Scholar
  25. Dunzendorfer S, Meierhofer C, Wiedermann CJ (1998) Signaling in neuropeptide-induced migration of human eosinophils. J Leukocyte Biol 64:828–834PubMedGoogle Scholar
  26. Ebner K, Singewald N (2006) The role of substance P in stress and anxiety responses. Amino Acids 31:251–272PubMedGoogle Scholar
  27. Ebner K, Rupniak NM, Saria A, Singewald N (2004) Substance P in the medial amygdala: emotional stress-sensitive release and modulation of anxiety-related behavior in rats. Proc Natl Acad Sci USA 101:4280–4285PubMedCentralPubMedGoogle Scholar
  28. Ebner K, Sartori SB, Singewald N (2009) Tachykinin receptors as therapeutic targets in stress-related disorders. Curr Pharm Des 15:1647–1674PubMedGoogle Scholar
  29. Esteban F, González-Moles MA, Castro D, Martín-Jaén MM, Redondo M, Ruiz-Avila I, Rosso M, Muñoz M (2009) Expression of substance P and neurokinin-1-receptor in laryngeal cancer: linking chronic inflammation to cancer promotion and progression. Histopathology 54:258–260PubMedGoogle Scholar
  30. Fackler OT, Grosse R (2008) Cell motility through plasma membrane blebbing. J Cell Biol 181:879–884PubMedCentralPubMedGoogle Scholar
  31. Feistritzer C, Clausen J, Sturn DH, Djanani A, Gunsilius E, Wiedermann CJ, Kahler CM (2003) Natural killer cell functions mediated by the neuropeptide substance P. Regul Pept 116:119–126PubMedGoogle Scholar
  32. Fong TM, Yu H, Strader CD (1992) Molecular basis for the species selectivity of the neurokinin-1 receptor antagonists CP-96,345 and RP-67,580. J Biol Chem 267:25668–25671Google Scholar
  33. Friess H, Zhu Z, Liard V, Shi X, Shrikhande SV, Wang L, Lieb K, Korc M, Palma C, Zimmermann A, Reubi JC, Buchler MW (2003) Neurokinin-1 receptor expression and its potential effects on tumor growth in human pancreatic cancer. Lab Invest 83:731–742PubMedGoogle Scholar
  34. Furmark T, Appel L, Michelgard A, Wahlstedt K, Ahs F, Zancan S, Jacobsson E, Flyckt K, Grohp M, Bergström M, Pich EM, Nilsson LG, Bani M, Långström B, Fredrikson M (2005) Cerebral blood flow changes after treatment of social phobia with the eurokinin-1 antagonist GR-205,171, citalopram, or placebo. Biol Psychiatry 58:132–142PubMedGoogle Scholar
  35. Fusayasu E, Kowa H, Takeshima T, Nakaso K, Nakashima K (2007) Increased plasma substance P and CGRP levels, and high ACE activity in migraineurs during headache-free periods. Pain 128:209–214PubMedGoogle Scholar
  36. Gallai V, Sarchielli P, Flofidi A, Francceschini M, Codini M, Trequattrini A, Palumbo R (1995) Vasoactive peptide levels in the plasma of young migraine patients with and without aura assessed both interictally and ictally. Cephalalgia 15:384–390PubMedGoogle Scholar
  37. Garant DS, Iadarola MJ, Gale K (1986) Substance P antagonists in substantia nigra are anticonvulsant. Brain Res 382:372–378PubMedGoogle Scholar
  38. George DT, Gilman J, Hersh J, Thorsell A, Herion D, Geyer C, Peng X, Kielbasa W, Rawlings R, Brandt JE, Gehlert DR, Tauscher JT, Hunt SP, Hommer D, Heilig M (2008) Neurokinin 1 receptor antagonism as a possible therapy for alcoholism. Science 319:1536–1539PubMedGoogle Scholar
  39. Goadsby PJ, Edvinsson L, Ekman R (1990) Vasoactive peptide release in the extracerebral circulation of human during migraine headache. Ann Neurol 28:183–187PubMedGoogle Scholar
  40. Goldstein DJ, Wang O, Saper JR, Stoltz R, Silberstein SD, Mathew NT (1997) Ineffectiveness of neurokinin-1 antagonist in acute migraine: a crossover study. Cephalalgia 17:785–790PubMedGoogle Scholar
