Loading Pathway...
Error: Pathway image not found.
Hide
Pathway Description
Duloxetine SNRI - Dopamine Norepinephrine Inhibition Action Pathway
Homo sapiens
Drug Action Pathway
Created: 2023-07-10
Last Updated: 2023-11-27
Duloxetine is a serotonin norepinephrine reuptake inhibitor used to treat generalized anxiety disorder, neuropathic pain, osteoarthritis, and stress incontinence. It blocks both sodium dependent serotonin and sodium dependent norepinephrine transporters from removing serotonin and norepinephrine respectively from the synaptic cleft. This allows an accumulation of the neurotransmitters to stimulate their receptors repeatedly increasing the signal of the receptors. In depressed individuals, serotonin and norepinephrine stimulation is low so an increase in serotonin and norepinephrine in the synapses can increase the stimulation of these receptors. The receptors that are being stimulated are 5-HT 2A, 2B, and 2C serotonin receptors and alpha 1 and beta 1 adrenergic receptors. Stimulation of the 2A, 2B and 3C receptor can increase cognitive abilities like learning, appetite, memory, mood and sleep. Sensitization of alpha A1 and beta B1 adrenergic receptors also improve cognitive function, fatigue, sleep and the immune system. In addition to its general SNRI properties, duloxetine also increases dopamine levels, specifically in the prefrontal cortex. Due to the involvement of the prefrontal cortex in depression, the actions of duloxetine in this region also contribute to its efficacy in the treatment of depression. However, the mechanism of action does not involve the inhibition of dopamine transporters. The mechanism of action behind the increase in dopamine levels involves the inhibition of norepinephrine transporters. These transporters have a significant affinity for dopamine, resulting in the transporter’s ability to act on both dopamine and norepinephrine. Therefore, inhibition of norepinephrine transporters can lead to an increase in dopamine. This increase in dopamine specifically occurs in the prefrontal cortex, where dopamine transporters are scarce, and reuptake relies more heavily on norepinephrine transporters. Duloxetine has no significant activity for muscarinic, cholinergic, alpha2-adrenergic, or H1 histaminergic receptors
References
Duloxetine SNRI - Dopamine Norepinephrine Inhibition pathway References
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M: DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. doi: 10.1093/nar/gkx1037.
Pubmed: 29126136
Dhaliwal JS, Spurling BC, Molla M: Duloxetine.
Pubmed: 31747213
Williams HJ, Bray N, Murphy KC, Cardno AG, Jones LA, Owen MJ: No evidence for allelic association between schizophrenia and a functional variant of the human dopamine beta-hydroxylase gene (DBH). Am J Med Genet. 1999 Oct 15;88(5):557-9.
Pubmed: 10490716
Humphray SJ, Oliver K, Hunt AR, Plumb RW, Loveland JE, Howe KL, Andrews TD, Searle S, Hunt SE, Scott CE, Jones MC, Ainscough R, Almeida JP, Ambrose KD, Ashwell RI, Babbage AK, Babbage S, Bagguley CL, Bailey J, Banerjee R, Barker DJ, Barlow KF, Bates K, Beasley H, Beasley O, Bird CP, Bray-Allen S, Brown AJ, Brown JY, Burford D, Burrill W, Burton J, Carder C, Carter NP, Chapman JC, Chen Y, Clarke G, Clark SY, Clee CM, Clegg S, Collier RE, Corby N, Crosier M, Cummings AT, Davies J, Dhami P, Dunn M, Dutta I, Dyer LW, Earthrowl ME, Faulkner L, Fleming CJ, Frankish A, Frankland JA, French L, Fricker DG, Garner P, Garnett J, Ghori J, Gilbert JG, Glison C, Grafham DV, Gribble S, Griffiths C, Griffiths-Jones S, Grocock R, Guy J, Hall RE, Hammond S, Harley JL, Harrison ES, Hart EA, Heath PD, Henderson CD, Hopkins BL, Howard PJ, Howden PJ, Huckle E, Johnson C, Johnson D, Joy AA, Kay M, Keenan S, Kershaw JK, Kimberley AM, King A, Knights A, Laird GK, Langford C, Lawlor S, Leongamornlert DA, Leversha M, Lloyd C, Lloyd DM, Lovell J, Martin S, Mashreghi-Mohammadi M, Matthews L, McLaren S, McLay KE, McMurray A, Milne S, Nickerson T, Nisbett J, Nordsiek G, Pearce AV, Peck AI, Porter KM, Pandian R, Pelan S, Phillimore B, Povey S, Ramsey Y, Rand V, Scharfe M, Sehra HK, Shownkeen R, Sims SK, Skuce CD, Smith M, Steward CA, Swarbreck D, Sycamore N, Tester J, Thorpe A, Tracey A, Tromans A, Thomas DW, Wall M, Wallis JM, West AP, Whitehead SL, Willey DL, Williams SA, Wilming L, Wray PW, Young L, Ashurst JL, Coulson A, Blocker H, Durbin R, Sulston JE, Hubbard T, Jackson MJ, Bentley DR, Beck S, Rogers J, Dunham I: DNA sequence and analysis of human chromosome 9. Nature. 2004 May 27;429(6990):369-74. doi: 10.1038/nature02465.
