neurokinin 1 receptors


Summary: A class of cell surface receptors for TACHYKININS with a preference for SUBSTANCE P. Neurokinin-1 (NK-1) receptors have been cloned and are members of the G protein coupled receptor superfamily. They are found on many cell types including central and peripheral neurons, smooth muscle cells, acinar cells, endothelial cells, fibroblasts, and immune cells.

Top Publications

  1. Yu Y, Arttamangkul S, Evans C, Williams J, von Zastrow M. Neurokinin 1 receptors regulate morphine-induced endocytosis and desensitization of mu-opioid receptors in CNS neurons. J Neurosci. 2009;29:222-33 pubmed publisher
    ..MORs are coexpressed with neurokinin 1 receptors (NK1Rs) in several regions of the CNS that control opioid dependence and reward...
  2. Sio S, Puthia M, Lu J, Moochhala S, Bhatia M. The neuropeptide substance P is a critical mediator of burn-induced acute lung injury. J Immunol. 2008;180:8333-41 pubmed
    ..The present findings show for the first time the role of SP in contributing to exaggerated pulmonary inflammatory damage after burn injury via activation of NK1R signaling. ..
  3. Springer J, Groneberg D, Dinh Q, Quarcoo D, Hamelmann E, Braun Dullaeus R, et al. Neurokinin-1 receptor activation induces reactive oxygen species and epithelial damage in allergic airway inflammation. Clin Exp Allergy. 2007;37:1788-97 pubmed
    ..Therefore, patients may possibly benefit from treatment regime that includes radical scavengers or tachykinin NK-1 receptor antagonists. ..
  4. Lai J, Cnaan A, Zhao H, Douglas S. Detection of full-length and truncated neurokinin-1 receptor mRNA expression in human brain regions. J Neurosci Methods. 2008;168:127-33 pubmed
  5. Al Khater K, Todd A. Collateral projections of neurons in laminae I, III, and IV of rat spinal cord to thalamus, periaqueductal gray matter, and lateral parabrachial area. J Comp Neurol. 2009;515:629-46 pubmed publisher
    ..These results confirm that neurons in these laminae have extensive collateral projections and suggest that different neuronal subpopulations in lamina I have characteristic patterns of supraspinal projection. ..
  6. Todd A, Polgár E, Watt C, Bailey M, Watanabe M. Neurokinin 1 receptor-expressing projection neurons in laminae III and IV of the rat spinal cord have synaptic AMPA receptors that contain GluR2, GluR3 and GluR4 subunits. Eur J Neurosci. 2009;29:718-26 pubmed publisher
    ..These results show that synaptic AMPArs on the dendrites of the lamina III/IV NK1r projection neurons contain GluR2, GluR3 and GluR4, but not GluR1 subunits. ..
  7. Xu J, Xu F, Barrett E. Metalloelastase in lungs and alveolar macrophages is modulated by extracellular substance P in mice. Am J Physiol Lung Cell Mol Physiol. 2008;295:L162-70 pubmed publisher
    ..These findings suggest that SP has a modulatory effect on pulmonary MMP-12 by acting on NK1R to trigger MMP-12 syntheses in the AMs. ..
  8. Almarestani L, Waters S, Krause J, Bennett G, Ribeiro da Silva A. Morphological characterization of spinal cord dorsal horn lamina I neurons projecting to the parabrachial nucleus in the rat. J Comp Neurol. 2007;504:287-97 pubmed
    ..In addition, our study provides further evidence that these distinct morphological types of neurons differ in their phenotypic properties, but not in their projection patterns. ..
  9. Almarestani L, Waters S, Krause J, Bennett G, Ribeiro da Silva A. De novo expression of the neurokinin 1 receptor in spinal lamina I pyramidal neurons in polyarthritis. J Comp Neurol. 2009;514:284-95 pubmed publisher

More Information


  1. Polgár E, Al Khater K, Shehab S, Watanabe M, Todd A. Large projection neurons in lamina I of the rat spinal cord that lack the neurokinin 1 receptor are densely innervated by VGLUT2-containing axons and possess GluR4-containing AMPA receptors. J Neurosci. 2008;28:13150-60 pubmed publisher
    ..Our results also provide the first evidence that postsynaptic GluR4-containing AMPA receptors are involved in spinal nociceptive transmission. ..
