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Pathway Description
Levomilnacipran SNRI - Norepinephrine reuptake Inhibition Action Pathway
Homo sapiens
Drug Action Pathway
Created: 2023-07-04
Last Updated: 2023-11-27
Levomilnacipran (the more active 1S, 2R - enantiomer of milnacipran) is a serotonin and norepinephrine reuptake inhibitor (SNRI). It is used in the management of major depressive disorder, generalized anxiety disorder, chronic musculoskeletal pain and diabetic peripheral neuropathy. It is generally believed that 5HT and NE participate in the modulation of endogenous analgesic mechanisms by way of the descending inhibitory pain pathways in the brain and spinal cord. Although the specific mechanism of action remains unclear, some studies have proposed that low levels of 5HT may be associated with increased sensitivity to pain - a condition that could subsequently be improved by milnacipran's capacity to enhance the presence of 5HT by inhibiting its reuptake via serotonin transporters at synaptic clefts. Furthermore, in the CNS it is also generally believed that NE released from descending pathways can mitigate pain sensations via eliciting inhibitory effects on alpha-2A-adrenoceptors on central terminals of primary afferent nociceptors, by direct alpha-2-adrenergic action on pain-relay neurons, and by alpha-1-adrenoceptor-mediated activation of inhibitory interneurons. Such NE pain mitigation is consequently also enhanced by milnacipran's ability to enhance the presence of NE by inhibiting its reuptake via norepinephrine transporters at synaptic clefts
References
Levomilnacipran SNRI - Norepinephrine reuptake Inhibition pathway References
Bruno A, Morabito P, Spina E, Muscatello MR: The Role of Levomilnacipran in the Management of Major Depressive Disorder: A Comprehensive Review. Curr Neuropharmacol. 2016;14(2):191-9. doi: 10.2174/1570159x14666151117122458.
Pubmed: 26572745
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
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
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
Williams ME, Feldman DH, McCue AF, Brenner R, Velicelebi G, Ellis SB, Harpold MM: Structure and functional expression of alpha 1, alpha 2, and beta subunits of a novel human neuronal calcium channel subtype. Neuron. 1992 Jan;8(1):71-84. doi: 10.1016/0896-6273(92)90109-q.
Pubmed: 1309651
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
Brust PF, Simerson S, McCue AF, Deal CR, Schoonmaker S, Williams ME, Velicelebi G, Johnson EC, Harpold MM, Ellis SB: Human neuronal voltage-dependent calcium channels: studies on subunit structure and role in channel assembly. Neuropharmacology. 1993 Nov;32(11):1089-102. doi: 10.1016/0028-3908(93)90004-m.
Pubmed: 8107964
Klugbauer N, Lacinova L, Marais E, Hobom M, Hofmann F: Molecular diversity of the calcium channel alpha2delta subunit. J Neurosci. 1999 Jan 15;19(2):684-91.
Pubmed: 9880589
Gao B, Sekido Y, Maximov A, Saad M, Forgacs E, Latif F, Wei MH, Lerman M, Lee JH, Perez-Reyes E, Bezprozvanny I, Minna JD: Functional properties of a new voltage-dependent calcium channel alpha(2)delta auxiliary subunit gene (CACNA2D2). J Biol Chem. 2000 Apr 21;275(16):12237-42. doi: 10.1074/jbc.275.16.12237.
Pubmed: 10766861
Hobom M, Dai S, Marais E, Lacinova L, Hofmann F, Klugbauer N: Neuronal distribution and functional characterization of the calcium channel alpha2delta-2 subunit. Eur J Neurosci. 2000 Apr;12(4):1217-26. doi: 10.1046/j.1460-9568.2000.01009.x.
Pubmed: 10762351
Williams ME, Brust PF, Feldman DH, Patthi S, Simerson S, Maroufi A, McCue AF, Velicelebi G, Ellis SB, Harpold MM: Structure and functional expression of an omega-conotoxin-sensitive human N-type calcium channel. Science. 1992 Jul 17;257(5068):389-95. doi: 10.1126/science.1321501.
Pubmed: 1321501
Kim DS, Jung HH, Park SH, Chin H: Isolation and characterization of the 5'-upstream region of the human N-type calcium channel alpha1B subunit gene. Chromosomal localization and promoter analysis. J Biol Chem. 1997 Feb 21;272(8):5098-104. doi: 10.1074/jbc.272.8.5098.
Pubmed: 9030575
Frielle T, Collins S, Daniel KW, Caron MG, Lefkowitz RJ, Kobilka BK: Cloning of the cDNA for the human beta 1-adrenergic receptor. Proc Natl Acad Sci U S A. 1987 Nov;84(22):7920-4. doi: 10.1073/pnas.84.22.7920.
Pubmed: 2825170
Moore JD, Mason DA, Green SA, Hsu J, Liggett SB: Racial differences in the frequencies of cardiac beta(1)-adrenergic receptor polymorphisms: analysis of c145A>G and c1165G>C. Hum Mutat. 1999 Sep 19;14(3):271. doi: 10.1002/(SICI)1098-1004(1999)14:3<271::AID-HUMU14>3.0.CO;2-Q.
Pubmed: 10477438
Deloukas P, Earthrowl ME, Grafham DV, Rubenfield M, French L, Steward CA, Sims SK, Jones MC, Searle S, Scott C, Howe K, Hunt SE, Andrews TD, Gilbert JG, Swarbreck D, Ashurst JL, Taylor A, Battles J, Bird CP, Ainscough R, Almeida JP, Ashwell RI, Ambrose KD, Babbage AK, Bagguley CL, Bailey J, Banerjee R, Bates K, Beasley H, Bray-Allen S, Brown AJ, Brown JY, Burford DC, Burrill W, Burton J, Cahill P, Camire D, Carter NP, Chapman JC, Clark SY, Clarke G, Clee CM, Clegg S, Corby N, Coulson A, Dhami P, Dutta I, Dunn M, Faulkner L, Frankish A, Frankland JA, Garner P, Garnett J, Gribble S, Griffiths C, Grocock R, Gustafson E, Hammond S, Harley JL, Hart E, Heath PD, Ho TP, Hopkins B, Horne J, Howden PJ, Huckle E, Hynds C, Johnson C, Johnson D, Kana A, Kay M, Kimberley AM, Kershaw JK, Kokkinaki M, Laird GK, Lawlor S, Lee HM, Leongamornlert DA, Laird G, Lloyd C, Lloyd DM, Loveland J, Lovell J, McLaren S, McLay KE, McMurray A, Mashreghi-Mohammadi M, Matthews L, Milne S, Nickerson T, Nguyen M, Overton-Larty E, Palmer SA, Pearce AV, Peck AI, Pelan S, Phillimore B, Porter K, Rice CM, Rogosin A, Ross MT, Sarafidou T, Sehra HK, Shownkeen R, Skuce CD, Smith M, Standring L, Sycamore N, Tester J, Thorpe A, Torcasso W, Tracey A, Tromans A, Tsolas J, Wall M, Walsh J, Wang H, Weinstock K, West AP, Willey DL, Whitehead SL, Wilming L, Wray PW, Young L, Chen Y, Lovering RC, Moschonas NK, Siebert R, Fechtel K, Bentley D, Durbin R, Hubbard T, Doucette-Stamm L, Beck S, Smith DR, Rogers J: The DNA sequence and comparative analysis of human chromosome 10. Nature. 2004 May 27;429(6990):375-81. doi: 10.1038/nature02462.
Pubmed: 15164054
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