Opioid receptor subtypes: Fact or artifact?

British Journal of Anaesthesia

Volumn 107, Issue 1, 2011, Pages 8-18

  Dietis, N ^a   Rowbotham, D J ^a   Lambert, D G ^a  

^a UNIVERSITY OF LEICESTER   (United Kingdom)

Author keywords

dimerization; opioid receptors; pharmacological classification; splice variants; subtypes

Indexed keywords

BETA FUNALTREXAMINE; CODEINE; DELTA 1 OPIATE RECEPTOR; DELTA 2 OPIATE RECEPTOR; DELTA OPIATE RECEPTOR; DIAMORPHINE; DIHYDROMORPHINE; ENKEPHALIN; KAPPA 1A OPIATE RECEPTOR; KAPPA 1B OPIATE RECEPTOR; KAPPA 2A OPIATE RECEPTOR; KAPPA 2B OPIATE RECEPTOR; KAPPA 3 OPIATE RECEPTOR; KAPPA OPIATE RECEPTOR; MORPHINE; MORPHINE 6 GLUCURONIDE; MU 1 OPIATE RECEPTOR; MU 2 OPIATE RECEPTOR; MU 3 OPIATE RECEPTOR; MU OPIATE RECEPTOR; N METHYL N [7 (1 PYRROLIDINYL) 1 OXASPIRO[4.5]DEC 8 YL]BENZENEACETAMIDE; NALORPHINE; NALOXONAZINE; NALOXONE; NALTREXONE; NOCICEPTIN RECEPTOR; NORBINALTORPHIMINE; OXYCODONE; RECEPTOR SUBTYPE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ALTERNATIVE RNA SPLICING; BINDING AFFINITY; CLASSIFICATION; DIMERIZATION; DRUG POTENCY; DRUG RECEPTOR BINDING; GENE INACTIVATION; HUMAN; KNOCKOUT MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN PROTEIN INTERACTION; REVIEW;

EID: 79959423686     PISSN: 00070912     EISSN: 14716771     Source Type: Journal    
DOI: 10.1093/bja/aer115     Document Type: Review

References (124)

