Candidate gene polymorphisms predicting individual sensitivity to opioids

Naunyn-Schmiedeberg's Archives of Pharmacology

Volumn 377, Issue 4-6, 2008, Pages 269-281

  Kasai, Shinya ^a   Hayashida, Masakazu ^b   Sora, Ichiro ^c   Ikeda, Kazutaka ^a  

^a TOKYO METROPOLITAN INSTITUTE OF MEDICAL SCIENCE   (Japan)

^b SAITAMA MEDICAL UNIVERSITY INTERNATIONAL MEDICAL CENTER   (Japan)

^c TOHOKU UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

Author keywords

Genetic polymorphisms; Interindividual differences; Mu opioid receptor; Opioid sensitivity

Indexed keywords

ABC TRANSPORTER; ADENOSINE RECEPTOR; ADRENERGIC RECEPTOR; BUPRENORPHINE; CANNABINOID RECEPTOR; CARRIER PROTEIN; CODEINE; CYTOCHROME P450; CYTOCHROME P450 1A2; CYTOCHROME P450 2B6; CYTOCHROME P450 2C19; CYTOCHROME P450 2C8; CYTOCHROME P450 2D6; CYTOCHROME P450 3A4; CYTOCHROME P450 3A5; DIHYDROCODEINE; FENTANYL; GLUCURONOSYLTRANSFERASE; HISTAMINE RECEPTOR; HYDROCODONE; METHADONE; MORPHINE; MUSCARINIC RECEPTOR; NOCICEPTIN RECEPTOR; OPIATE; OPIATE RECEPTOR; OXYCODONE; POTASSIUM CHANNEL; TRAMADOL; UNINDEXED DRUG;

ANALGESIA; CONFERENCE PAPER; DNA POLYMORPHISM; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG EFFICACY; DRUG METABOLISM; DRUG SENSITIVITY; DRUG TRANSPORT; GENE IDENTIFICATION; GENETIC VARIABILITY; HUMAN; KNOCKOUT GENE; KNOCKOUT MOUSE; MOLECULAR DYNAMICS; NONHUMAN; PAIN; PHARMACODYNAMICS; PHARMACOGENETICS; SIGNAL TRANSDUCTION; SINGLE NUCLEOTIDE POLYMORPHISM;

ANALGESICS, OPIOID; ANIMALS; DATABASES, FACTUAL; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG RESISTANCE; FORECASTING; HUMANS; MICE; PAIN; PHARMACOGENETICS; POLYMORPHISM, GENETIC; SIGNAL TRANSDUCTION;

EID: 45849109198     PISSN: 00281298     EISSN: None     Source Type: Journal    
DOI: 10.1007/s00210-007-0205-3     Document Type: Conference Paper

References (174)

