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Pathway Description
Methadone Action Pathway
Homo sapiens
Drug Action Pathway
Created: 2013-08-22
Last Updated: 2019-08-16
Methadone exerts its analgesic by acting on the mu-opioid receptor of sensory neurons. Binding to the mu-opioid receptor activates associated G(i) proteins. These subsequently act to inhibit adenylate cyclase, reducing the level of intracellular cAMP. G(i) also activates potassium channels and inactivates calcium channels causing the neuron to hyperpolarize. The end result is decreased nerve conduction and reduced neurotransmitter release, which blocks the perception of pain signals. Methadone further acts as an antagonist at the NMDA receptor, reducting calcium influx and neuronal excitability.
References
Methadone Pathway References
Fredheim OM, Moksnes K, Borchgrevink PC, Kaasa S, Dale O: Clinical pharmacology of methadone for pain. Acta Anaesthesiol Scand. 2008 Aug;52(7):879-89. doi: 10.1111/j.1399-6576.2008.01597.x. Epub 2008 Mar 7.
Pubmed: 18331375
Opioids. (2009). e-CPS (online version of Compendium of Pharmaceuticals and Specialties). Retrieved October 25, 2009.
Ohba C, Shiina M, Tohyama J, Haginoya K, Lerman-Sagie T, Okamoto N, Blumkin L, Lev D, Mukaida S, Nozaki F, Uematsu M, Onuma A, Kodera H, Nakashima M, Tsurusaki Y, Miyake N, Tanaka F, Kato M, Ogata K, Saitsu H, Matsumoto N: GRIN1 mutations cause encephalopathy with infantile-onset epilepsy, and hyperkinetic and stereotyped movement disorders. Epilepsia. 2015 Jun;56(6):841-8. doi: 10.1111/epi.12987. Epub 2015 Apr 10.
Pubmed: 25864721
Foldes RL, Rampersad V, Kamboj RK: Cloning and sequence analysis of cDNAs encoding human hippocampus N-methyl-D-aspartate receptor subunits: evidence for alternative RNA splicing. Gene. 1993 Sep 15;131(2):293-8. doi: 10.1016/0378-1119(93)90309-q.
Pubmed: 8406025
Karp SJ, Masu M, Eki T, Ozawa K, Nakanishi S: Molecular cloning and chromosomal localization of the key subunit of the human N-methyl-D-aspartate receptor. J Biol Chem. 1993 Feb 15;268(5):3728-33.
Pubmed: 7679115
Wei X, Walia V, Lin JC, Teer JK, Prickett TD, Gartner J, Davis S, Stemke-Hale K, Davies MA, Gershenwald JE, Robinson W, Robinson S, Rosenberg SA, Samuels Y: Exome sequencing identifies GRIN2A as frequently mutated in melanoma. Nat Genet. 2011 May;43(5):442-6. doi: 10.1038/ng.810. Epub 2011 Apr 15.
Pubmed: 21499247
Lemke JR, Lal D, Reinthaler EM, Steiner I, Nothnagel M, Alber M, Geider K, Laube B, Schwake M, Finsterwalder K, Franke A, Schilhabel M, Jahn JA, Muhle H, Boor R, Van Paesschen W, Caraballo R, Fejerman N, Weckhuysen S, De Jonghe P, Larsen J, Moller RS, Hjalgrim H, Addis L, Tang S, Hughes E, Pal DK, Veri K, Vaher U, Talvik T, Dimova P, Guerrero Lopez R, Serratosa JM, Linnankivi T, Lehesjoki AE, Ruf S, Wolff M, Buerki S, Wohlrab G, Kroell J, Datta AN, Fiedler B, Kurlemann G, Kluger G, Hahn A, Haberlandt DE, Kutzer C, Sperner J, Becker F, Weber YG, Feucht M, Steinbock H, Neophythou B, Ronen GM, Gruber-Sedlmayr U, Geldner J, Harvey RJ, Hoffmann P, Herms S, Altmuller J, Toliat MR, Thiele H, Nurnberg P, Wilhelm C, Stephani U, Helbig I, Lerche H, Zimprich F, Neubauer BA, Biskup S, von Spiczak S: Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat Genet. 2013 Sep;45(9):1067-72. doi: 10.1038/ng.2728. Epub 2013 Aug 11.