1. Beckett AH, Casy AF. Synthetic analgesics: stereochemical considerations. J Pharm Pharmacol 1954; 6: 986-1001
2. Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue. Science 1973; 179: 1011-4
3. Simon EJ, Hiller JM, Edelman I. Stereospecific binding of the potent narcotic analgesic (3H) Etorphine to rat-brain homogen-ate. Proc Natl Acad Sci USA 1973; 70: 1947-9
4. Terenius L. Characteristics of the 'receptor' for narcotic analgesics in synaptic plasma membrane fraction from rat brain. Acta Pharmacol Toxicol (Copenh) 1973; 33: 377-84
5. Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE. The effects of morphine-and nalorphine-like drugs in the nondepen-dent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther 1976; 197: 517-32
6. Lord JA, Waterfield AA, Hughes J, Kosterlitz HW. Endogenous opioid peptides: multiple agonists and receptors. Nature 1977; 267: 495-9 (Pubitemid 8098466)
7. Hughes J, Smith TW, Kosterlitz HW, Fothergill LA, Morgan BA, Morris HR. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature 1975; 258: 577-80
8. Cox BM, Goldstein A, Hi CH. Opioid activity of a peptide, beta-lipotropin-(61-91), derived from beta-lipotropin. Proc Natl Acad Sci USA 1976; 73: 1821-3
9. Goldstein A, Tachibana S, Lowney LI, Hunkapiller M, Hood L. Dynorphin-(1-13), an extraordinarily potent opioid peptide. Proc Natl Acad Sci USA 1979; 76: 6666-70 (Pubitemid 10166229)
10. Zadina JE, Hackler L, Ge LJ, Kastin AJ. A potent and selective endogenous agonist for the mu-opiate receptor. Nature 1997; 386: 499-502 (Pubitemid 27164076)
11. Kieffer BL, Befort K, Gaveriaux-Ruff C, Hirth CG. The delta-opioid receptor: isolation of a cDNA by expression cloning and pharmacological characterization. Proc Natl Acad Sci USA 1992; 89: 12048-52 (Pubitemid 23004782)
12. Evans CJ, Keith DE, Morrison H, Magendzo K, Edwards RH. Cloning of a delta opioid receptor by functional expression. Science 1992; 258: 1952-5
13. Zastawny RL, George SR, Nguyen T, et al. Cloning, characterization, and distribution of a mu-opioid receptor in rat brain. J Neurochem 1994; 62: 2099-105 (Pubitemid 24179487)
14. Thompson RC, Mansour A, Akil H, Watson SJ. Cloning and pharmacological characterization of a rat mu opioid receptor. Neuron 1993; 11: 903-13 (Pubitemid 23347475)
15. Chen Y, Mestek A, Liu J, Hurley JA, Yu L. Molecular cloning and functional expression of a mu-opioid receptor from rat brain. Mol Pharmacol 1993; 44: 8-12 (Pubitemid 23230453)
16. Wang JB, Imai Y, Eppler CM, Gregor P, Spivak CE, Uhl GR. mu opiate receptor: cDNA cloning and expression. Proc Natl Acad Sci USA 1993; 90: 10230-4 (Pubitemid 23328286)
17. Li S, Zhu J, Chen C, et al. Molecular cloning and expression of a rat kappa opioid receptor. Biochem J 1993; 295: 629-33 (Pubitemid 23323480)
18. Meng F, Xie GX, Thompson RC, et al. Cloning and pharmacological characterization of a rat kappa opioid receptor. Proc Natl Acad Sci USA 1993; 90: 9954-8 (Pubitemid 23328229)
19. Mollereau C, Parmentier M, Mailleux P, et al. ORL1, a novel member of the opioid receptor family. Cloning, functional expression and localization. FEBS Lett 1994; 341: 33-8
20. Bunzow JR, Saez C, Mortrud M, et al. Molecular cloning and tissue distribution of a putative member of the rat opioid receptor gene family that is not a mu, delta or kappa opioid receptor type. FEBS Lett 1994; 347: 284-8 (Pubitemid 24215413)
21. Portoghese PS. A new concept on the mode of interaction of narcotic analgesics with receptors. J Med Chem 1965; 8: 609-16
22. Wolozin BL, Pasternak GW. Classification of multiple morphine and enkephalin binding sites in the central nervous system. Proc Natl Acad Sci USA 1981; 78: 6181-5 (Pubitemid 12174847)
23. Pasternak GW, Childers SR, Snyder SH. Opiate analgesia: evidence for mediation by a subpopulation of opiate receptors. Science 1980; 208: 514-6 (Pubitemid 10032880)
24. Pasternak GW, Hahn EF. Long-acting opiate agonists and antagonists: 14-hydroxydihydromorphinone hydrazones. J Med Chem 1980; 23: 674-6 (Pubitemid 11237827)
25. Pasternak GW, Childers SR, Snyder SH. Naloxazone, a long-acting opiate antagonist: effects on analgesia in intact animals and on opiate receptor binding in vitro. J Pharmacol Exp Ther 1980; 214: 455-62 (Pubitemid 10061384)