  41. Goldstein DJ, Wang O, Gitter BD, Iyengar S (2001) Dose-response study of the analgesic effect of lanepitant in patients with painful diabetic neuropathy. Clin Neuropharmacol 24:16–22PubMedGoogle Scholar
  42. González-Moles MA, Mosqueda-Taylor A, Esteban F, Gil-Montoya JA, Díaz-Franco MA, Delgado M, Muñoz M (2008) Cell proliferation associated with actions of the substance P/NK-1 receptor complex in keratocystic odontogenic tumours. Oral Oncol 44:1127–1133PubMedGoogle Scholar
  43. Graham GJ, Stevens JM, Page NM, Grant AD, Brain SD, Lowry PJ, Gibbins JM (2004) Tachykinins regulate the function of platelets. Blood 104:1058–1065PubMedGoogle Scholar
  44. Green SA, Alon A, Ianus J, McNaughton KS, Tozzi CA, Reiss TF (2006) Efficacy and safety of a neurokinin-1 receptor antagonist in postmenopausal women with overactive bladder with urge urinary incontinence. J Urol 176:2535–2540PubMedGoogle Scholar
  45. Guha S, Eibl G, Kisfalvi K, Fan RS, Burdick M, Reber H, Hines OJ, Strieter R, Rozengurt E (2005) Broad-spectrum G protein–coupled receptor antagonist, [D-Arg1, DTrp5,7,9, Leu11]SP: a dual inhibitor of growth and angiogenesis in pancreatic cancer. Cancer Res 65:2738–2745PubMedGoogle Scholar
  46. Harrison S, Geppetti P (2001) Substance P. Int J Biochem Cell Biol 33:555–576PubMedGoogle Scholar
  47. Harrowe G, Mitsuhashi M, Payan DG (1990) Measles virus-substance P receptor interactions. Possible novel mechanism of viral fusion. J Clin Invest 85:1324–1327PubMedCentralPubMedGoogle Scholar
  48. Hegde A, Zhang H, Moochhala SM, Bhatia M (2007) Neurokinin-1 receptor antagonist treatment protects mice against lung injury in polymicrobial sepsis. J Leukoc Biol 82:678–685PubMedGoogle Scholar
  49. Hegde A, Tamizhselvi R, Manikandan J, Melendez AJ, Moochhala SM, Bhatia M (2010a) Substance P in polymicrobial sepsis: molecular fingerprint of lung injury in preprotachykinin-A −/− mice. Mol Med 16:188–198PubMedCentralPubMedGoogle Scholar
  50. Hegde A, Koh YH, Moochhala SM, Bhatia M (2010b) Neurokinin-1 receptor antagonist treatment in polymicrobial sepsis: molecular insights. Int J Inflam 2010:601098PubMedCentralPubMedGoogle Scholar
  51. Herrstedt J, Apornwirat W, Shaharyar A, Aziz Z, Roila F, Van Belle S, Russo MW, Levin J, Ranganathan S, Guckert M, Gunberg SM (2009) Phase III trial of casopitant, a novel neurokinin-1 receptor antagonist, for the prevention of nausea and vomiting in patients receiving moderately emetogenic chemotherapy. J Clin Oncol 27:5363–5369PubMedGoogle Scholar
  52. Hesketh PJ, Gralla RJ, Webb RT, Ueno W, DelPrete S, Bachinsky ME, Dirlam NL, Stack CB, Silberman SL (1999) Randomized Phase II study of the neurokinin 1 receptor antagonist CJ-11,974 in the control of cisplatin-induced emesis. J Clin Oncol 17:338–343PubMedGoogle Scholar
  53. Hill R (2000) NK1 (substance P) receptor antagonists: why are they not analgesic in humans? Trends Pharmacol Sci 21:244–246PubMedGoogle Scholar
  54. Ho WZ, Cnaan A, Li YH, Zhao H, Lee HR, Song L, Douglas SD (1996) Substance P modulates human immunodeficiency virus replication in human peripheral blood monocyte-derived macrophages. AIDS Res Hum Retroviruses 12:195–198PubMedGoogle Scholar
  55. Hökfelt T, Pernow B, Nilsson G, Wetterberg L, Goldstein M, Jeffcoate SL (1978) Dense plexus of substance P-immunoreactive nerve terminals in eminentia medialis of the primate hypothalamus. Proc Natl Acad Sci USA 74:1013–1015Google Scholar