  2. Garza A, Weinstock J, Robinson P. Absence of the SP/SP receptor circuitry in the substance P-precursor knockout mice or SP receptor, neurokinin (NK)1 knockout mice leads to an inhibited cytokine response in granulomas associated with murine Taenia crassiceps infection. J Parasitol. 2008;94:1253-8 pubmed publisher
    ..These study established that the absence of an SP/SP receptor circuitry in the SP precursor knockout mice or NK1 receptor knockout mice led to an inhibited cytokine response...
  3. Zhang H, Cang C, Kawasaki Y, Liang L, Zhang Y, Ji R, et al. Neurokinin-1 receptor enhances TRPV1 activity in primary sensory neurons via PKCepsilon: a novel pathway for heat hyperalgesia. J Neurosci. 2007;27:12067-77 pubmed
    ..These results reveal a novel mechanism of NK-1 in primary sensory neurons via a possible autocrine and paracrine action of SP. Activation of NK-1 in these neurons induces heat hyperalgesia via PKCepsilon-mediated potentiation of TRPV1. ..
  4. Al Ghamdi K, Polgar E, Todd A. Soma size distinguishes projection neurons from neurokinin 1 receptor-expressing interneurons in lamina I of the rat lumbar spinal dorsal horn. Neuroscience. 2009;164:1794-804 pubmed publisher
    ..Since almost all of the NK1r-immunoreactive cells with soma size >200 microm(2) were retrogradely labelled, cells of this type can be identified as projection cells in anatomical studies. ..
  5. Xu J, Xu F, Wang R, Seagrave J, Lin Y, March T. Cigarette smoke-induced hypercapnic emphysema in C3H mice is associated with increases of macrophage metalloelastase and substance P in the lungs. Exp Lung Res. 2007;33:197-215 pubmed
    ..These data suggest a possible involvement of SP and MMP-12 in the pathogenesis of severe COPD. ..
  6. Kulka M, Sheen C, Tancowny B, Grammer L, Schleimer R. Neuropeptides activate human mast cell degranulation and chemokine production. Immunology. 2008;123:398-410 pubmed
    ..These results are likely to have direct relevance to neuronally induced inflammatory diseases. ..
  7. Jones S, Gibbins J. The neurokinin 1 receptor: a potential new target for anti-platelet therapy?. Curr Opin Pharmacol. 2008;8:114-9 pubmed publisher
    ..The pro-thrombotic effects of tachykinins on platelets are mediated through the neurokinin 1 receptor, which may therefore offer a novel therapeutic drug target in the prevention and the treatment of arterial thrombosis. ..
  8. Li P, Chen W, Chang L, Lin S. Substance P acts via the neurokinin receptor 1 to elicit bronchoconstriction, oxidative stress, and upregulated ICAM-1 expression after oil smoke exposure. Am J Physiol Lung Cell Mol Physiol. 2008;294:L912-20 pubmed publisher
    ..These findings suggest that SP acts via the NK-1 receptor to provoke neurogenic inflammation, oxidative stress, and ICAM-1 expression after OSE in rats. ..
  9. Wiley R. Substance P receptor-expressing dorsal horn neurons: lessons from the targeted cytotoxin, substance P-saporin. Pain. 2008;136:7-10 pubmed publisher
  10. George D, Gilman J, Hersh J, Thorsell A, Herion D, Geyer C, et al. Neurokinin 1 receptor antagonism as a possible therapy for alcoholism. Science. 2008;319:1536-9 pubmed publisher
    ..Thus, as assessed by these surrogate markers of efficacy, NK1R antagonism warrants further investigation as a treatment in alcoholism. ..
  11. Jones S, Tucker K, Sage T, Kaiser W, Barrett N, Lowry P, et al. Peripheral tachykinins and the neurokinin receptor NK1 are required for platelet thrombus formation. Blood. 2008;111:605-12 pubmed
    ..Inhibition of the NK1 receptor may therefore provide benefit in patients vulnerable to thrombosis and may offer an alternative therapeutic target. ..