Pubmed: 15164053
Lamouroux A, Vigny A, Faucon Biguet N, Darmon MC, Franck R, Henry JP, Mallet J: The primary structure of human dopamine-beta-hydroxylase: insights into the relationship between the soluble and the membrane-bound forms of the enzyme. EMBO J. 1987 Dec 20;6(13):3931-7.
Pubmed: 3443096
Ichinose H, Kurosawa Y, Titani K, Fujita K, Nagatsu T: Isolation and characterization of a cDNA clone encoding human aromatic L-amino acid decarboxylase. Biochem Biophys Res Commun. 1989 Nov 15;164(3):1024-30. doi: 10.1016/0006-291x(89)91772-5.
Pubmed: 2590185
Scherer LJ, McPherson JD, Wasmuth JJ, Marsh JL: Human dopa decarboxylase: localization to human chromosome 7p11 and characterization of hepatic cDNAs. Genomics. 1992 Jun;13(2):469-71.
Pubmed: 1612608
Sumi-Ichinose C, Ichinose H, Takahashi E, Hori T, Nagatsu T: Molecular cloning of genomic DNA and chromosomal assignment of the gene for human aromatic L-amino acid decarboxylase, the enzyme for catecholamine and serotonin biosynthesis. Biochemistry. 1992 Mar 3;31(8):2229-38. doi: 10.1021/bi00123a004.
Pubmed: 1540578
Kaneda N, Kobayashi K, Ichinose H, Kishi F, Nakazawa A, Kurosawa Y, Fujita K, Nagatsu T: Isolation of a novel cDNA clone for human tyrosine hydroxylase: alternative RNA splicing produces four kinds of mRNA from a single gene. Biochem Biophys Res Commun. 1987 Aug 14;146(3):971-5. doi: 10.1016/0006-291x(87)90742-x.
Pubmed: 2887169
Grima B, Lamouroux A, Boni C, Julien JF, Javoy-Agid F, Mallet J: A single human gene encoding multiple tyrosine hydroxylases with different predicted functional characteristics. Nature. 1987 Apr 16-22;326(6114):707-11. doi: 10.1038/326707a0.
Pubmed: 2882428
Kobayashi K, Kaneda N, Ichinose H, Kishi F, Nakazawa A, Kurosawa Y, Fujita K, Nagatsu T: Isolation of a full-length cDNA clone encoding human tyrosine hydroxylase type 3. Nucleic Acids Res. 1987 Aug 25;15(16):6733. doi: 10.1093/nar/15.16.6733.
Pubmed: 2888085
Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. doi: 10.1038/ng1285. Epub 2003 Dec 21.