Pubmed: 23933819
Yuan H, Hansen KB, Zhang J, Pierson TM, Markello TC, Fajardo KV, Holloman CM, Golas G, Adams DR, Boerkoel CF, Gahl WA, Traynelis SF: Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy. Nat Commun. 2014;5:3251. doi: 10.1038/ncomms4251.
Pubmed: 24504326
Andersson O, Stenqvist A, Attersand A, von Euler G: Nucleotide sequence, genomic organization, and chromosomal localization of genes encoding the human NMDA receptor subunits NR3A and NR3B. Genomics. 2001 Dec;78(3):178-84. doi: 10.1006/geno.2001.6666.
Pubmed: 11735224
Eriksson M, Nilsson A, Froelich-Fabre S, Akesson E, Dunker J, Seiger A, Folkesson R, Benedikz E, Sundstrom E: Cloning and expression of the human N-methyl-D-aspartate receptor subunit NR3A. Neurosci Lett. 2002 Mar 22;321(3):177-81. doi: 10.1016/s0304-3940(01)02524-1.
Pubmed: 11880201
Nagase T, Kikuno R, Ohara O: Prediction of the coding sequences of unidentified human genes. XXII. The complete sequences of 50 new cDNA clones which code for large proteins. DNA Res. 2001 Dec 31;8(6):319-27. doi: 10.1093/dnares/8.6.319.
Pubmed: 11853319
Wang JB, Johnson PS, Persico AM, Hawkins AL, Griffin CA, Uhl GR: Human mu opiate receptor. cDNA and genomic clones, pharmacologic characterization and chromosomal assignment. FEBS Lett. 1994 Jan 31;338(2):217-22. doi: 10.1016/0014-5793(94)80368-4.
Pubmed: 7905839
Bare LA, Mansson E, Yang D: Expression of two variants of the human mu opioid receptor mRNA in SK-N-SH cells and human brain. FEBS Lett. 1994 Nov 7;354(2):213-6. doi: 10.1016/0014-5793(94)01129-x.
Pubmed: 7957926
Mestek A, Hurley JH, Bye LS, Campbell AD, Chen Y, Tian M, Liu J, Schulman H, Yu L: The human mu opioid receptor: modulation of functional desensitization by calcium/calmodulin-dependent protein kinase and protein kinase C. J Neurosci. 1995 Mar;15(3 Pt 2):2396-406.
Pubmed: 7891175
Lang T, Klein K, Fischer J, Nussler AK, Neuhaus P, Hofmann U, Eichelbaum M, Schwab M, Zanger UM: Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver. Pharmacogenetics. 2001 Jul;11(5):399-415.
Pubmed: 11470993
Lang T, Klein K, Richter T, Zibat A, Kerb R, Eichelbaum M, Schwab M, Zanger UM: Multiple novel nonsynonymous CYP2B6 gene polymorphisms in Caucasians: demonstration of phenotypic null alleles. J Pharmacol Exp Ther. 2004 Oct;311(1):34-43. doi: 10.1124/jpet.104.068973. Epub 2004 Jun 9.
Pubmed: 15190123
Yamano S, Nhamburo PT, Aoyama T, Meyer UA, Inaba T, Kalow W, Gelboin HV, McBride OW, Gonzalez FJ: cDNA cloning and sequence and cDNA-directed expression of human P450 IIB1: identification of a normal and two variant cDNAs derived from the CYP2B locus on chromosome 19 and differential expression of the IIB mRNAs in human liver. Biochemistry. 1989 Sep 5;28(18):7340-8. doi: 10.1021/bi00444a029.