  56. Hökfelt T, Broberger C, David Xu Z-Q, Sergeyev V, Ubink R, Diez M (2000) Neuropeptides: an overview. Neuropharmacology 39:1337–1356PubMedGoogle Scholar
  57. Hökfelt T, Pernow B, Wahren J (2001) Substance P: a pioneer amongst neuropeptides. J Intern Med 249:27–40PubMedGoogle Scholar
  58. Holzer P (1988) Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides. Neuroscience 24:739–768PubMedGoogle Scholar
  59. Janelsins BM, Mathers AR, Tkacheva OA, Erdos G, Shufesky WJ, Morelli AE, Larregina AT (2009) Proinflammatory tachykinins that signal through the neurokinin 1 receptor promote survival of dendritic cells and potent cellular immunity. Blood 113:3017–3026PubMedCentralPubMedGoogle Scholar
  60. Jang JH, Nam TS, Paik KS, Leem JW (2004) Involvement of peripherally released substance P and calcitonin gene-related peptide in mediating mechanical hyperalgesia in a traumatic neuropathy model of the rat. Neurosci Lett 360:129–132PubMedGoogle Scholar
  61. Kalinichev M, Bradford A, Bison S, Lucas A, Sartori I, Garbati N, Andreetta F, Bate S, Austin NE, Jones DN, Read KD, Alvaro G, Large CH (2010) Potentiation of the anticonvulsant efficacy of sodium channel inhibitors by an NK1-receptor antagonist in the rat. Epilepsia 51:1543–1551PubMedGoogle Scholar
  62. Keller M, Montgomery S, Ball W, Morrison M, Snavely D, Liu G, Hargreaves R, Hietala J, Lines C, Beebe K, Reines S (2006) Lack of efficacy of the substance P (neurokinin-1 receptor) antagonist aprepitant in the treatment of major depressive disorder. Biol Psychiatry 59:216–223PubMedGoogle Scholar
  63. King KA, Hu C, Rodriguez MM, Romaguera R, Jiang X, Piedimonte G (2001) Exaggerated neurogenic inflammation and substance P receptor upregulation in RSV-infected weanling rats. Am J Respir Cell Mol Biol 24:101–107PubMedGoogle Scholar
  64. Ko FJ, Chiang CH, Liu WJ, Chiang W (1991) Somatostatin, substance P, prolactin and vasoactive intestinal peptide levels in serum and cerebrospinal fluid of children with seizure disorders. Gaoxiong Yi Xue Ke Xue Za Zhi 7:391–397PubMedGoogle Scholar
  65. Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ, Reines SA, Liu G, Snavely D, Wyatt-Knowles E, Halle JJ, Mills SG, MacCoss M, Swain CJ, Harrison T, Hill RG, Hefti F, Scolnick EM, Cascieri MA, Chicchi GG, Sadowski S, Williams AR, Hewson L, Smith D, Carlsson EJ, Hargreaves RJ, Rupniak NM (1998) Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 281:1640–1645PubMedGoogle Scholar
  66. Kramer MS, Winokur A, Kelsey J, Preskorn SH, Rothschild AJ, Snavely D, Ghosh K, Ball WA, Reines SA, Munjack D, Apter JT, Cunningham L, Kling M, Bari M, Getson A, Lee Y (2004) Demonstration of the efficacy and safety of a novel substance P (NK-1) receptor antagonist in major depression. Neuropsychopharmacology 29:385–392PubMedGoogle Scholar
  67. Lai JP, Douglas SD, Rappaport E, Wu JM, Ho WZ (1998) Identification of a delta isoform of preprotachykinin mRNA in human mononuclear phagocytes and lymphocytes. J Neuroimmunol 91:121–128PubMedGoogle Scholar
  68. Lambrecht BN, Germonpre PR, Everaert EG, Carro-Muino I, De Veerman M, de Felipe C, Hunt SP, Thielemans K, Joos GF, Pauwels RA (1999) Endogenously produced substance P contributes to lymphocyte proliferation induced by dendritic cells and direct TCR ligation. Eur J Immunol 29:3815–3825PubMedGoogle Scholar