1. Abbott FV, Palmour RM (1988) Morphine-6-glucuronide: analgesic effects and receptor binding profile in rats. Life Sci 43:1685-1695
2. Arias A, Feinn R, Kranzler HR (2006) Association of an Asn40Asp (A118G) polymorphism in the μ-opioid receptor gene with substance dependence: a meta-analysis. Drug Alcohol Depend 83:262-268
3. Bailey DW (1971) Cumulative effect or independent effect? Transplantation 11:419-422
4. Bart G, Heilig M, LaForge KS, Pollak L, Leal SM, Ott J, Kreek MJ (2004) Substantial attributable risk related to a functional mu-opioid receptor gene polymorphism in association with heroin addiction in central Sweden. Mol Psychiatry 9:547-549
5. Bart G, Kreek MJ, Ott J, LaForge KS, Proudnikov D, Pollak L, Heilig M (2005) Increased attributable risk related to a functional μ-opioid receptor gene polymorphism in association with alcohol dependence in central Sweden. Neuropsychopharmacology 30:417-422
6. Basile AS, Fedorova I, Zapata A, Liu X, Shippenberg T, Duttaroy A, Yamada M, Wess J (2002) Deletion of the M5 muscarinic acetylcholine receptor attenuates morphine reinforcement and withdrawal but not morphine analgesia. Proc Natl Acad Sci USA 99:11452-11457
7. Befort K, Filliol D, Decaillot FM, Gaveriaux-Ruff C, Hoehe MR, Kieffer BL (2001) A single nucleotide polymorphic mutation in the human μ-opioid receptor severely impairs receptor signaling. J Biol Chem 276:3130-3137
8. Belfer I, Wu T, Kingman A, Krishnaraju RK, Goldman D, Max MB (2004) Candidate gene studies of human pain mechanisms: methods for optimizing choice of polymorphisms and sample size. Anesthesiology 100:1562-1572
9. Bertilsson L, Dahl ML, Ekqvist B, Jerling M, Lierena A (1991) Genetic regulation of the disposition of psychotropic drugs. In: Meltzer HY, Nerozzi D (eds) Current practices and future developments in the pharmacotherapy of mental disorders. Elsevier, Amsterdam, pp 73-80
10. Beyer A, Koch T, Schroder H, Schulz S, Hollt V (2004) Effect of the A118G polymorphism on binding affinity, potency and agonist-mediated endocytosis, desensitization, and resensitization of the human mu-opioid receptor. J Neurochem 89:553-560
11. Bhasker CR, McKinnon W, Stone A, Lo AC, Kubota T, Ishizaki T, Miners JO (2000) Genetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268: ethnic diversity of alleles and potential clinical significance. Pharmacogenetics 10:679-685
12. Bianchi M, Maggi R, Pimpinelli F, Rubino T, Parolaro D, Poli V, Ciliberto G, Panerai AE, Sacerdote P (1999) Presence of a reduced opioid response in interleukin-6 knock out mice. Eur J Neurosci 11:1501-1507
13. Bohn LM, Lefkowitz RJ, Gainetdinov RR, Peppel K, Caron MG, Lin FT (1999) Enhanced morphine analgesia in mice lacking β-arrestin 2. Science 286:2495-2498
14. Bohn LM, Xu F, Gainetdinov RR, Caron MG (2000a) Potentiated opioid analgesia in norepinephrine transporter knock-out mice. J Neurosci 20:9040-9045
15. Bohn LM, Gainetdinov RR, Lin FT, Lefkowitz RJ, Caron MG (2000b) μ-Opioid receptor desensitization by β-arrestin-2 determines morphine tolerance but not dependence. Nature 408:720-723
16. Bohn LM, Lefkowitz RJ, Caron MG (2002) Differential mechanisms of morphine antinociceptive tolerance revealed in βarrestin-2 knock-out mice. J Neurosci 22:10494-10500
17. Bohn LM, Gainetdinov RR, Sotnikova TD, Medvedev IO, Lefkowitz RJ, Dykstra LA, Caron MG (2003) Enhanced rewarding properties of morphine, but not cocaine, in βarrestin-2 knock-out mice. J Neurosci 23:10265-10273
18. Bond C, LaForge KS, Tian M, Melia D, Zhang S, Borg L, Gong J, Schluger J, Strong JA, Leal SM, Tischfield JA, Kreek MJ, Yu L (1998) Single-nucleotide polymorphism in the human mu opioid receptor gene alters β-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci USA 95:9608-9613
19. Bourasset F, Cisternino S, Temsamani J, Scherrmann JM (2003) Evidence for an active transport of morphine-6-β-d-glucuronide but not P-glycoprotein-mediated at the blood-brain barrier. J Neurochem 86:1564-1567
20. Callaghan R, Riordan JR (1993) Synthetic and natural opiates interact with P-glycoprotein in multidrug-resistant cells. J Biol Chem 268:16059-16064
21. Caraco Y, Sheller J, Wood AJ (1996) Pharmacogenetic determination of the effects of codeine and prediction of drug interactions. J Pharmacol Exp Ther 278:1165-1174
22. Carrigan KA, Dykstra LA (2007) Behavioral effects of morphine and cocaine in M1 muscarinic acetylcholine receptor-deficient mice. Psychopharmacology 191:985-993
23. Chou WY, Wang CH, Liu PH, Liu CC, Tseng CC, Jawan B (2006) Human opioid receptor A118G polymorphism affects intravenous patient-controlled analgesia morphine consumption after total abdominal hysterectomy. Anesthesiology 105:334-337
24. Chung S, Pohl S, Zeng J, Civelli O, Reinscheid RK (2006) Endogenous orphanin FQ/nociceptin is involved in the development of morphine tolerance. J Pharmacol Exp Ther 318:262-267
25. Clark JD, Tempel BL (1998) Hyperalgesia in mice lacking the Kv1.1 potassium channel gene. Neurosci Lett 251:121-124