Pubmed: 2573390
Miyazawa M, Shindo M, Shimada T: Metabolism of (+)- and (-)-limonenes to respective carveols and perillyl alcohols by CYP2C9 and CYP2C19 in human liver microsomes. Drug Metab Dispos. 2002 May;30(5):602-7. doi: 10.1124/dmd.30.5.602.
Pubmed: 11950794
Ibeanu GC, Goldstein JA, Meyer U, Benhamou S, Bouchardy C, Dayer P, Ghanayem BI, Blaisdell J: Identification of new human CYP2C19 alleles (CYP2C19*6 and CYP2C19*2B) in a Caucasian poor metabolizer of mephenytoin. J Pharmacol Exp Ther. 1998 Sep;286(3):1490-5.
Pubmed: 9732415
Ibeanu GC, Blaisdell J, Ghanayem BI, Beyeler C, Benhamou S, Bouchardy C, Wilkinson GR, Dayer P, Daly AK, Goldstein JA: An additional defective allele, CYP2C19*5, contributes to the S-mephenytoin poor metabolizer phenotype in Caucasians. Pharmacogenetics. 1998 Apr;8(2):129-35.
Pubmed: 10022751
Dai D, Zeldin DC, Blaisdell JA, Chanas B, Coulter SJ, Ghanayem BI, Goldstein JA: Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid. Pharmacogenetics. 2001 Oct;11(7):597-607.
Pubmed: 11668219
Okino ST, Quattrochi LC, Pendurthi UR, McBride OW, Tukey RH: Characterization of multiple human cytochrome P-450 1 cDNAs. The chromosomal localization of the gene and evidence for alternate RNA splicing. J Biol Chem. 1987 Nov 25;262(33):16072-9.
Pubmed: 3500169
Kimura S, Pastewka J, Gelboin HV, Gonzalez FJ: cDNA and amino acid sequences of two members of the human P450IIC gene subfamily. Nucleic Acids Res. 1987 Dec 10;15(23):10053-4. doi: 10.1093/nar/15.23.10053.
Pubmed: 3697070
Kimura S, Umeno M, Skoda RC, Meyer UA, Gonzalez FJ: The human debrisoquine 4-hydroxylase (CYP2D) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene, and a pseudogene. Am J Hum Genet. 1989 Dec;45(6):889-904.
Pubmed: 2574001
Gaedigk A, Bhathena A, Ndjountche L, Pearce RE, Abdel-Rahman SM, Alander SW, Bradford LD, Rogan PK, Leeder JS: Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans. Pharmacogenomics J. 2005;5(3):173-82. doi: 10.1038/sj.tpj.6500305.
Pubmed: 15768052
Sridar C, Snider NT, Hollenberg PF: Anandamide oxidation by wild-type and polymorphically expressed CYP2B6 and CYP2D6. Drug Metab Dispos. 2011 May;39(5):782-8. doi: 10.1124/dmd.110.036707. Epub 2011 Feb 2.
Pubmed: 21289075
Hsieh KP, Lin YY, Cheng CL, Lai ML, Lin MS, Siest JP, Huang JD: Novel mutations of CYP3A4 in Chinese. Drug Metab Dispos. 2001 Mar;29(3):268-73.
Pubmed: 11181494
Molowa DT, Schuetz EG, Wrighton SA, Watkins PB, Kremers P, Mendez-Picon G, Parker GA, Guzelian PS: Complete cDNA sequence of a cytochrome P-450 inducible by glucocorticoids in human liver. Proc Natl Acad Sci U S A. 1986 Jul;83(14):5311-5. doi: 10.1073/pnas.83.14.5311.