  69. Lang K, Drell TL, Lindecke A, Niggemann B, Kaltschmidt C, Zaenker KS, Entschladen F (2004) Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs. Int J Cancer 112:231–238PubMedGoogle Scholar
  70. Lembeck F, Donnerer J, Tsuchiya M, Nagahisa A (1992) The non-peptide tachykinin antagonist, CP-96.345, is a potent inhibitor of neurogenic inflammation. Br J Pharmacol 105:527–530PubMedCentralPubMedGoogle Scholar
  71. Lieb K, Fiebich BL, Berger M, Bauer J, Schulze-Osthoff K (1997) The neuropeptide substance P activates transcription factor NF-kappa B and kappa B-dependent gene expression in human astrocytoma cells. J Immunol 159:4952–4958PubMedGoogle Scholar
  72. Lieb KL, Treffurth Y, Hamke M, Akundi RS, von Kleinsorgen M, Fiebich BL (2003) Valproic acid inhibits substance P-induced activation of protein kinase C epsilon and expression of the substance P receptor. J Neurochem 86:69–76PubMedGoogle Scholar
  73. Liu H, Cao Y, Basbaum AI, Mazarati AM, Sankar R, Wasterlain CG (1999) Resistance to excitotoxin-induced seizures and neuronal death in mice lacking the preprotachykinin A gene. Proc Natl Acad Sci USA 96:12096–12101PubMedCentralPubMedGoogle Scholar
  74. Lotz M, Vaughan JH, Carson DA (1988) Effect of neuropeptides on production of inflammatory cytokines by human monocytes. Science 241:1218–1221PubMedGoogle Scholar
  75. Maeno H, Kiyama H, Tohyama M (1993) Distribution of the substance P (NK1) receptor in the central nervous system. Mol Brain Res 18:43–58PubMedGoogle Scholar
  76. Mai JK, Stephens PH, Hopf A, Cuello AC (1986) Substance P in the human brain. Neuroscience 17:709–739PubMedGoogle Scholar
  77. Makhortova NR, Askovich P, Patterson CE, Gechman LA, Gerard NP, Rall GF (2007) Neurokinin-1 enables measles virus trans-synaptic spread in neurons. Virology 362:235–244PubMedCentralPubMedGoogle Scholar
  78. Manak MM, Moshkoff DA, Nguyen LT, Meshki J, Tebas P, Tuluc F, Douglas SD (2010) Anti-HIV-1 activity of the neurokinin-1 receptor antagonist aprepitant and synergistic interactions with other antiretrovirals. AIDS 24:2789–2796PubMedCentralPubMedGoogle Scholar
  79. Marriott I, Mason MJ, Elhofy A, Bost KL (2000) Substance P activates NF-kappaB independent of elevations in intracellular calcium in murine macrophages and dendritic cells. J Neuroimmunol 102:163–171PubMedGoogle Scholar
  80. Meshki J, Douglas SD, Lai JP, Schwartz L, Kilpatrick LE, Tuluc F (2009) Neurokinin 1 receptor mediates membrane blebbing in HEK293 cells through a Rho/Rho-associated coiled-coil kinase-dependent mechanism. J Biol Chem 284:9280–9289PubMedCentralPubMedGoogle Scholar
  81. Muñoz M, Coveñas R (2010) A new frontier in the treatment of cancer: NK-1 receptor antagonists. Curr Med Chem 17:504–516PubMedGoogle Scholar
  82. Muñoz M, Coveñas R (2011) NK-1 receptor antagonists: a new paradigm in pharmacological therapy. Curr Med Chem 18:1820–1831PubMedGoogle Scholar
  83. Muñoz M, Coveñas R (2013a) Involvement of substance P and the NK-1 receptor in cancer. Peptides 48:1–9PubMedGoogle Scholar
  84. Muñoz M, Coveñas R (2013b) Safety of neurokinin-1 receptor antagonists. Expert Opin Drug Saf 12:673–685PubMedGoogle Scholar
  85. Muñoz M, Rosso M, Coveñas R, Montero I, González-Moles MA, Robles MJ (2007) Neurokinin-1 receptors located in human retinoblastoma cell lines: antitumor action of its antagonist, L-732,138. Invest Ophthalmol Vis Sci 48:2775–2781PubMedGoogle Scholar