26. Coller JK, Barratt DT, Dahlen K, Loennechen MH, Somogyi AA (2006) ABCB1 genetic variability and methadone dosage requirements in opioid-dependent individuals. Clin Pharmacol Ther 80:682-690
27. Cossu G, Ledent C, Fattore L, Imperato A, Bohme GA, Parmentier M, Fratta W (2001) Cannabinoid CB1 receptor knockout mice fail to self-administer morphine but not other drugs of abuse. Behav Brain Res 118:61-65
28. Dayer P, Desmeules J, Leemann T, Striberni R (1988) Bioactivation of the narcotic drug codeine in human liver is mediated by the polymorphic monooxygenase catalyzing debrisoquine 4-hydroxylation (cytochrome P-450 dbl/bufI). Biochem Biophys Res Commun 152:411-416
29. Dean M, Rzhetsky A, Allikmets R (2001) The human ATP-binding cassette (ABC) transporter superfamily. Genome Res 11:1156-1166
30. Drouin C, Darracq L, Trovero F, Blanc G, Glowinski J, Cotecchia S, Tassin JP (2002) α1b-Adrenergic receptors control locomotor and rewarding effects of psychostimulants and opiates. J Neurosci 22:2873-2884
31. Eckhardt K, Li S, Ammon S, Schanzle G, Mikus G, Eichelbaum M (1998) Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation. Pain 76:27-33
32. Elmer GI, Pieper JO, Levy J, Rubinstein M, Low MJ, Grandy DK, Wise RA (2005) Brain stimulation and morphine reward deficits in dopamine D2 receptor-deficient mice. Psychopharmacology 182:33-44
33. Ferrari A, Coccia CP, Bertolini A, Sternieri E (2004) Methadone: metabolism, pharmacokinetics and interactions. Pharmacol Res 50:551-559
34. Foster DJ, Somogyi AA, Bochner F (1999) Methadone N-demethylation in human liver microsomes: lack of stereoselectivity and involvement of CYP3A4. Br J Clin Pharmacol 47:403-412
35. Franke P, Wang T, Nothen MM, Knapp M, Neidt H, Albrecht S, Jahnes E, Propping P, Maier W (2001) Nonreplication of association between μ-opioid-receptor gene (OPRM1) A118G polymorphism and substance dependence. Am J Med Genet 105:114-119
36. Fromm MF, Hofmann U, Griese EU, Mikus G (1995) Dihydrocodeine: a new opioid substrate for the polymorphic CYP2D6 in humans. Clin Pharmacol Ther 58:374-382
37. Fujimoto JM, Way EL (1957) Isolation and crystallization of bound morphine from urine of human addicts. J Pharmacol Exp Ther 121:340-346
38. Gasche Y, Daali Y, Fathi M, Chiappe A, Cottini S, Dayer P, Desmeules J (2004) Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med 351:2827-2831
39. Gerber JG, Rhodes RJ, Gal J (2004) Stereoselective metabolism of methadone N-demethylation by cytochrome P4502B6 and 2C19. Chirality 16:36-44
40. Glass PSA, Shafer SL, Reves JG (2000) Intravenous drug delivery systems. In: Miller RD (ed) Miller's anesthesia, 5th edn. Elsevier/Churchill Livingstone, Philadelphia, pp 377-411
41. Glatt SJ, Bousman C, Wang RS, Murthy KK, Rana BK, Lasky-Su JA, Zhu SC, Zhang R, Li J, Zhang B, Li J, Lyons MJ, Faraone SV, Tsuang MT (2007) Evaluation of OPRM1 variants in heroin dependence by family-based association testing and meta-analysis. Drug Alcohol Depend 90:159-165
42. Gscheidel N, Sander T, Wendel B, Heere P, Schmidt LG, Rommelspacher H, Hoehe MR, Samochowiec J (2000) Five exon 1 variants of mu opioid receptor and vulnerability to alcohol dependence. Pol J Pharmacol 52:27-31
43. Han W, Kasai S, Hata H, Takahashi T, Takamatsu Y, Yamamoto H, Uhl GR, Sora I, Ikeda K (2006) Intracisternal A-particle element in the 3′ noncoding region of the mu-opioid receptor gene in CXBK mice: a new genetic mechanism underlying differences in opioid sensitivity. Pharmacogenet Genomics 16:451-460
44. Hedenmalm K, Sundgren M, Granberg K, Spigset O, Dahlqvist R (1997) Urinary excretion of codeine, ethylmorphine, and their metabolites: relation to the CYP2D6 activity. Ther Drug Monit 19:643-649
45. Hendry IA, Kelleher KL, Bartlett SE, Leck KJ, Reynolds AJ, Heydon K, Mellick A, Megirian D, Matthaei KI (2000) Hypertolerance to morphine in Gzα-deficient mice. Brain Res 870:10-19
46. Hnasko TS, Sotak BN, Palmiter RD (2005) Morphine reward in dopamine-deficient mice. Nature 438:854-857
47. Hoehe MR, Kopke K, Wendel B, Rohde K, Flachmeier C, Kidd KK, Berrettini WH, Church GM (2000) Sequence variability and candidate gene analysis in complex disease: association of μ opioid receptor gene variation with substance dependence. Hum Mol Genet 9:2895-2908
48. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmöller J, Johne A, Cascorbi I, Gerloff T, Roots I, Eichelbaum M, Brinkmann U (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 97:3473-3478
49. Holthe M, Klepstad P, Zahlsen K, Borchgrevink PC, Hagen L, Dale O, Kaasa S, Krokan HE, Skorpen F (2002) Morphine glucuronide-to-morphine plasma ratios are unaffected by the UGT2B7 H268Y and UGT1A1*28 polymorphisms in cancer patients on chronic morphine therapy. Eur J Clin Pharmacol 58:353-356
50. Holthe M, Rakvag TN, Klepstad P, Idle JR, Kaasa S, Krokan HE, Skorpen F (2003) Sequence variations in the UDP-glucuronosyltransferase 2B7 (UGT2B7) gene: identification of 10 novel single nucleotide polymorphisms (SNPs) and analysis of their relevance to morphine glucuronidation in cancer patients. Pharmacogenomics J 3:17-26