Pubmed: 3460094
Gonzalez FJ, Schmid BJ, Umeno M, Mcbride OW, Hardwick JP, Meyer UA, Gelboin HV, Idle JR: Human P450PCN1: sequence, chromosome localization, and direct evidence through cDNA expression that P450PCN1 is nifedipine oxidase. DNA. 1988 Mar;7(2):79-86. doi: 10.1089/dna.1988.7.79.
Pubmed: 3267210
Neuron Function References
Lovinger DM: Communication networks in the brain: neurons, receptors, neurotransmitters, and alcohol. Alcohol Res Health. 2008;31(3):196-214.
Pubmed: 23584863
Kress GJ, Mennerick S: Action potential initiation and propagation: upstream influences on neurotransmission. Neuroscience. 2009 Jan 12;158(1):211-22. doi: 10.1016/j.neuroscience.2008.03.021. Epub 2008 Mar 19.
Pubmed: 18472347
Platkiewicz J, Brette R: A threshold equation for action potential initiation. PLoS Comput Biol. 2010 Jul 8;6(7):e1000850. doi: 10.1371/journal.pcbi.1000850.
Pubmed: 20628619
Ohba C, Shiina M, Tohyama J, Haginoya K, Lerman-Sagie T, Okamoto N, Blumkin L, Lev D, Mukaida S, Nozaki F, Uematsu M, Onuma A, Kodera H, Nakashima M, Tsurusaki Y, Miyake N, Tanaka F, Kato M, Ogata K, Saitsu H, Matsumoto N: GRIN1 mutations cause encephalopathy with infantile-onset epilepsy, and hyperkinetic and stereotyped movement disorders. Epilepsia. 2015 Jun;56(6):841-8. doi: 10.1111/epi.12987. Epub 2015 Apr 10.
Pubmed: 25864721
Foldes RL, Rampersad V, Kamboj RK: Cloning and sequence analysis of cDNAs encoding human hippocampus N-methyl-D-aspartate receptor subunits: evidence for alternative RNA splicing. Gene. 1993 Sep 15;131(2):293-8. doi: 10.1016/0378-1119(93)90309-q.
Pubmed: 8406025
Karp SJ, Masu M, Eki T, Ozawa K, Nakanishi S: Molecular cloning and chromosomal localization of the key subunit of the human N-methyl-D-aspartate receptor. J Biol Chem. 1993 Feb 15;268(5):3728-33.
Pubmed: 7679115
Wei X, Walia V, Lin JC, Teer JK, Prickett TD, Gartner J, Davis S, Stemke-Hale K, Davies MA, Gershenwald JE, Robinson W, Robinson S, Rosenberg SA, Samuels Y: Exome sequencing identifies GRIN2A as frequently mutated in melanoma. Nat Genet. 2011 May;43(5):442-6. doi: 10.1038/ng.810. Epub 2011 Apr 15.
Pubmed: 21499247
Lemke JR, Lal D, Reinthaler EM, Steiner I, Nothnagel M, Alber M, Geider K, Laube B, Schwake M, Finsterwalder K, Franke A, Schilhabel M, Jahn JA, Muhle H, Boor R, Van Paesschen W, Caraballo R, Fejerman N, Weckhuysen S, De Jonghe P, Larsen J, Moller RS, Hjalgrim H, Addis L, Tang S, Hughes E, Pal DK, Veri K, Vaher U, Talvik T, Dimova P, Guerrero Lopez R, Serratosa JM, Linnankivi T, Lehesjoki AE, Ruf S, Wolff M, Buerki S, Wohlrab G, Kroell J, Datta AN, Fiedler B, Kurlemann G, Kluger G, Hahn A, Haberlandt DE, Kutzer C, Sperner J, Becker F, Weber YG, Feucht M, Steinbock H, Neophythou B, Ronen GM, Gruber-Sedlmayr U, Geldner J, Harvey RJ, Hoffmann P, Herms S, Altmuller J, Toliat MR, Thiele H, Nurnberg P, Wilhelm C, Stephani U, Helbig I, Lerche H, Zimprich F, Neubauer BA, Biskup S, von Spiczak S: Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat Genet. 2013 Sep;45(9):1067-72. doi: 10.1038/ng.2728. Epub 2013 Aug 11.