Pubmed: 14702039
Schmutz J, Martin J, Terry A, Couronne O, Grimwood J, Lowry S, Gordon LA, Scott D, Xie G, Huang W, Hellsten U, Tran-Gyamfi M, She X, Prabhakar S, Aerts A, Altherr M, Bajorek E, Black S, Branscomb E, Caoile C, Challacombe JF, Chan YM, Denys M, Detter JC, Escobar J, Flowers D, Fotopulos D, Glavina T, Gomez M, Gonzales E, Goodstein D, Grigoriev I, Groza M, Hammon N, Hawkins T, Haydu L, Israni S, Jett J, Kadner K, Kimball H, Kobayashi A, Lopez F, Lou Y, Martinez D, Medina C, Morgan J, Nandkeshwar R, Noonan JP, Pitluck S, Pollard M, Predki P, Priest J, Ramirez L, Retterer J, Rodriguez A, Rogers S, Salamov A, Salazar A, Thayer N, Tice H, Tsai M, Ustaszewska A, Vo N, Wheeler J, Wu K, Yang J, Dickson M, Cheng JF, Eichler EE, Olsen A, Pennacchio LA, Rokhsar DS, Richardson P, Lucas SM, Myers RM, Rubin EM: The DNA sequence and comparative analysis of human chromosome 5. Nature. 2004 Sep 16;431(7006):268-74. doi: 10.1038/nature02919.
Pubmed: 15372022
Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. doi: 10.1101/gr.2596504.
Pubmed: 15489334
Mattera R, Codina J, Crozat A, Kidd V, Woo SL, Birnbaumer L: Identification by molecular cloning of two forms of the alpha-subunit of the human liver stimulatory (GS) regulatory component of adenylyl cyclase. FEBS Lett. 1986 Sep 29;206(1):36-42. doi: 10.1016/0014-5793(86)81336-9.
Pubmed: 3093273
Harris BA: Complete cDNA sequence of a human stimulatory GTP-binding protein alpha subunit. Nucleic Acids Res. 1988 Apr 25;16(8):3585. doi: 10.1093/nar/16.8.3585.
Pubmed: 3131741
Kozasa T, Itoh H, Tsukamoto T, Kaziro Y: Isolation and characterization of the human Gs alpha gene. Proc Natl Acad Sci U S A. 1988 Apr;85(7):2081-5. doi: 10.1073/pnas.85.7.2081.
Pubmed: 3127824
Surratt CK, Persico AM, Yang XD, Edgar SR, Bird GS, Hawkins AL, Griffin CA, Li X, Jabs EW, Uhl GR: A human synaptic vesicle monoamine transporter cDNA predicts posttranslational modifications, reveals chromosome 10 gene localization and identifies TaqI RFLPs. FEBS Lett. 1993 Mar 8;318(3):325-30. doi: 10.1016/0014-5793(93)80539-7.
Pubmed: 8095030
Erickson JD, Eiden LE: Functional identification and molecular cloning of a human brain vesicle monoamine transporter. J Neurochem. 1993 Dec;61(6):2314-7. doi: 10.1111/j.1471-4159.1993.tb07476.x.
Pubmed: 8245983
Peter D, Finn JP, Klisak I, Liu Y, Kojis T, Heinzmann C, Roghani A, Sparkes RS, Edwards RH: Chromosomal localization of the human vesicular amine transporter genes. Genomics. 1993 Dec;18(3):720-3.
Pubmed: 7905859
Pacholczyk T, Blakely RD, Amara SG: Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter. Nature. 1991 Mar 28;350(6316):350-4. doi: 10.1038/350350a0.
Pubmed: 2008212
Porzgen P, Bonisch H, Bruss M: Molecular cloning and organization of the coding region of the human norepinephrine transporter gene. Biochem Biophys Res Commun. 1995 Oct 24;215(3):1145-50. doi: 10.1006/bbrc.1995.2582.
Pubmed: 7488042
Porzgen P, Bonisch H, Hammermann R, Bruss M: The human noradrenaline transporter gene contains multiple polyadenylation sites and two alternatively spliced C-terminal exons. Biochim Biophys Acta. 1998 Jul 9;1398(3):365-70. doi: 10.1016/s0167-4781(98)00072-4.
Pubmed: 9655936
Highlighted elements will appear in red.
Highlight Compounds
Highlight Proteins
Enter relative concentration values (without units). Elements will be highlighted in a color gradient where red = lowest concentration and green = highest concentration. For the best results, view the pathway in Black and White.
Visualize Compound Data
Visualize Protein Data
Downloads
Settings