51. Hutchinson MR, Menelaou A, Foster DJ, Coller JK, Somogyi AA (2004) CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes. Br J Clin Pharmacol 57:287-297
52. Ide S, Kobayashi H, Ujike H, Ozaki N, Sekine Y, Inada T, Harano M, Komiyama T, Yamada M, Iyo M, Iwata N, Tanaka K, Shen H, Iwahashi K, Itokawa M, Minami M, Satoh M, Ikeda K, Sora I (2006) Linkage disequilibrium and association with methamphetamine dependence/psychosis of μ-opioid receptor gene polymorphisms. Pharmacogenomics J 6:179-188
53. Ikeda K, Ichikawa T, Kobayashi T, Kumanishi T, Oike S, Yano R (1999) Unique behavioural phenotypes of recombinant-inbred CXBK mice: partial deficiency of sensitivity to μ- and κ-agonists. Neurosci Res 34:149-155
54. Ikeda K, Kobayashi T, Kumanishi T, Niki H, Yano R (2000) Involvement of G-protein-activated inwardly rectifying K (GIRK) channels in opioid-induced analgesia. Neurosci Res 38:113-116
55. Ikeda K, Kobayashi T, Ichikawa T, Kumanishi T, Niki H, Yano R (2001) The untranslated region of μ-opioid receptor mRNA contributes to reduced opioid sensitivity in CXBK mice. J Neurosci 21:1334-1339
56. Ikeda K, Ide S, Han W, Hayashida M, Uhl GR, Sora I (2005) How individual sensitivity to opiates can be predicted by gene analyses. Trends Pharmacol Sci 26:311-317
57. International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437:1299-1320
58. Ishiguro H, Liu QR, Gong JP, Hall FS, Ujike H, Morales M, Sakurai T, Grumet M, Uhl GR (2006) NrCAM in addiction vulnerability: positional cloning, drug-regulation, haplotype-specific expression, and altered drug reward in knockout mice. Neuropsychopharmacology 31:572-584
59. Jadad AR, Browman GP (1995) The WHO analgesic ladder for cancer pain management: stepping up the quality of its evaluation. JAMA 274:1870-1873
60. Jasmin L, Tien D, Weinshenker D, Palmiter RD, Green PG, Janni G, Ohara PT (2002) The NK1 receptor mediates both the hyperalgesia and the resistance to morphine in mice lacking noradrenaline. Proc Natl Acad Sci USA 99:1029-1034
61. Johansson B, Halldner L, Dunwiddie TV, Masino SA, Poelchen W, Gimenez-Llort L, Escorihuela RM, Fernandez-Teruel A, Wiesenfeld-Hallin Z, Xu XJ, Hardemark A, Betsholtz C, Herlenius E, Fredholm BB (2001) Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A1 receptor. Proc Natl Acad Sci USA 98:9407-9412
62. Kalso E, Vainio A (1990) Morphine and oxycodone hydrochloride in the management of cancer pain. Clin Pharmacol Ther 47:639-646
63. Kasai S, Han W, Ide S, Hata H, Takamatsu Y, Yamamoto H, Uhl GR, Sora I, Ikeda K (2006) Involvement of the 3′ non-coding region of the mu opioid receptor gene in morphine-induced analgesia. Psychiatry Clin Neurosci 60(Suppl 1):S11-S17
64. Kest B, Hopkins E, Palmese CA, Chen ZP, Mogil JS, Pintar JE (2001) Morphine tolerance and dependence in nociceptin/orphanin FQ transgenic knock-out mice. Neuroscience 104:217-222
65. Kieffer BL (1995) Recent advances in molecular recognition and signal transduction of active peptides: receptors for opioid peptides. Cell Mol Neurobiol 15:615-635
66. Kieffer BL, Gavériaux-Ruff C (2002) Exploring the opioid system by gene knockout. Prog Neurobiol 66:285-306
67. Kim KS, Lee KW, Lee KW, Im JY, Yoo JY, Kim SW, Lee JK, Nestler EJ, Han PL (2006) Adenylyl cyclase type 5 (AC5) is an essential mediator of morphine action. Proc Natl Acad Sci USA 103:3908-3913
68. King CD, Rios GR, Green MD, Tephly TR (2000) UDP- glucuronosyltransferases. Curr Drug Metab 1:143-161
69. King MA, Bradshaw S, Chang AH, Pintar JE, Pasternak GW (2001) Potentiation of opioid analgesia in dopamine2 receptor knock-out mice: evidence for a tonically active anti-opioid system. J Neurosci 21:7788-7792
70. Kirkwood LC, Nation RL, Somogyi AA (1997) Characterization of the human cytochrome P450 enzymes involved in the metabolism of dihydrocodeine. Br J Clin Pharmacol 44:549-555
71. Klees TM, Sheffels P, Dale O, Kharasch ED (2005) Metabolism of alfentanil by cytochrome p4503a (cyp3a) enzymes. Drug Metab Dispos 33:303-311
72. Klepstad P, Dale O, Kaasa S, Zahlsen K, Aamo T, Fayers P, Borchgrevink PC (2003) Influences on serum concentrations of morphine, M6G and M3G during routine clinical drug monitoring: a prospective survey in 300 adult cancer patients. Acta Anaesthesiol Scand 47:725-731
73. Klepstad P, Rakvåg TT, Kaasa S, Holthe M, Dale O, Borchgrevink PC, Baar C, Vikan T, Krokan HE, Skorpen F (2004) The 118 A > G polymorphism in the human μ-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease. Acta Anaesthesiol Scand 48:1232-1239
74. Ko SW, Jia Y, Xu H, Yim SJ, Jang DH, Lee YS, Zhao MG, Toyoda H, Wu LJ, Chatila T, Kaang BK, Zhuo M (2006) Evidence for a role of CaMKIV in the development of opioid analgesic tolerance. Eur J Neurosci 23:2158-2168
75. Kobayashi K, Yamamoto T, Chiba K, Tani M, Shimada N, Ishizaki T, Kuroiwa Y (1998) Human buprenorphine N-dealkylation is catalyzed by cytochrome P450 3A4. Drug Metab Dispos 26:818-821