Pubmed: 23933819
Yuan H, Hansen KB, Zhang J, Pierson TM, Markello TC, Fajardo KV, Holloman CM, Golas G, Adams DR, Boerkoel CF, Gahl WA, Traynelis SF: Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy. Nat Commun. 2014;5:3251. doi: 10.1038/ncomms4251.
Pubmed: 24504326
Andersson O, Stenqvist A, Attersand A, von Euler G: Nucleotide sequence, genomic organization, and chromosomal localization of genes encoding the human NMDA receptor subunits NR3A and NR3B. Genomics. 2001 Dec;78(3):178-84. doi: 10.1006/geno.2001.6666.
Pubmed: 11735224
Eriksson M, Nilsson A, Froelich-Fabre S, Akesson E, Dunker J, Seiger A, Folkesson R, Benedikz E, Sundstrom E: Cloning and expression of the human N-methyl-D-aspartate receptor subunit NR3A. Neurosci Lett. 2002 Mar 22;321(3):177-81. doi: 10.1016/s0304-3940(01)02524-1.
Pubmed: 11880201
Nagase T, Kikuno R, Ohara O: Prediction of the coding sequences of unidentified human genes. XXII. The complete sequences of 50 new cDNA clones which code for large proteins. DNA Res. 2001 Dec 31;8(6):319-27. doi: 10.1093/dnares/8.6.319.
Pubmed: 11853319
Wang JB, Johnson PS, Persico AM, Hawkins AL, Griffin CA, Uhl GR: Human mu opiate receptor. cDNA and genomic clones, pharmacologic characterization and chromosomal assignment. FEBS Lett. 1994 Jan 31;338(2):217-22. doi: 10.1016/0014-5793(94)80368-4.
Pubmed: 7905839
Bare LA, Mansson E, Yang D: Expression of two variants of the human mu opioid receptor mRNA in SK-N-SH cells and human brain. FEBS Lett. 1994 Nov 7;354(2):213-6. doi: 10.1016/0014-5793(94)01129-x.
Pubmed: 7957926
Mestek A, Hurley JH, Bye LS, Campbell AD, Chen Y, Tian M, Liu J, Schulman H, Yu L: The human mu opioid receptor: modulation of functional desensitization by calcium/calmodulin-dependent protein kinase and protein kinase C. J Neurosci. 1995 Mar;15(3 Pt 2):2396-406.
Pubmed: 7891175
Lang T, Klein K, Fischer J, Nussler AK, Neuhaus P, Hofmann U, Eichelbaum M, Schwab M, Zanger UM: Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver. Pharmacogenetics. 2001 Jul;11(5):399-415.
Pubmed: 11470993
Lang T, Klein K, Richter T, Zibat A, Kerb R, Eichelbaum M, Schwab M, Zanger UM: Multiple novel nonsynonymous CYP2B6 gene polymorphisms in Caucasians: demonstration of phenotypic null alleles. J Pharmacol Exp Ther. 2004 Oct;311(1):34-43. doi: 10.1124/jpet.104.068973. Epub 2004 Jun 9.
Pubmed: 15190123
Yamano S, Nhamburo PT, Aoyama T, Meyer UA, Inaba T, Kalow W, Gelboin HV, McBride OW, Gonzalez FJ: cDNA cloning and sequence and cDNA-directed expression of human P450 IIB1: identification of a normal and two variant cDNAs derived from the CYP2B locus on chromosome 19 and differential expression of the IIB mRNAs in human liver. Biochemistry. 1989 Sep 5;28(18):7340-8. doi: 10.1021/bi00444a029.