  12. Hegde A, Bhatia M. Neurogenic inflammation in acute pancreatitis. JOP. 2005;6:417-21 pubmed
    ..This editorial focuses on the role of substance P and its receptors in the development of acute pancreatitis...
  13. Polgár E, Campbell A, MacIntyre L, Watanabe M, Todd A. Phosphorylation of ERK in neurokinin 1 receptor-expressing neurons in laminae III and IV of the rat spinal dorsal horn following noxious stimulation. Mol Pain. 2007;3:4 pubmed
    ..Our results demonstrate that lamina III/IV NK1r-immunoreactive neurons show receptor internalisation and ERK phosphorylation after mechanical, thermal or chemical noxious stimuli. ..
  14. Gobbi G, Cassano T, Radja F, Morgese M, Cuomo V, Santarelli L, et al. Neurokinin 1 receptor antagonism requires norepinephrine to increase serotonin function. Eur Neuropsychopharmacol. 2007;17:328-38 pubmed
    ..In addition, the desensitization of 5-HT(1A) autoreceptors produced by NK1 receptor antagonism is not critical for enhancing 5-HT neuronal firing. ..
  15. Meurer L, Finke P, Owens K, Tsou N, Ball R, Mills S, et al. Cyclopentane-based human NK1 antagonists. Part 2: development of potent, orally active, water-soluble derivatives. Bioorg Med Chem Lett. 2006;16:4504-11 pubmed
    ..Sub-nanomolar hNK1 binding was achieved and oral activity comparable to Aprepitant in two in vivo models will be described. ..
  16. Bardelli C, Gunella G, Varsaldi F, Balbo P, Del Boca E, Bernardone I, et al. Expression of functional NK1 receptors in human alveolar macrophages: superoxide anion production, cytokine release and involvement of NF-kappaB pathway. Br J Pharmacol. 2005;145:385-96 pubmed
    ..5 These results clearly indicate that human AMs possess functional NK-1R on their surface, which are upregulated in healthy smokers, providing new insights on the mechanisms involved in tobacco smoke toxicity. ..
  17. Jasmin L, Narasaiah M, Tien D. Noradrenaline is necessary for the hedonic properties of addictive drugs. Vascul Pharmacol. 2006;45:243-50 pubmed
    ..The reversibility of this phenomenon, by restoring NA, indicates that even when this behavioral deficit is genetically determined it can be reversed...
  18. Duric V, McCarson K. Persistent pain produces stress-like alterations in hippocampal neurogenesis and gene expression. J Pain. 2006;7:544-55 pubmed
    ..Targeting these mechanisms (which are potential contributors to the emotional impact of pain) may provide novel therapeutic approaches for relieving depression-like aspects of chronic pain. ..
  19. Herpfer I, Hunt S, Stanford S. A comparison of neurokinin 1 receptor knock-out (NK1-/-) and wildtype mice: exploratory behaviour and extracellular noradrenaline concentration in the cerebral cortex of anaesthetised subjects. Neuropharmacology. 2005;48:706-19 pubmed
    ..Finally, alpha(2)-adrenoceptors are possibly desensitised in NK1-/- mice. We have yet to establish whether this is a cause or a consequence of the increased noradrenaline efflux. ..
  20. Keller M, Montgomery S, Ball W, Morrison M, Snavely D, Liu G, et al. Lack of efficacy of the substance p (neurokinin1 receptor) antagonist aprepitant in the treatment of major depressive disorder. Biol Psychiatry. 2006;59:216-23 pubmed
    ..The concept of neurokinin(1) receptor antagonism as an antidepressant mechanism was not supported. ..
  21. Krolewski D, Bishop C, Walker P. Intrastriatal dopamine D1 receptor agonist-mediated motor behavior is reduced by local neurokinin 1 receptor antagonism. Synapse. 2005;57:1-7 pubmed
    ..The results of this study suggest that functional NK1Rs within the striatum play a permissive role in the motor behaviors induced by D1R stimulation. ..