76. Kubo Y, Reuveny E, Slesinger PA, Jan YN, Jan LY (1993) Primary structure and functional expression of a rat G-protein-coupled muscarinic potassium channel. Nature 364:802-806
77. Labroo RB, Paine MF, Thummel KE, Kharasch ED (1997) Fentanyl metabolism by human hepatic and intestinal cytochrome P450 3A4: implications for interindividual variability in disposition, efficacy, and drug interactions. Drug Metab Dispos 25:1072-1080
78. Lalovic B, Phillips B, Risler LL, Howald W, Shen DD (2004) Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes. Drug Metab Dispos 32:447-454
79. Laurent P, Becker JA, Valverde O, Ledent C, de Kerchove d'Exaerde A, Schiffmann SN, Maldonado R, Vassart G, Parmentier M (2005) The prolactin-releasing peptide antagonizes the opioid system through its receptor GPR10. Nat Neurosci 8:1735-1741
80. Leck KJ, Bartlett SE, Smith MT, Megirian D, Holgate J, Powell KL, Matthaei KI, Hendry IA (2004) Deletion of guanine nucleotide binding protein alpha z subunit in mice induces a gene dose dependent tolerance to morphine. Neuropharmacology 46:836-846
81. Ledent C, Valverde O, Cossu G, Petitet F, Aubert JF, Beslot F, Bohme GA, Imperato A, Pedrazzini T, Roques BP, Vassart G, Fratta W, Parmentier M (1999) Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 283:401-404
82. Lesage F, Guillemare E, Fink M, Duprat F, Heurteaux C, Fosset M, Romey G, Barhanin J, Lazdunski M (1995) Molecular properties of neuronal G-protein-activated inwardly rectifying K+ channels. J Biol Chem 270:28660-28667
83. Li S, Lee ML, Bruchas MR, Chan GC, Storm DR, Chavkin C (2006) Calmodulin-stimulated adenylyl cyclase gene deletion affects morphine responses. Mol Pharmacol 70:1742-1749
84. Liang D, Li X, Lighthall G, Clark JD (2003) Heme oxygenase type 2 modulates behavioral and molecular changes during chronic exposure to morphine. Neuroscience 121:999-1005
85. Liang DY, Shi X, Li X, Li J, Clark JD (2007) The β2 adrenergic receptor regulates morphine tolerance and physical dependence. Behav Brain Res 181:118-126
86. Lipkowski AW, Carr DB, Langlade A, Osgood PF, Szyfelbein SK (1994) Morphine-3-glucuronide: silent regulator of morphine actions. Life Sci 55:149-154
87. Liu NJ, vonGizycki H, Gintzler AR (2006) Phospholipase Cβ1 modulates pain sensitivity, opioid antinociception and opioid tolerance formation. Brain Res 1069:47-53
88. Loh HH, Liu HC, Cavalli A, Yang W, Chen YF, Wei LN (1998) μ Opioid receptor knockout in mice: effects on ligand-induced analgesia and morphine lethality. Brain Res Mol Brain Res 54:321-326
89. Löser SV, Meyer J, Freudenthaler S, Sattler M, Desel C, Meineke I, Gundert-Remy U (1996) Morphine-6-O-β-D-glucuronide but not morphine-3-O-β-D-glucuronide binds to μ-, δ- and κ-specific opioid binding sites in cerebral membranes. Naunyn Schmiedebergs Arch Pharmacol 354:192-197
90. Lötsch J, Skarke C, Grösch S, Darimont J, Schmidt H, Geisslinger G (2002) The polymorphism A118G of the human mu-opioid receptor gene decreases the pupil constrictory effect of morphine-6-glucuronide but not that of morphine. Pharmacogenetics 12:3-9
91. Lötsch J, Skarke C, Wieting J, Oertel BG, Schmidt H, Brockmöller J, Geisslinger G (2006) Modulation of the central nervous effects of levomethadone by genetic polymorphisms potentially affecting its metabolism, distribution, and drug action. Clin Pharmacol Ther 79:72-89
92. Mansour A, Khachaturian H, Lewis ME, Akil H, Watson SJ (1988) Anatomy of CNS opioid receptors. Trends Neurosci 11:308-314
93. Marker CL, Cintora SC, Roman MI, Stoffel M, Wickman K (2002) Hyperalgesia and blunted morphine analgesia in G protein-gated potassium channel subunit knockout mice. Neuroreport 13:2509-2513
94. Marker CL, Stoffel M, Wickman K (2004) Spinal G-protein-gated K+ channels formed by GIRK1 and GIRK2 subunits modulate thermal nociception and contribute to morphine analgesia. J Neurosci 24:2806-2812
95. Martin M, Ledent C, Parmentier M, Maldonado R, Valverde O (2000) Cocaine, but not morphine, induces conditioned place preference and sensitization to locomotor responses in CB1 knockout mice. Eur J Neurosci 12:4038-4046
96. Matthes HW, Maldonado R, Simonin F, Valverde O, Slowe S, Kitchen I, Befort K, Dierich A, Le Meur M, Dolle P, Tzavara E, Hanoune J, Roques BP, Kieffer BL (1996) Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the μ-opioid-receptor gene. Nature 383:819-823
97. McQuay H (1999) Opioids in pain management. Lancet 353:2229-2232
98. Mitchell JM, Paul BD, Welch P, Cone EJ (1991) Forensic drug testing for opiates. II. Metabolism and excretion rate of morphine in humans after morphine administration. J Anal Toxicol 15:49-53
99. Mitrovic I, Margeta-Mitrovic M, Bader S, Stoffel M, Jan LY, Basbaum AI (2003) Contribution of GIRK2-mediated postsynaptic signaling to opiate and α2-adrenergic analgesia and analgesic sex differences. Proc Natl Acad Sci USA 100:271-276
100. Miyamoto Y, Yamada K, Nagai T, Mori H, Mishina M, Furukawa H, Noda Y, Nabeshima T (2004) Behavioural adaptations to addictive drugs in mice lacking the NMDA receptor ε1 subunit. Eur J Neurosci 19:151-158