26. Ling GS, Spiegel K, Lockhart SH, Pasternak GW. Separation of opioid analgesia from respiratory depression: evidence for different receptor mechanisms. J Pharmacol Exp Ther 1985; 232: 149-55 (Pubitemid 15193665)
27. Paul D, Pasternak GW. Differential blockade by naloxonazine of two mu opiate actions: analgesia and inhibition of gastrointestinal transit. Eur J Pharmacol 1988; 149: 403-4
28. Andoh T, Yageta Y, Konno M, et al. Evidence for separate involvement of different mu-opioid receptor subtypes in itch and analgesia induced by supraspinal action of opioids. J Pharmacol Sci 2008; 106: 667-70 (Pubitemid 351556248)
29. Hahn EF, Carroll-Buatti M, Pasternak GW. Irreversible opiate agonists and antagonists: the 14-hydroxydihydromorphinone azines. J Neurosci 1982; 2: 572-6 (Pubitemid 12034856)
30. Chaijale NN, Aloyo VJ, Simansky KJ. A naloxonazine sensitive (mu1 receptor) mechanism in the parabrachial nucleus modulates eating. Brain Res 2008; 1240: 111-8
31. Paul D, Bodnar RJ, Gistrak MA, Pasternak GW. Different mu receptor subtypes mediate spinal and supraspinal analgesia in mice. Eur J Pharmacol 1989; 168: 307-14 (Pubitemid 19231507)
32. Pasternak GW. Molecular biology of opioid analgesia. J Pain Symptom Manage 2005; 29: S2-9 (Pubitemid 40720242)
33. Rothman RB, Jacobson AE, Rice KC, Herkenham M. Autoradio-graphic evidence for two classes of mu opioid binding sites in rat brain using [125I]FK33824. Peptides 1987; 8: 1015-21 (Pubitemid 18018091)
34. Franklin TG, Traynor JR. Alkylation with beta-funaltrexamine suggests differences between mu-opioid receptor systems in guinea-pig brain and myenteric-plexus. Br J Pharmacol 1991; 102: 718-22
35. Elliott J, Smart D, Lambert DG, Traynor JR. Characterisation of mu-opioid receptors on SH-SY5Y cells using naloxonazine and beta-funaltrexamine. Eur J Pharmacol 1994; 268: 447-50
36. Tive LA, Pick CG, Paul D, Roques BP, Gacel GA, Pasternak GW. Analgesic potency of TRIMU-5: a mixed mu 2 opioid receptor agonist/mu 1 opioid receptor antagonist. Eur J Pharmacol 1992; 216: 249-55
37. Pick CG, Roques B, Gacel G, Pasternak GW. Supraspinal mu 2-opioid receptors mediate spinal/supraspinal morphine synergy. Eur J Pharmacol 1992; 220: 275-7
38. Moskowitz AS, Goodman RR. Autoradiographic distribution of mu1 and mu2 opioid binding in the mouse central nervous system. Brain Res 1985; 360: 117-29 (Pubitemid 16171008)
39. Chang A, Emmel DW, Rossi GC, Pasternak GW. Methadone analgesia in morphine-insensitive CXBK mice. Eur J Pharmacol 1998; 351: 189-91 (Pubitemid 28312930)
40. Pick CG, Nejat RJ, Pasternak GW. Independent expression of two pharmacologically distinct supraspinal mu analgesic systems in genetically different mouse strains. J Pharmacol Exp Ther 1993; 265: 166-71 (Pubitemid 23320957)
41. Cadet P, Mantione KJ, Stefano GB. Molecular identification and functional expression of mu 3, a novel alternatively spliced variant of the human mu opiate receptor gene. J Immunol 2003; 170: 5118-23 (Pubitemid 36554743)
42. Cadet P. Mu opiate receptor subtypes. Med Sci Monit 2004; 10: MS28-32 (Pubitemid 38878790)
43. Stefano GB, Hartman A, Bilfinger TV, et al. Presence of the mu3 opiate receptor in endothelial cells. Coupling to nitric oxide production and vasodilation. J Biol Chem 1995; 270: 30290-3
44. Stefano GB, Goumon Y, Bilfinger TV, Welters ID, Cadet P. Basal nitric oxide limits immune, nervous and cardiovascular excitation: human endothelia express a mu opiate receptor. Prog Neurobiol 2000; 60: 513-30 (Pubitemid 30100397)
45. Stefano GB, Digenis A, Spector S, et al. Opiate-like substances in an invertebrate, an opiate receptor on invertebrate and human immunocytes, and a role in immunosuppression. Proc Natl Acad Sci USA 1993; 90: 11099-103 (Pubitemid 23354376)
46. Davis RL, Buck DJ, Saffarian N, et al. Beta-funaltrexamine inhibits inducible nitric-oxide synthase expression in human astroglial cells. J Neuroimmune Pharmacol 2008; 3: 150-3
47. Lambert DG, Atcheson R, Hirst RA, Rowbotham DJ. Effects of morphine and its metabolites on opiate receptor binding, cAMP formation and [3H]noradrenaline release from SH-SY5Y cells. Biochem Pharmacol 1993; 46: 1145-50 (Pubitemid 23306734)