  22. Elliott J, Carlson E, Chicchi G, Dirat O, Dominguez M, Gerhard U, et al. NK1 antagonists based on seven membered lactam scaffolds. Bioorg Med Chem Lett. 2006;16:2929-32 pubmed
    ..This series, with relatively simple, compact structures, includes compounds with high affinity, good selectivity, and promising in vivo properties. ..
  23. Griffante C, Carletti R, Andreetta F, Corsi M. [3H]GR205171 displays similar NK1 receptor binding profile in gerbil and human brain. Br J Pharmacol. 2006;148:39-45 pubmed
  24. Hietala J, Nyman M, Eskola O, Laakso A, Grönroos T, Oikonen V, et al. Visualization and quantification of neurokinin-1 (NK1) receptors in the human brain. Mol Imaging Biol. 2005;7:262-72 pubmed
  25. Thomson C, Carlson E, Chicchi G, Kulagowski J, Kurtz M, Swain C, et al. Synthesis and structure-activity relationships of 8-azabicyclo[3.2.1]octane benzylamine NK1 antagonists. Bioorg Med Chem Lett. 2006;16:811-4 pubmed
    ..Acidic substituents at C6 give a series of high affinity compounds for hNK1 with selectivity over the hERG channel. ..
  26. Andersson K. Tachykinins: role in detrusor overactivity?. Eur Urol. 2006;49:423-5 pubmed
  27. Meza U, Thapliyal A, Bannister R, Adams B. Neurokinin 1 receptors trigger overlapping stimulation and inhibition of CaV2.3 (R-type) calcium channels. Mol Pharmacol. 2007;71:284-93 pubmed
    ..This new information concerning R-type calcium channels and NK1 receptors may help in understanding nociception, synaptic plasticity, and other physiological processes. ..
  28. Gao M, Mock B, Hutchins G, Zheng Q. Synthesis and initial PET imaging of new potential NK1 receptor radioligands 1-[2-(3,5-bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-4-[11C]methyl-piperazine and {4-[2-(3,5-bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazine-1-yl}-acetic acid . Nucl Med Biol. 2005;32:543-52 pubmed
    ..These results suggest that the localization of [(11)C]BMP and [(11)C]BME in rat brain is mediated by nonspecific processes, and the visualization of [(11)C]BMP-PET and [(11)C]BME-PET on rat brain is related to nonspecific binding. ..
  29. Torsney C, Macdermott A. Disinhibition opens the gate to pathological pain signaling in superficial neurokinin 1 receptor-expressing neurons in rat spinal cord. J Neurosci. 2006;26:1833-43 pubmed
    ..These disinhibition-induced changes, in particular the novel polysynaptic low-threshold input onto lamina I NK1R+ neurons, may be an underlying component of the hypersensitivity present in chronic pain states. ..
  30. Fisher A, Stewart R, Yan T, Hunt S, Stanford S. Disruption of noradrenergic transmission and the behavioural response to a novel environment in NK1R-/- mice. Eur J Neurosci. 2007;25:1195-204 pubmed
    ..These changes could contribute to the difference in the behavioural phenotypes. ..
  31. Huscroft I, Carlson E, Chicchi G, Kurtz M, London C, Raubo P, et al. 1-Phenyl-8-azabicyclo[3.2.1]octane ethers: a novel series of neurokinin (NK1) antagonists. Bioorg Med Chem Lett. 2006;16:2008-12 pubmed
    ..Incorporation of an alpha-methyl substituent in the pendent benzyl ether side chain gave compounds with increased selectivity over the hERG channel. ..
  32. Shue H, Chen X, Shih N, Blythin D, Paliwal S, Lin L, et al. Cyclic urea derivatives as potent NK1 selective antagonists. Bioorg Med Chem Lett. 2005;15:3896-9 pubmed
    ..Several compounds in this series exhibited good oral activity and brain penetration. Syntheses of these compounds are also described herein. ..
  33. Schelfhout V, Louis R, Lenz W, Heyrman R, Pauwels R, Joos G. The triple neurokinin-receptor antagonist CS-003 inhibits neurokinin A-induced bronchoconstriction in patients with asthma. Pulm Pharmacol Ther. 2006;19:413-8 pubmed
    ..This did not occur under placebo treatment. A single dose of 200 mg CS-003 protected significantly against NKA-induced bronchoconstriction at 1 and 8h post-dose in mild asthmatics. ..