  86. Muñoz M, Rosso M, Robles-Frías MJ, Salinas-Martín MV, Coveñas R (2010) The NK-1 receptor is expressed in human melanoma and is involved in the antitumor action of the NK-1 receptor antagonist aprepitant on melanoma cell lines. Lab Invest 90:1259–1269PubMedGoogle Scholar
  87. Muñoz M, González-Ortega A, Rosso M, Robles-Frías MJ, Carranza A, Salinas-Martín MV, Coveñas R (2012) The substance P/Neurokinin-1 receptor system in lung cancer: focus on the antitumor action of neurokinin-1 receptor antagonists. Peptides 38:318–325PubMedGoogle Scholar
  88. Muñoz M, Berger M, Rosso M, González-Ortega A, Carranza A, Coveñas R (2014) Antitumor activity of neurokinin-1 receptor antagonists in MG-63 human osteosarcoma xenografts. Int J Oncol 44:137–146PubMedGoogle Scholar
  89. Murtra P, Sheasby AM, Hunt SP, de Felipe C (2000) Rewarding effects of opiates are absent in mice lacking the receptor for substance P. Nature 405:180–183PubMedGoogle Scholar
  90. Nakaya Y, Kaneko T, Shigemoto R, Nakanishi S, Mizuno N (1994) Immunohistochemical localization of substance P receptor in the central nervous system of the adult rat. J Comp Neurol 347:249–274PubMedGoogle Scholar
  91. Nikolaus S, Huston JP, Hasenohrl RU (1999a) The neurokinin-1 receptor antagonist WIN51,708 attenuates the anxiolytic-like effects of ventralpallidal substance P injection. NeuroReport 10:2293–2296PubMedGoogle Scholar
  92. Nikolaus S, Huston JP, Hasenohrl RU (1999b) Reinforcing effects of neurokinin substance P in the ventral pallidum: mediation by the tachykinin NK1 receptor. Eur J Pharmacol 370:93–99PubMedGoogle Scholar
  93. Nikolaus S, Huston JP, Hasenohrl RU (2000) Anxiolytic-like effects in rats produced by ventral pallidal injection of both N- and C-terminal fragments of substance P. Neurosci Lett 283:37–40PubMedGoogle Scholar
  94. Nio DA, Moylan RN, Roche JK (1993) Modulation of T lymphocyte function by neuropeptides. Evidence for their role as local immunoregulatory elements. J Immunol 150:5281–5288PubMedGoogle Scholar
  95. Norman B (1998) A placebo-controlled, in-clinic study to explore the preliminary safety and efficacy of intravenous L-758,298 (a prodrug of the NK-1 receptor antagonist L-754,030) in the acute treatment of migraine. Cephalalgia 18:407Google Scholar
  96. O’Connor TM, O’Connell J, O’Brien DI, Goode T, Bredin CP, Shanahan F (2004) The role of substance P in inflammatory disease. J Cell Physiol 201:167–180PubMedGoogle Scholar
  97. Olver IN, Grimison P, Chatfield M, Stockler MR, Toner GC, Gebski V, Harrup R, Underhill C, Kichenadasse G, Singhal N, Davis ID, Boland A, McDonald A, Thomson D, Australian and New Zealand Urogenital and Prostate Cancer Trials Group (2013) Results of a 7-day aprepitant schedule for the prevention of nausea and vomiting in 5-day cisplatin-based germ cell tumor chemotherapy. Suport Care Cancer 21:1561–1568Google Scholar
  98. Pascual DW, Bost KL (1990) Substance P production by P388D1 macrophages: a possible autocrine function for this neuropeptide. Immunology 71:52–56PubMedCentralPubMedGoogle Scholar
  99. Pfister HW, Kümpfel T, Koedel U (1995) Involvement of substance P in pial arteriolar vasodilatation during pneumococcal meningitis in the rat. NeuroReport 6:1301–1305PubMedGoogle Scholar
  100. Piedimonte G, Rodriguez MM, King KA, McLean S, Jiang X (1999) Respiratory syncytial virus upregulates expression of the substance P receptor in rat lungs. Am J Physiol 277:L831–L840PubMedGoogle Scholar