101. Mobarakeh JI, Sakurada S, Hayashi T, Orito T, Okuyama K, Sakurada T, Kuramasu A, Watanabe T, Watanabe T, Yanai K (2002) Enhanced antinociception by intrathecally-administered morphine in histamine H1 receptor gene knockout mice. Neuropharmacology 42:1079-1088
102. Mobarakeh JI, Takahashi K, Sakurada S, Kuramasu A, Yanai K (2006) Enhanced antinociceptive effects of morphine in histamine H2 receptor gene knockout mice. Neuropharmacology 51:612-622
103. Mogil JS, Grisel JE (1998) Transgenic studies of pain. Pain 77:107-128
104. Mogil JS, Max MB (2006) The genetics of pain. In: McMahon SB, Koltzenburg M (eds) Wall and Melzack's textbook of pain, 5th edn. Elsevier/Churchill Livingstone, Philadelphia, pp 159-174
105. Mogil JS, Wilson SG, Chesler EJ, Rankin AL, Nemmani KV, Lariviere WR, Groce MK, Wallace MR, Kaplan L, Staud R, Ness TJ, Glover TL, Stankova M, Mayorov A, Hruby VJ, Grisel JE, Fillingim RB (2003) The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans. Proc Natl Acad Sci USA 100:4867-4872
106. Mogil JS, Ritchie J, Smith SB, Strasburg K, Kaplan L, Wallace MR, Romberg RR, Bijl H, Sarton EY, Fillingim RB, Dahan A (2007) Melanocortin-1 receptor gene variants affect pain and μ-opioid analgesia in mice and humans. J Med Genet 42:583-587
107. Murthy BR, Pollack GM, Brouwer KL (2002) Contribution of morphine-6-glucuronide to antinociception following intravenous administration of morphine to healthy volunteers. J Clin Pharmacol 42:569-576
108. Murtra P, Sheasby AM, Hunt SP, De Felipe C (2000) Rewarding effects of opiates are absent in mice lacking the receptor for substance P. Nature 405:180-183
109. Nagai T, Yamada K, Yoshimura M, Ishikawa K, Miyamoto Y, Hashimoto K, Noda Y, Nitta A, Nabeshima T (2004) The tissue plasminogen activator-plasmin system participates in the rewarding effect of morphine by regulating dopamine release. Proc Natl Acad Sci USA 101:3650-3655
110. Narita M, Mizuo K, Mizoguchi H, Sakata M, Narita M, Tseng LF, Suzuki T (2003) Molecular evidence for the functional role of dopamine D3 receptor in the morphine-induced rewarding effect and hyperlocomotion. J Neurosci 23:1006-1012
111. Narita M, Shibasaki M, Nagumo Y, Narita M, Yajima Y, Suzuki T (2005) Implication of cyclin-dependent kinase 5 in the development of psychological dependence on and behavioral sensitization to morphine. J Neurochem 93:1463-1468
112. Newton PM, Kim JA, McGeehan AJ, Paredes JP, Chu K, Wallace MJ, Roberts AJ, Hodge CW, Messing RO (2007) Increased response to morphine in mice lacking protein kinase C epsilon. Genes Brain Behav 6:329-338
113. Nitsche JF, Schuller AG, King MA, Zengh M, Pasternak GW, Pintar JE (2002) Genetic dissociation of opiate tolerance and physical dependence in delta-opioid receptor-1 and preproenkephalin knock-out mice. J Neurosci 22:10906-10913
114. Noda Y, Mamiya T, Nabeshima T, Nishi M, Higashioka M, Takeshima H (1998) Loss of antinociception induced by naloxone benzoylhydrazone in nociceptin receptor-knockout mice. J Biol Chem 273:18047-18051
115. Ogawa M, Miyakawa T, Nakamura K, Kitano J, Furushima K, Kiyonari H, Nakayama R, Nakao K, Moriyoshi K, Nakanishi S (2007) Altered sensitivities to morphine and cocaine in scaffold protein tamalin knockout mice. Proc Natl Acad Sci USA 104:14789-14794
116. Oguri K, Ida S, Yoshimura H, Tsukamoto H (1970) Metabolism of drugs: LXIX. Studies on the urinary metabolites of morphine in several mammalian species. Chem Pharm Bull (Tokyo) 18:2414-2419
117. Olson VG, Heusner CL, Bland RJ, During MJ, Weinshenker D, Palmiter RD (2006) Role of noradrenergic signaling by the nucleus tractus solitarius in mediating opiate reward. Science 311:1017-1020
118. Osborne R, Joel S, Trew D, Slevin M (1988) Analgesic activity of morphine-6-glucuronide. Lancet 1(8589):828
119. Otton SV, Schadel M, Cheung SW, Kaplan HL, Busto UE, Sellers EM (1993) CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone. Clin Pharmacol Ther 54:463-472
120. Özdoǧan UK, Lähdesmäki J, Scheinin M (2006) The analgesic efficacy of partial opioid agonists is increased in mice with targeted inactivation of the α2A-adrenoceptor gene. Eur J Pharmacol 529:105-113
121. Pauli-Magnus C, Feiner J, Brett C, Lin E, Kroetz DL (2003) No effect of MDR1 C3435T variant on loperamide disposition and central nervous system effects. Clin Pharmacol Ther 74:487-498
122. Pommier B, Beslot F, Simon A, Pophillat M, Matsui T, Dauge V, Roques BP, Noble F (2002) Deletion of CCK2 receptor in mice results in an upregulation of the endogenous opioid system. J Neurosci 22:2005-2011
123. Poulsen L, Brøsen K, Arendt-Nielsen L, Gram LF, Elbaek K, Sindrup SH (1996) Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects. Eur J Clin Pharmacol 51:289-295
124. Projean D, Morin PE, Tu TM, Ducharme J (2003) Identification of CYP3A4 and CYP2C8 as the major cytochrome P450 s responsible for morphine N-demethylation in human liver microsomes. Xenobiotica 33:841-854