  34. Bradesi S, Kokkotou E, Simeonidis S, Patierno S, Ennes H, Mittal Y, et al. The role of neurokinin 1 receptors in the maintenance of visceral hyperalgesia induced by repeated stress in rats. Gastroenterology. 2006;130:1729-42 pubmed
    The neurokinin 1 receptors (NK(1)Rs) and substance P (SP) have been implicated in the stress and/or pain pathways involved in chronic pain conditions...
  35. Van der Mey M, Janssen C, Janssens F, Jurzak M, Langlois X, Sommen F, et al. Synthesis and biodistribution of [(11)C]R116301, a promising PET ligand for central NK(1) receptors. Bioorg Med Chem. 2005;13:1579-86 pubmed
    ..33 and 1.62 was also observed for olfactory bulb and olfactory tubercules, respectively (20 min p.i.). In summary, [(11)C]R116301 appears to be a promising radioligand suitable for the visualization of NK(1) receptors in vivo using PET...
  36. Duric V, McCarson K. Hippocampal neurokinin-1 receptor and brain-derived neurotrophic factor gene expression is decreased in rat models of pain and stress. Neuroscience. 2005;133:999-1006 pubmed
    ..These data may provide useful markers of hippocampal activation during chronic pain, and suggest similarities in the mechanisms underlying chronic pain and depression. ..
  37. Ebner K, Singewald N. The role of substance P in stress and anxiety responses. Amino Acids. 2006;31:251-72 pubmed
    ..Preclinical and clinical studies have found evidence in favour of such an assumption. The status of this research is reviewed here. ..
  38. Nakatsuka T, Chen M, Takeda D, King C, Ling J, Xing H, et al. Substance P-driven feed-forward inhibitory activity in the mammalian spinal cord. Mol Pain. 2005;1:20 pubmed
    ..Our findings reveal a fundamental role of SP in recruiting inhibitory activity for sensory processing, which may have important therapeutic implications in treating pathological pain conditions using SP receptors as targets. ..
  39. Yu X, Ribeiro Da Silva A, De Koninck Y. Morphology and neurokinin 1 receptor expression of spinothalamic lamina I neurons in the rat spinal cord. J Comp Neurol. 2005;491:56-68 pubmed
    ..As in the monkey, most pyramidal STT neurons did not express NK-1r. These results provide further evidence that distinct morphological types of neurons differ in phenotype but not in their projection pattern. ..
  40. Rigby M, O Donnell R, Rupniak N. Species differences in tachykinin receptor distribution: further evidence that the substance P (NK1) receptor predominates in human brain. J Comp Neurol. 2005;490:335-53 pubmed
    ..These findings demonstrate that the NK1 receptor is the predominant tachykinin receptor expressed in primate and human brain, but that low levels of NK3 receptor are present in nonhuman, primate brain. ..
  41. Hoffmann Emery F, Hilpert H, Scalone M, Waldmeier P. Efficient synthesis of novel NK1 receptor antagonists: selective 1,4-addition of grignard reagents to 6-chloronicotinic acid derivatives. J Org Chem. 2006;71:2000-8 pubmed
  42. Wiley R, Kline R, Vierck C. Anti-nociceptive effects of selectively destroying substance P receptor-expressing dorsal horn neurons using [Sar9,Met(O2)11]-substance P-saporin: behavioral and anatomical analyses. Neuroscience. 2007;146:1333-45 pubmed
    ..SSP-sap is an attractive agent for possible treatment of chronic pain. ..
  43. Duric V, McCarson K. Effects of analgesic or antidepressant drugs on pain- or stress-evoked hippocampal and spinal neurokinin-1 receptor and brain-derived neurotrophic factor gene expression in the rat. J Pharmacol Exp Ther. 2006;319:1235-43 pubmed
  44. Koon H, Zhao D, Zhan Y, Rhee S, Moyer M, Pothoulakis C. Substance P stimulates cyclooxygenase-2 and prostaglandin E2 expression through JAK-STAT activation in human colonic epithelial cells. J Immunol. 2006;176:5050-9 pubmed
    ..Our results demonstrate that SP stimulates COX-2 expression and PGE2 production in human colonocytes via activation of the JAK2-STAT3/5 pathway. ..
