The NK1 receptor can be found in both the central and peripheral nervous system. It is present in neurons, brainstem, vascular endothelial cells, muscle, gastrointestinal tracts, genitourinary tract, pulmonary tissue, thyroid gland and different types of immune cells. The binding of SP to the NK1 receptor has been associated with the transmission of stress signals and pain, the contraction of smooth muscles and inflammation. NK1 receptor antagonists have also been studied in migraine, emesis and psychiatric disorders. In fact, aprepitant has been proved effective in a number of pathophysiological models of anxiety and depression. Other diseases in which the NK1 receptor system is involved include asthma, rheumatoid arthritis and gastrointestinal disorders.
SP is synthesized by neurons and transported to synaptic vesicles; the release of SP is accomplished through the depolarizing action of calcium-dependent mechanisms.
When NK1 receptors are stimulated, they can generate various second messengers, which can trigger a wide range of effector mechanisms that regulate cellular excitability and function. One of those three well-defined, independent second messenger systems is stimulation, via phospholipase C, of phosphatidyl inositol, turnover leading to Ca mobilization from both intra- and extracellular sources. Second is the arachidonic acid mobilization via phospholipase A2 and third is the cAMP accumulation via stimulation of adenylate cyclase. It has also been reported that SP elicits interleukin-1 (IL-1) production in macrophages, it is known to sensitize neutrophils and enhance dopamine release in the substantia nigra region in cat brain. From spinal neurons, SP is known to evoke release of neurotransmitters like acetylcholine, histamine and GABA. It is also known to secrete catecholamines and play a role in the regulation of blood pressure and hypertension. Likewise, SP is known to bind to N-methyl-D-aspartate (NMDA) receptors by eliciting excitation with calcium ion influx, which further releases nitric oxide. Studies in frogs have shown that SP elicits the release of prostaglandin E2 and prostacyclin by the arachidonic acid pathway, which leads to an increase in corticosteroid output.
In combination therapy, NK1 receptor antagonists appear to offer better control of delayed emesis and post-operative emesis than drug therapy without NK1 receptor antagonists. NK1 receptor antagonists block responses to a broader range of emetic stimuli than the established 5-HT3 antagonist treatments. It has been reported that centrally-acting NK1 receptors antagonists, such as CP-99994, inhibit emesis induced by apomorphine and loperimidine, which are two compounds that act through central mechanisms.
↑Takeda Y, Chou KB, Takeda J, Sachais BS, Krause JE (Sep 1991). "Molecular cloning, structural characterization and functional expression of the human substance P receptor". Biochemical and Biophysical Research Communications. 179 (3): 1232–40. doi:10.1016/0006-291X(91)91704-G. PMID1718267.
↑Perlis RH, Purcell S, Fagerness J, Kirby A, Petryshen TL, Fan J, Sklar P (Jan 2008). "Family-based association study of lithium-related and other candidate genes in bipolar disorder". Archives of General Psychiatry. 65 (1): 53–61. doi:10.1001/archgenpsychiatry.2007.15. PMID18180429.
↑Munoz M, Covenas R, Esteban F, Redondo M (2015). "The substance P/NK-1 receptor system: NK-1 receptor antagonists as anti-cancer drugs". Journal of Biosciences. 40 (2): 441–63. doi:10.1007/s12038-015-9530-8. PMID25963269.
Kowall NW, Quigley BJ, Krause JE, Lu F, Kosofsky BE, Ferrante RJ (Jul 1993). "Substance P and substance P receptor histochemistry in human neurodegenerative diseases". Regulatory Peptides. 46 (1–2): 174–85. doi:10.1016/0167-0115(93)90028-7. PMID7692486.
Saito R, Takano Y, Kamiya HO (Feb 2003). "Roles of substance P and NK(1) receptor in the brainstem in the development of emesis". Journal of Pharmacological Sciences. 91 (2): 87–94. doi:10.1254/jphs.91.87. PMID12686752.
Fong TM, Yu H, Huang RR, Strader CD (Dec 1992). "The extracellular domain of the neurokinin-1 receptor is required for high-affinity binding of peptides". Biochemistry. 31 (47): 11806–11. doi:10.1021/bi00162a019. PMID1280161.
Fong TM, Huang RR, Strader CD (Dec 1992). "Localization of agonist and antagonist binding domains of the human neurokinin-1 receptor". The Journal of Biological Chemistry. 267 (36): 25664–7. PMID1281469.
Fong TM, Anderson SA, Yu H, Huang RR, Strader CD (Jan 1992). "Differential activation of intracellular effector by two isoforms of human neurokinin-1 receptor". Molecular Pharmacology. 41 (1): 24–30. PMID1310144.
Takahashi K, Tanaka A, Hara M, Nakanishi S (Mar 1992). "The primary structure and gene organization of human substance P and neuromedin K receptors". European Journal of Biochemistry / FEBS. 204 (3): 1025–33. doi:10.1111/j.1432-1033.1992.tb16724.x. PMID1312928.
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. PMID1657150.
Hopkins B, Powell SJ, Danks P, Briggs I, Graham A (Oct 1991). "Isolation and characterisation of the human lung NK-1 receptor cDNA". Biochemical and Biophysical Research Communications. 180 (2): 1110–7. doi:10.1016/S0006-291X(05)81181-7. PMID1659396.
Takeda Y, Chou KB, Takeda J, Sachais BS, Krause JE (Sep 1991). "Molecular cloning, structural characterization and functional expression of the human substance P receptor". Biochemical and Biophysical Research Communications. 179 (3): 1232–40. doi:10.1016/0006-291X(91)91704-G. PMID1718267.
Giuliani S, Barbanti G, Turini D, Quartara L, Rovero P, Giachetti A, Maggi CA (Oct 1991). "NK2 tachykinin receptors and contraction of circular muscle of the human colon: characterization of the NK2 receptor subtype". European Journal of Pharmacology. 203 (3): 365–70. doi:10.1016/0014-2999(91)90892-T. PMID1723045.
Ichinose H, Katoh S, Sueoka T, Titani K, Fujita K, Nagatsu T (Aug 1991). "Cloning and sequencing of cDNA encoding human sepiapterin reductase--an enzyme involved in tetrahydrobiopterin biosynthesis". Biochemical and Biophysical Research Communications. 179 (1): 183–9. doi:10.1016/0006-291X(91)91352-D. PMID1883349.
Thöny B, Heizmann CW, Mattei MG (Mar 1995). "Human GTP-cyclohydrolase I gene and sepiapterin reductase gene map to region 14q21-q22 and 2p14-p12, respectively, by in situ hybridization". Genomics. 26 (1): 168–70. doi:10.1016/0888-7543(95)80101-Q. PMID7782081.
Fong TM, Cascieri MA, Yu H, Bansal A, Swain C, Strader CD (Mar 1993). "Amino-aromatic interaction between histidine 197 of the neurokinin-1 receptor and CP 96345". Nature. 362 (6418): 350–3. doi:10.1038/362350a0. PMID8384323.
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. PMID8985172.
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. doi:10.1038/32904. PMID9537323.