48. Rossi GC, Brown GP, Leventhal L, Yang K, Pasternak GW. Novel receptor mechanisms for heroin and morphine-6 beta-glucuronide analgesia. Neurosci Lett 1996; 216: 1-4 (Pubitemid 26321035)
49. Rossi GC, Standifer KM, Pasternak GW. Differential blockade of morphine and morphine-6 beta-glucuronide analgesia by anti-sense oligodeoxynucleotides directed against MOR-1 and G-protein alpha subunits in rats. Neurosci Lett 1995; 198: 99-102
50. Vanderah T, Takemori AE, Sultana M, et al. Interaction of [D-Pen2,D-Pen5]enkephalin and [D-Ala2,Glu4]deltorphin with delta-opioid receptor subtypes in vivo. Eur J Pharmacol 1994; 252: 133-7
51. Hirose N, Murakawa K, Takada K, et al. Interactions among mu-and delta-opioid receptors, especially putative delta1-and delta2-opioid receptors, promote dopamine release in the nucleus accumbens. Neuroscience 2005; 135: 213-25 (Pubitemid 41219750)
52. ′-isothiocyanate: evidence for delta receptor subtypes. J Pharmacol Exp Ther 1991; 257: 1069-75
53. Maslov LN, Lishmanov YB, Oeltgen PR, et al. Activation of peripheral delta2 opioid receptors increases cardiac tolerance to ische-mia/reperfusion injury Involvement of protein kinase C, NO-synthase, KATP channels and the autonomic nervous system. Life Sci 2009; 84: 657-63
54. Rawls SM, Hewson JM, Inan S, Cowan A. Brain delta2 opioid receptors mediate SNC-80-evoked hypothermia in rats. Brain Res 2005; 1049: 61-9 (Pubitemid 40814575)
55. Dietis N, Guerrini R, Calo G, Salvadori S, Rowbotham DJ, Lambert DG. Simultaneous targeting of multiple opioid receptors: a strategy to improve side-effect profile. Br J Anaesth 2009; 103: 38-49
56. Traynor JR, Elliott J. delta-Opioid receptor subtypes and crosstalk with mu-receptors. Trends Pharmacol Sci 1993; 14: 84-6 (Pubitemid 23096438)
57. Wollemann M, Benyhe S, Simon J. The kappa-opioid receptor: evidence for the different subtypes. Life Sci 1993; 52: 599-611
58. Clark JA, Liu L, Price M, Hersh B, Edelson M, Pasternak GW. Kappa opiate receptor multiplicity: evidence for two U50,488-sensitive kappa 1 subtypes and a novel kappa 3 subtype. J Pharmacol Exp Ther 1989; 251: 461-8 (Pubitemid 20005585)
59. Nielsen CK, Ross FB, Lotfipour S, Saini KS, Edwards SR, Smith MT. Oxycodone and morphine have distinctly different pharmacological profiles: radioligand binding and behavioural studies in two rat models of neuropathic pain. Pain 2007; 132: 289-300 (Pubitemid 350051566)
60. Zukin RS, Eghbali M, Olive D, Unterwald EM, Tempel A. Characterization and visualization of rat and guinea pig brain kappa opioid receptors: evidence for kappa 1 and kappa 2 opioid receptors. Proc Natl Acad Sci USA 1988; 85: 4061-5
61. Rothman RB, Bykov V, Xue BG, et al. Interaction of opioid pep-tides and other drugs with multiple kappa receptors in rat and human brain. Evidence for species differences. Peptides 1992; 13: 977-87
62. Su X, Sengupta JN, Gebhart GF. Effects of kappa opioid receptor-selective agonists on responses of pelvic nerve afferents to noxious colorectal distension. J Neurophysiol 1997; 78: 1003-12 (Pubitemid 27353561)
63. Childers SR, Xiao R, Vogt L, Sim LJ. Lack of evidence of kappa2-selective activation of G-proteins: kappa opioid receptor stimulation of [35S] GTPgammaS binding in guinea pig brain. Biochem Pharmacol 1998; 56: 113-20 (Pubitemid 28477458)
64. Pan YX, Cheng J, Xu J, et al. Cloning and functional characterization through antisense mapping of a kappa 3-related opioid receptor. Mol Pharmacol 1995; 47: 1180-8
65. Lambert DG. The nociceptin/orphanin FQ receptor: a target with broad therapeutic potential. Nat Rev Drug Discov 2008; 7: 694-710
66. Paul D, Pick CG, Tive LA, Pasternak GW. Pharmacological characterization of nalorphine, a kappa 3 analgesic. J Pharmacol Exp Ther 1991; 257: 1-7
67. Connor M, Kitchen I. Has the sun set on kappa3-opioid receptors? Br J Pharmacol 2006; 147: 349-50 (Pubitemid 43292277)
68. Nielsen CK, Ross FB, Smith MT. Incomplete, asymmetric, and route-dependent cross-tolerance between oxycodone and morphine in the Dark Agouti rat. J Pharmacol Exp Ther 2000; 295: 91-9
69. Nozaki C, Kamei J. Involvement of mu1-opioid receptor on oxycodone-induced antinociception in diabetic mice. Eur J Pharmacol 2007; 560: 160-2 (Pubitemid 46341307)