  45. Lucattelli M, Fineschi S, Geppetti P, Gerard N, Lungarella G. Neurokinin-1 receptor blockade and murine lung tumorigenesis. Am J Respir Crit Care Med. 2006;174:674-83 pubmed
    ..This animal model may provide new information on the biology of AC and will facilitate designing and testing of new therapeutic interventions. ..
  46. Sekizawa S, Chen C, Bechtold A, Tabor J, Bric J, Pinkerton K, et al. Extended secondhand tobacco smoke exposure induces plasticity in nucleus tractus solitarius second-order lung afferent neurons in young guinea pigs. Eur J Neurosci. 2008;28:771-81 pubmed publisher
    ..The mechanism may help to explain some of the exaggerated respiratory responses of children exposed to SHS. ..
  47. Douglas S, Lai J, Tuluc F, Schwartz L, Kilpatrick L. Neurokinin-1 receptor expression and function in human macrophages and brain: perspective on the role in HIV neuropathogenesis. Ann N Y Acad Sci. 2008;1144:90-6 pubmed publisher
    ..g., THP-1 cells); and differences in regional tissue distribution (e.g., differences in different brain regions). NK1R-SP receptor pathways are important cell regulatory pathways. ..
  48. de la Puente Redondo V, Tingley F, Schneider R, Hickman M. The neurokinin-1 antagonist activity of maropitant, an antiemetic drug for dogs, in a gerbil model. J Vet Pharmacol Ther. 2007;30:281-7 pubmed
    ..59. These data demonstrate the central functional action of maropitant as a selective and potent NK1 receptor antagonist and help to support and explain its clinical potential as a broad-spectrum antiemetic agent. ..
  49. Di Fabio R, Griffante C, Alvaro G, Pentassuglia G, Pizzi D, Donati D, et al. Discovery process and pharmacological characterization of 2-(S)-(4-fluoro-2-methylphenyl)piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethylphenyl)ethyl]methylamide (vestipitant) as a potent, selective, and orally active NK1 receptor antagon. J Med Chem. 2009;52:3238-47 pubmed publisher
    ..On the basis of its preclinical profile, this compound was selected as a drug candidate. ..
  50. Lao L, Song B, Chen W, Marvizon J. Noxious mechanical stimulation evokes the segmental release of opioid peptides that induce mu-opioid receptor internalization in the presence of peptidase inhibitors. Brain Res. 2008;1197:85-93 pubmed publisher
    ..Lumbar spinal segments were double-stained with antibodies against MORs and neurokinin 1 receptors (NK1Rs) using immunofluorescence...
  51. Kalinichev M, Bradford A, Bison S, Lucas A, Sartori I, Garbati N, et al. Potentiation of the anticonvulsant efficacy of sodium channel inhibitors by an NK1-receptor antagonist in the rat. Epilepsia. 2010;51:1543-51 pubmed publisher
    ..These results suggest that there may be benefit in adding treatment with a suitable NK1-receptor antagonist to treatment with a sodium channel blocker in patients with refractory epilepsy. ..
  52. Chen W, Zhang G, Marvizón J. NMDA receptors in primary afferents require phosphorylation by Src family kinases to induce substance P release in the rat spinal cord. Neuroscience. 2010;166:924-34 pubmed publisher
    ..These results show that tyrosine-phosphorylation of these NMDA receptors is regulated by the opposite actions of Src family kinases and protein tyrosine phosphatases, and is required to induce substance P release...
  53. Lam F, Ng E. Substance P and glutamate receptor antagonists improve the anti-arthritic actions of dexamethasone in rats. Br J Pharmacol. 2010;159:958-69 pubmed publisher
    ..The efficacy of dexamethasone in reducing arthritic pain and joint swelling can be improved by co-administration of substance P and glutamate receptor antagonists. ..