  101. Puneet P, Hegde A, Ng SW, Lau HY, Lu J, Moochhala SM, Bhatia M (2006) Preprotachykinin-A gene products are key mediators of lung injury in polymicrobial sepsis. J Immunol 176:3813–3820PubMedGoogle Scholar
  102. Quartara L, Maggi CA (1998) The tachykinin NK1 receptor part II: distribution and pathophysiological roles. Neuropeptides 32:1–49PubMedGoogle Scholar
  103. Ramalho R, Almeida J, Beltrão M, Pirraco A, Costa R, Sokhatska O, Guardão L, Palmares C, Guimarães JT, Delgado L, Moreira A, Soares R (2013) Substance P antagonist improves both obesity and asthma in a mouse model. Allergy 68:48–54PubMedGoogle Scholar
  104. Reid MS, Herrera-Marschitz M, Hökfelt T, Ohlin M, Valentino KL, Ungerstedt U (1990a) Effects of intranigral substance P and neurokinin A on striatal dopamine release-I. Interactions with substance P antagonists. Neuroscience 36:643–658PubMedGoogle Scholar
  105. Reid MS, Herrera-Marschitz M, Kehr J, Ungerstedt U (1990b) Striatal dopamine and glutamate release: effects of intranigral injections of substance P. Acta Physiol Scand 140:527–537PubMedGoogle Scholar
  106. Reinhardt R (1998) Comparison of neurokinin-1 antagonist, L-745,030, to placebo, acetaminophen and ibuprofen in the dental pain model. Clin Pharmacol Ther 63:168Google Scholar
  107. Ripley TL, Gadd CA, De Felipe C, Hunt SP, Stephens DN (2002) Lack of self-administration and behavioural sensitisation to morphine, but not cocaine, in mice lacking NK1 receptors. Neuropharmacology 43:1258–1268PubMedGoogle Scholar
  108. Rittner HL, Lux C, Labuz D, Mousa SA, Achäfer M, Stein C, Brack A (2007) Neurokinin-1 receptor antagonists inhibit the recruitment of opioid-containing leukocytes and impair peripheral antinociception. Anesthesiology 107:1009–1017PubMedGoogle Scholar
  109. Robinson P, Garza A, Moore J, Eckols TK, Parti S, Balaji V, Vallejo J, Tweardy DJ (2009) Substance P is required for the pathogenesis of EMCV infection in mice. Int J Clin Exp Med 2:76–86PubMedCentralPubMedGoogle Scholar
  110. Robinson P, Garza A, Weinstock J, Serpa JA, Goodman JC, Eckols KT, Firozgary B, Tweardy DJ (2012) Substance P causes seizures in neurocysticercosis. PLoS Pathog 8:e1002489PubMedCentralPubMedGoogle Scholar
  111. Rodríguez FD, Coveñas R (2011) Targeting opioid and neurokinin-1 receptors to treat alcoholism. Curr Med Chem 18:4321–4334PubMedGoogle Scholar
  112. Rosenberg ZF, Fauci AS (1990) Immunopathogenic mechanisms of HIV infection: cytokine induction of HIV expression. Immunol Today 11:176–180PubMedGoogle Scholar
  113. Rosenberg ZF, Fauci AS (1991) Immunopathogenesis of HIV infection. FASEB J 5:2382–2390PubMedGoogle Scholar
  114. Ruff MR, Wahl SM, Pert CB (1985) Substance P receptor-mediated chemotaxis of human monocytes. Peptides 6:107–111PubMedGoogle Scholar
  115. Rupniak NM, Carlson EC, Boyce S, Webb JK, Hill RG (1996) Enantioselective inhibition of the formalin paw late phase by the NK-1 receptor antagonist L-733,060 in gerbils. Pain 67:189–195PubMedGoogle Scholar
  116. Rupniak NM, Carlson EC, Harrison T, Oates B, Seward E, Owen S, de Felipe C, Hunt S, Wheeldon A (2000) Pharmacological blockade or genetic deletion of substance P (NK1) receptors attenuates neonatal vocalisation in guinea-pigs and mice. Neuropharmacology 39:1413–1421PubMedGoogle Scholar
  117. Rupniak NM, Calrson EJ, Webb JK, Harrison T, Porsolt RD, Roux S, de Felipe C, Hunt SP, Oates B, Wheeldon A (2001) Comparison of the phenotype of NK1R-/- mice with pharmacological blockade of the substance P (NK1) receptor in assays for antidepressant and anxiolytic drugs. Behav Pharmacol 12:497–508PubMedGoogle Scholar