125. Rakvåg TT, Klepstad P, Baar C, Kvam TM, Dale O, Kaasa S, Krokan HE, Skorpen F (2005) The Val158Met polymorphism of the human catechol-O- methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients. Pain 116:73-78
126. Reyes-Gibby CC, Shete S, Rakvåg T, Bhat SV, Skorpen F, Bruera E, Kaasa S, Klepstad P (2007) Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene. Pain 130:25-30
127. Ripley TL, Gadd CA, De Felipe C, Hunt SP, Stephens DN (2002) Lack of self-administration and behavioural sensitisation to morphine, but not cocaine, in mice lacking NK1 receptors. Neuropharmacology 43:1258-1268
128. Ross JR, Rutter D, Welsh K, Joel SP, Goller K, Wells AU, Du Bois R, Riley J (2005) Clinical response to morphine in cancer patients and genetic variation in candidate genes. Pharmacogenomics J 5:324-336
129. Sachse C, Brockmoller J, Bauer S, Roots I (1997) Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet 60:284-295
130. Sánchez-Blázquez P, Rodríguez-Díaz M, López-Fando A, Rodríguez-Muñoz M, Garzón J (2003) The GBeta5 subunit that associates with the R7 subfamily of RGS proteins regulates mu-opioid effects. Neuropharmacology 45:82-95
131. Sander T, Gscheidel N, Wendel B, Samochowiec J, Smolka M, Rommelspacher H, Schmidt LG, Hoehe MR (1998) Human μ-opioid receptor variation and alcohol dependence. Alcohol Clin Exp Res 22:2108-2110
132. Sawyer MB, Innocenti F, Das S, Cheng C, Ramírez J, Pantle-Fisher FH, Wright C, Badner J, Pei D, Boyett JM, Cook E, Ratain MJ (2003) A pharmacogenetic study of uridine diphosphate-glucuronosyltransferase 2B7 in patients receiving morphine. Clin Pharmacol Ther 73:566-574
133. Schinka JA, Town T, Abdullah L, Crawford FC, Ordorica PI, Francis E, Hughes P, Graves AB, Mortimer JA, Mullan M (2002) A functional polymorphism within the μ-opioid receptor gene and risk for abuse of alcohol and other substances. Mol Psychiatry 7:224-228
134. Schinkel AH, Wagenaar E, van Deemter L, Mol CA, Borst P (1995) Absence of the mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest 96:1698-1705
135. Schug SA, Gandham N (2006) Opioids: clinical use. In: McMahon SB, Koltzenburg M (eds) Wall and Melzack's textbook of pain, 5th edn. Elsevier/Churchill Livingstone, Philadelphia, pp 443-457
136. Shi J, Hui L, Xu Y, Wang F, Huang W, Hu G (2002) Sequence variations in the μ-opioid receptor gene (OPRM1) associated with human addiction to heroin. Hum Mutat 19:459-460
137. Shimomura K, Kamata O, Ueki S, Ida S, Oguri K (1971) Analgesic effect of morphine glucuronides. Tohoku J Exp Med 105:45-52
138. Simonin F, Valverde O, Smadja C, Slowe S, Kitchen I, Dierich A, Le Meur M, Roques BP, Maldonado R, Kieffer BL (1998) Disruption of the κ-opioid receptor gene in mice enhances sensitivity to chemical visceral pain, impairs pharmacological actions of the selective κ-agonist U-50,488H and attenuates morphine withdrawal. EMBO J 17:886-897
139. Sindrup SH, Brøsen K, Bjerring P, Arendt-Nielsen L, Larsen U, Angelo HR, Gram LF (1990) Codeine increases pain thresholds to copper vapor laser stimuli in extensive but not poor metabolizers of sparteine. Clin Pharmacol Ther 48:686-693
140. Skarke C, Darimont J, Schmidt H, Geisslinger G, Lötsch J (2003a) Analgesic effects of morphine and morphine-6-glucuronide in a transcutaneous electrical pain model in healthy volunteers. Clin Pharmacol Ther 73:107-121
141. Skarke C, Jarrar M, Schmidt H, Kauert G, Langer M, Geisslinger G, Lotsch J (2003b) Effects of ABCB1 (multidrug resistance transporter) gene mutations on disposition and central nervous effects of loperamide in healthy volunteers. Pharmacogenetics 13:651-660
142. Smith MT, Watt JA, Cramond T (1990) Morphine-3-glucuronide: a potent antagonist of morphine analgesia. Life Sci 47:579-585
143. Smith DJ, Leil TA, Liu X (2003) Neurotrophin-4 is required for tolerance to morphine in the mouse. Neurosci Lett 340:103-106
144. Sora I, Takahashi N, Funada M, Ujike H, Revay RS, Donovan DM, Miner LL, Uhl GR (1997) Opiate receptor knockout mice define μ receptor roles in endogenous nociceptive responses and morphine-induced analgesia. Proc Natl Acad Sci USA 94:1544-1549
145. Spielewoy C, Roubert C, Hamon M, Nosten-Bertrand M, Betancur C, Giros B (2000) Behavioural disturbances associated with hyperdopaminergia in dopamine-transporter knockout mice. Behav Pharmacol 11:279-290
146. Stamer UM, Musshoff F, Kobilay M, Madea B, Hoeft A, Stuber F (2007) Concentrations of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes. Clin Pharmacol Ther 82:41-47
147. Subrahmanyam V, Renwick AB, Walters DG, Young PJ, Price RJ, Tonelli AP, Lake BG (2001) Identification of cytochrome P-450 isoforms responsible for cis-tramadol metabolism in human liver microsomes. Drug Metab Dispos 29:1146-1155
148. Szeto CY, Tang NL, Lee DT, Stadlin A (2001) Association between mu opioid receptor gene polymorphisms and Chinese heroin addicts. Neuroreport 12:1103-1106
149. Tan EC, Tan CH, Karupathivan U, Yap EP (2003) Mu opioid receptor gene polymorphisms and heroin dependence in Asian populations. Neuroreport 14:569-572