Pubmed: 2573390
Miyazawa M, Shindo M, Shimada T: Metabolism of (+)- and (-)-limonenes to respective carveols and perillyl alcohols by CYP2C9 and CYP2C19 in human liver microsomes. Drug Metab Dispos. 2002 May;30(5):602-7. doi: 10.1124/dmd.30.5.602.
Pubmed: 11950794
Ibeanu GC, Goldstein JA, Meyer U, Benhamou S, Bouchardy C, Dayer P, Ghanayem BI, Blaisdell J: Identification of new human CYP2C19 alleles (CYP2C19*6 and CYP2C19*2B) in a Caucasian poor metabolizer of mephenytoin. J Pharmacol Exp Ther. 1998 Sep;286(3):1490-5.
Pubmed: 9732415
Ibeanu GC, Blaisdell J, Ghanayem BI, Beyeler C, Benhamou S, Bouchardy C, Wilkinson GR, Dayer P, Daly AK, Goldstein JA: An additional defective allele, CYP2C19*5, contributes to the S-mephenytoin poor metabolizer phenotype in Caucasians. Pharmacogenetics. 1998 Apr;8(2):129-35.
Pubmed: 10022751
Dai D, Zeldin DC, Blaisdell JA, Chanas B, Coulter SJ, Ghanayem BI, Goldstein JA: Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid. Pharmacogenetics. 2001 Oct;11(7):597-607.
Pubmed: 11668219
Okino ST, Quattrochi LC, Pendurthi UR, McBride OW, Tukey RH: Characterization of multiple human cytochrome P-450 1 cDNAs. The chromosomal localization of the gene and evidence for alternate RNA splicing. J Biol Chem. 1987 Nov 25;262(33):16072-9.
Pubmed: 3500169
Kimura S, Pastewka J, Gelboin HV, Gonzalez FJ: cDNA and amino acid sequences of two members of the human P450IIC gene subfamily. Nucleic Acids Res. 1987 Dec 10;15(23):10053-4. doi: 10.1093/nar/15.23.10053.
Pubmed: 3697070
Kimura S, Umeno M, Skoda RC, Meyer UA, Gonzalez FJ: The human debrisoquine 4-hydroxylase (CYP2D) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene, and a pseudogene. Am J Hum Genet. 1989 Dec;45(6):889-904.
Pubmed: 2574001
Gaedigk A, Bhathena A, Ndjountche L, Pearce RE, Abdel-Rahman SM, Alander SW, Bradford LD, Rogan PK, Leeder JS: Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans. Pharmacogenomics J. 2005;5(3):173-82. doi: 10.1038/sj.tpj.6500305.
Pubmed: 15768052
Sridar C, Snider NT, Hollenberg PF: Anandamide oxidation by wild-type and polymorphically expressed CYP2B6 and CYP2D6. Drug Metab Dispos. 2011 May;39(5):782-8. doi: 10.1124/dmd.110.036707. Epub 2011 Feb 2.
Pubmed: 21289075
Hsieh KP, Lin YY, Cheng CL, Lai ML, Lin MS, Siest JP, Huang JD: Novel mutations of CYP3A4 in Chinese. Drug Metab Dispos. 2001 Mar;29(3):268-73.
Pubmed: 11181494
Molowa DT, Schuetz EG, Wrighton SA, Watkins PB, Kremers P, Mendez-Picon G, Parker GA, Guzelian PS: Complete cDNA sequence of a cytochrome P-450 inducible by glucocorticoids in human liver. Proc Natl Acad Sci U S A. 1986 Jul;83(14):5311-5. doi: 10.1073/pnas.83.14.5311.
Pubmed: 3460094
Gonzalez FJ, Schmid BJ, Umeno M, Mcbride OW, Hardwick JP, Meyer UA, Gelboin HV, Idle JR: Human P450PCN1: sequence, chromosome localization, and direct evidence through cDNA expression that P450PCN1 is nifedipine oxidase. DNA. 1988 Mar;7(2):79-86. doi: 10.1089/dna.1988.7.79.
Pubmed: 3267210
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