  118. Sachais BS, Snider RM, Lowe JA 3rd, Krause JE (1993) Molecular basis for the species selectivity of the substance P antagonist CP-96,345. J Biol Chem 268:2319–2323Google Scholar
  119. Saffroy M, Beaujouan JC, Torrens Y, Besseyre J, Bergstrom L, Glowinski J (1988) Localization of tachykinin binding sites (NK1, NK2, NK3 ligands) in the rat brain. Peptides 9:227–241PubMedGoogle Scholar
  120. Saito H, Yoshizawa H, Yoshimori K, Katakami N, Katsumata N, Kawahara M, Eguchi K (2013) Efficacy and safety of single-dose fosaprepitant in the prevention of chemotherapy-induced nausea and vomiting in patients receiving high-dose cisplatin: a multicentre, randomised, double-bind, placebo-controlled phase 3 trial. Ann Oncol 24:1067–1073PubMedCentralPubMedGoogle Scholar
  121. Samsam M, Coveñas R, Ahangari R, Yajeya J, Narváez JA, Tramu G (2000) Simultaneous depletion of neurokinin A, substance P and calcitonin gene-related peptide from the caudal trigeminal nucleus of the rat during electrical stimulation of the trigeminal ganglion. Pain 84:389–395PubMedGoogle Scholar
  122. Samsam M, Coveñas R, Csillik B, Ahangari R, Yajeya J, Riquelme R, Narváez JA, Tramu G (2001) Depletion of substance P, neurokinin A and calcitonin gene-related peptide from the contralateral and ipsilateral caudal trigeminal nucleus following unilateral electrical stimulation of the trigeminal ganglion; A possible neurophysiological and neuroanatomical link to generalized head pain. J Chem Neuroanat 21:161–169PubMedGoogle Scholar
  123. Santini D, Vincenzi B, Guida FM, Imperatori M, Schiavon G, Venditti O, Frezza AM, Berti P, Tonini G (2012) Aprepitant for management of severe pruritus related to biological cancer treatments: a pilot study. Lancet Oncol 13:1020–1024PubMedGoogle Scholar
  124. Sartori SB, Burnet PWJ, Sharp T, Singewald N (2004) Evaluation of the effect of chronic antidepressant treatment on neurokinin-1 receptor expression in the rat brain. Neuropharmacology 46:1177–1183PubMedGoogle Scholar
  125. Schratzberger P, Reinisch N, Prodinger WM, Kahler CM, Sitte BA, Bellmann R, Fischer-Colbrie R, Winkler H, Wiedermann CJ (1997) Differential chemotactic activities of sensory neuropeptides for human peripheral blood mononuclear cells. J Immunol 158:3895–3901PubMedGoogle Scholar
  126. Scicchinato R, Biennenstock J, Stanisz AM (1988) In vivo immunomodulation by the neuropeptide substance P. Immunology 63:733–735Google Scholar
  127. Shibata H, Mio M, Tasaka K (1985) Analysis of the mechanism of histamine release induced by substance P. Biochem Biophys Acta 846:1–7PubMedGoogle Scholar
  128. Shirayama Y, Mitsushio H, Takashima M, Ichinawa H, Takahashi K (1996) Reduction of substance P after chronic antidepressants treatment in the striatum, substantia nigra and amygdala of the rat. Brain Res 739:70–78PubMedGoogle Scholar
  129. Singh D, Joshi DD, Hameed M, Qian J, Gascón P, Maloof PB, Mosenthal A, Rameshwar P (2000) Increased expression of preprotachykinin-I and neurokinin receptors in human breast cancer cells: implications for bone marrow metastasis. Proc Natl Acad Sci USA 97:388–393PubMedCentralPubMedGoogle Scholar
  130. Sperk G, Wieser R, Widmann R, Singer EA (1986) Kainic acid induced seizures: changes in somatostatin, substance P and neurotensin. Neuroscience 17:1117–1126PubMedGoogle Scholar
  131. Sporn MB (1996) The war on cancer. Lancet 347:1377–1381PubMedGoogle Scholar