150. Terman GW, Jin W, Cheong YP, Lowe J, Caron MG, Lefkowitz RJ, Chavkin C (2004) G-protein receptor kinase 3 (GRK3) influences opioid analgesic tolerance but not opioid withdrawal. Br J Pharmacol 141:55-64
151. Thompson SJ, Koszdin K, Bernards CM (2000) Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein. Anesthesiology 92:1392-1399
152. Uhl GR, Sora I, Wang Z (1999) The μ opiate receptor as a candidate gene for pain: polymorphisms, variations in expression, nociception, and opiate responses. Proc Natl Acad Sci USA 96:7752-7755
153. Vekovischeva OY, Zamanillo D, Echenko O, Seppala T, Uusi-Oukari M, Honkanen A, Seeburg PH, Sprengel R, Korpi ER (2001) Morphine-induced dependence and sensitization are altered in mice deficient in AMPA-type glutamate receptor-A subunits. J Neurosci 21:4451-4459
154. Walters CL, Wang BC, Godfrey M, Sun D, Funk CD, Blendy JA (2003) Augmented responses to morphine and cocaine in mice with a 12-lipoxygenase gene disruption. Psychopharmacology 170:124-131
155. Walters CL, Godfrey M, Li X, Blendy JA (2005) Alterations in morphine-induced reward, locomotor activity, and thermoregulation in CREB-deficient mice. Brain Res 1032:193-199
156. Wandel C, Kim R, Wood M, Wood A (2002) Interaction of morphine, fentanyl, sufentanil, alfentanil, and loperamide with the efflux drug transporter P-glycoprotein. Anesthesiology 96:913-920
157. Wang JS, DeVane CL (2003) Involvement of CYP3A4, CYP2C8, and CYP2D6 in the metabolism of (R)- and (S)-methadone in vitro. Drug Metab Dispos 31:742-747
158. Wickman K, Seldin MF, Gendler SJ, Clapham DE (1997) Partial structure, chromosome localization, and expression of the mouse Girk4 gene. Genomics 40:395-401
159. Wu WP, Hao JX, Halldner L, Lovdahl C, DeLander GE, Wiesenfeld-Hallin Z, Fredholm BB, Xu XJ (2005) Increased nociceptive response in mice lacking the adenosine A1 receptor. Pain 113:395-404
160. Xie W, Samoriski GM, McLaughlin JP, Romoser VA, Smrcka A, Hinkle PM, Bidlack JM, Gross RA, Jiang H, Wu D (1999) Genetic alteration of phospholipase C β3 expression modulates behavioral and cellular responses to μ opioids. Proc Natl Acad Sci USA 96:10385-103890
161. Xuei X, Flury-Wetherill L, Bierut L, Dick D, Nurnberger J Jr, Foroud T, Edenberg HJ (2007) The opioid system in alcohol and drug dependence: family-based association study. Am J Med Genet B Neuropsychiatr Genet 144B:877-884
162. Yamada M, Basile AS, Fedorova I, Zhang W, Duttaroy A, Cui Y, Lamping KG, Faraci FM, Deng CX, Wess J (2003) Novel insights into M5 muscarinic acetylcholine receptor function by the use of gene targeting technology. Life Sci 74:345-353
163. Yan Y, Yamada K, Mizoguchi H, Noda Y, Nagai T, Nitta A, Nabeshima T (2007) Reinforcing effects of morphine are reduced in tissue plasminogen activator-knockout mice. Neuroscience 146:50-59
164. Yeh SY (1975) Urinary excretion of morphine and its metabolites in morphine-dependent subjects. J Pharmacol Exp Ther 192:201-210
165. Yeh SY, Gorodetzky CW, Krebs HA (1977) Isolation and identification of morphine 3- and 6-glucuronides, morphine 3,6-diglucuronide, morphine 3-ethereal sulfate, normorphine, and normorphine 6-glucuronide as morphine metabolites in humans. J Pharm Sci 66:1288-1293
166. Yokoyama K, Kurihara T, Saegusa H, Zong S, Makita K, Tanabe T (2004) Blocking the R-type (Cav2.3) Ca2+ channel enhanced morphine analgesia and reduced morphine tolerance. Eur J Neurosci 20:3516-3519
167. Yoshimura H, Oguri K, Tsukamoto H (1969) Metabolism of drugs: LXII. Isolation and identification of morphine glucuronides in urine and bile of rabbits. Biochem Pharmacol 18:279-286
168. Zachariou V, Georgescu D, Sanchez N, Rahman Z, DiLeone R, Berton O, Neve RL, Sim-Selley LJ, Selley DE, Gold SJ, Nestler EJ (2003) Essential role for RGS9 in opiate action. Proc Natl Acad Sci USA 100:13656-13661
169. Zanger UM, Raimundo S, Eichelbaum M (2004) Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol 369:23-37
170. Zelcer N, van de Wetering K, Hillebrand M, Sarton E, Kuil A, Wielinga PR, Tephly T, Dahan A, Beijnen JH, Borst P (2005) Mice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and morphine-6-glucuronide antinociception. Proc Natl Acad Sci USA 102:7274-7279
171. Zhang Y, Wang D, Johnson AD, Papp AC, Sadée W (2005) Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G. J Biol Chem 280:32618-32624
172. Zhao ZQ, Gao YJ, Sun YG, Zhao CS, Gereau RW 4th, Chen ZF (2007) Central serotonergic neurons are differentially required for opioid analgesia but not for morphine tolerance or morphine reward. Proc Natl Acad Sci USA 104:14519-14524
173. Zhu Y, King MA, Schuller AG, Nitsche JF, Reidl M, Elde RP, Unterwald E, Pasternak GW, Pintar JE (1999) Retention of supraspinal delta-like analgesia and loss of morphine tolerance in δ opioid receptor knockout mice. Neuron 24:243-252
174. Zubieta JK, Heitzeg MM, Smith YR, Bueller JA, Xu K, Xu Y, Koeppe RA, Stohler CS, Goldman D (2003) COMT val158met genotype affects μ-opioid neurotransmitter responses to a pain stressor. Science 299:1240-1243