  132. Ständer S, Siepmann D, Herrgott I, Sunderkötter C, Luger TA (2010) Targeting the neurokinin receptor 1 with aprepitant: a novel antipruritic strategy. PLoS One 5:e10968PubMedCentralPubMedGoogle Scholar
  133. Tebas P, Tuluc F, Barret JS, Wagner W, Kim D, Zhao H, Gonin R, Korelitz J, Douglas SD (2011) A randomized, placebo controlled, double masked phase Ib study evaluating the safety and antiviral activity of aprepitant, a neurokinin-1 receptor antagonist in HIV-1 infected adults. PLoS One 6:e24180PubMedCentralPubMedGoogle Scholar
  134. Teodoro FC, Tronco Júnior MF, Zampronio AR, Martini AC, Rae GA, Chichorro JG (2013) Peripheral substance P and neurokinin-1 receptors have a role in inflammatory and neuropathic orofacial pain models. Neuropeptides 47:199–206PubMedGoogle Scholar
  135. Thornton E, Vink R (2012) Treatment with a substance P receptor antagonist is neuroprotective in the intrastriatal 6-hydroxydopamine model of early Parkinson’s disease. PLoS One 7:e34138PubMedCentralPubMedGoogle Scholar
  136. Thorsell A, Schank JR, Singley E, Hunt SP, Heilig M (2010) Neurokinin-1 receptors (NK1R:s), alcohol consumption, and alcohol reward in mice. Psychopharmacology 209:103–111PubMedGoogle Scholar
  137. Trivedi M, Bergasa NV (2010) Serum concentrations of substance P in cholestasis. Ann Hepatol 9:177–180PubMedGoogle Scholar
  138. Twardy BS, Channappanavar R, Suvas S (2011) Substance P in the corneal stroma regulates the severity of herpetic stromal keratitis lesions. Invest Ophthalmol Vis Sci 52:8604–8613PubMedCentralPubMedGoogle Scholar
  139. Unger T, Rascher W, Schuster C, Pavlovitch R, Schömig A, Dietz R, Ganten D (1981) Central blood pressure effects of substance P and angiotensin II: role of the sympathetic nervous system and vasopressin. Eur J Pharmacol 71:33–42PubMedGoogle Scholar
  140. Wallace-Boone TL, Newton AE, Wright RN, Lodge NJ, McElroy JF (2008) Behavioral and pharmacological validation of the gerbil forced-swim test: effects of neurokinin-1 receptor antagonists. Neuropsychopharmacology 33:1919–1928PubMedGoogle Scholar
  141. Wolf SS, Moody TW, Quirion R, O’Donohue TL (1985) Biochemical characterization and autoradiographic localization of central SP receptor using [125I] physalaemin. Brain Res 332:299–307PubMedGoogle Scholar
  142. Yu J, Cadet JL, Angulo JA (2002) Neurokinin-1 (NK-1) receptor antagonists abrogate methamphetamine-induced striatal dopaminergic neurotoxicity in the murine brain. J Neurochem 83:613–622PubMedGoogle Scholar
  143. Zachrisson O, Lindefors N, Brené S (1998) A tachykinin NK1 receptor antagonist, CP-122,721-1, attenuates kainic acid-induced seizure activity. Brain Res Mol Brain Res 60:291–295PubMedGoogle Scholar
  144. Ziche M, Morbidelli L, Pacini M, Gepetti P, Alessandri G, Maggi CA (1990) Substance P stimulates neovascularization in vivo and proliferation of cultured endothelial cells. Microvasc Res 40:264–278PubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2014

Authors and Affiliations

  1. 1.Research Laboratory on Neuropeptides (IBIS)Virgen del Rocío University HospitalSevillaSpain
  2. 2.Unidad de Cuidados Intensivos PediátricosHospital Infantil Universitario Virgen del RocíoSevillaSpain
  3. 3.Laboratory of Neuroanatomy of the Peptidergic Systems (Lab. 14), Institute of Neurosciences of Castilla y León (INCYL)University of SalamancaSalamancaSpain

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