70. Meunier JC, Mollereau C, Toll L, et al. Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature 1995; 377: 532-5
71. Reinscheid RK, Nothacker HP, Bourson A, et al. Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor. Science 1995; 270: 792-4
72. McDonald J, Barnes TA, Okawa H, et al. Partial agonist behaviour depends upon the level of nociceptin/orphanin FQ receptor expression: studies using the ecdysone-inducible mammalian expression system. Br J Pharmacol 2003; 140: 61-70 (Pubitemid 37175831)
73. Mason SL, Ho M, Nicholson J, McKnight AT. In vitro characterization of Ac-RYYRWK-NH(2), Ac-RYYRIK-NH(2) and [Phe1Psi(CH(2)-NH)Gly2] nociceptin(1-13)NH(2) at rat native and recombinant ORL(1) receptors. Neuropeptides 2001; 35: 244-56 (Pubitemid 34587507)
74. Okawa H, Nicol B, Bigoni R, et al. Comparison of the effects of [Phe1psi(CH2-NH)Gly2]nociceptin(1-13)NH2 in rat brain, rat vas deferens and CHO cells expressing recombinant human nociceptin receptors. Br J Pharmacol 1999; 127: 123-30 (Pubitemid 29213240)
75. Xie G, Ito E, Maruyama K, et al. An alternatively spliced transcript of the rat nociceptin receptor ORL1 gene encodes a truncated receptor. Brain Res Mol Brain Res 2000; 77: 1-9 (Pubitemid 30256186)
76. Currò D, Yoo JH, Anderson M, Song I, Del Valle J, Owyang C. Molecular cloning of the orphanin FQ receptor gene and differential tissue expression of splice variants in rat. Gene 2001; 266: 139-45 (Pubitemid 32268665)
77. Xie GX, Meuser T, Pietruck C, Sharma M, Palmer PP. Presence of opioid receptor-like (ORL1) receptor mRNA splice variants in peripheral sensory and sympathetic neuronal ganglia. Life Sci 1999; 64: 2029-37 (Pubitemid 29236586)
78. Pan YX, Xu J, Wan BL, Zuckerman A, Pasternak GW. Identification and differential regional expression of KOR-3/ORL-1 gene splice variants in mouse brain. FEBS Lett 1998; 435: 65-8 (Pubitemid 28432016)
79. Liao YY, Teng SF, Lin LC, et al. Functional heterogeneity of noci-ceptin/orphanin FQ receptors revealed by (+)-5a Compound and Ro 64-6198 in rat periaqueductal grey slices. Int J Neuropsycho-pharmacol 2010; Oct 29 [Epub ahead of print] 1-13
80. Chiou LC, Chuang KC, Wichmann J, Adam G. Ro 64-6198 [(1S,3aS)-8-(2,3,3a, 4,5,6-Hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one] acts differently from nociceptin/orphanin FQ in rat periaqueductal gray slices. J Pharmacol Exp Ther 2004; 311: 645-51 (Pubitemid 39391551)
81. Rizzi A, Molinari S, Marti M, Marzola G, Calo' G. Nociceptin/orpha-nin FQ receptor knockout rats: in vitro and in vivo studies. Neuro-pharmacology 2011; 60: 572-9
82. Ueda H, Yamaguchi T, Tokuyama S, Inoue M, Nishi M, Takeshima H. Partial loss of tolerance liability to morphine analgesia in mice lacking the nociceptin receptor gene. Neurosci Lett 1997; 237: 136-8 (Pubitemid 28004975)
83. Chung S, Pohl S, Zeng J, Civelli O, Reinscheid RK. Endogenous orphanin FQ/nociceptin is involved in the development of morphine tolerance. J Pharmacol Exp Ther 2006; 318: 262-7
84. Burmeister MA, Ansonoff MA, Pintar JE, Kapusta DR. Nociceptin/ orphanin FQ (N/OFQ)-evoked bradycardia, hypotension, and diuresis are absent in N/OFQ peptide (NOP) receptor knockout mice. J Pharmacol Exp Ther 2008; 326: 897-904
85. Noda Y, Mamiya T, Nabeshima T, Nishi M, Higashioka M, Takeshima H. Loss of antinociception induced by naloxone ben-zoylhydrazone in nociceptin receptor-knockout mice. J Biol Chem 1998; 273: 18047-51 (Pubitemid 28334719)
86. Nitsche JF, Schuller AG, King MA, Zengh M, Pasternak GW, Pintar JE. Genetic dissociation of opiate tolerance and physical dependence in delta-opioid receptor-1 and preproenkephalin knock-out mice. J Neurosci 2002; 22: 10906-13 (Pubitemid 36005166)
87. Kitchen I, Slowe SJ, Matthes HW, Kieffer B. Quantitative auto-radiographic mapping of mu-, delta-and kappa-opioid receptors in knockout mice lacking the mu-opioid receptor gene. Brain Res 1997; 778: 73-88 (Pubitemid 28039890)
88. Kieffer BL. Opioids: first lessons from knockout mice. Trends Pharmacol Sci 1999; 20: 19-26 (Pubitemid 29304521)
89. Zhu Y, King MA, Schuller AG, et al. Retention of supraspinal delta-like analgesia and loss of morphine tolerance in delta opioid receptor knockout mice. Neuron 1999; 24: 243-52 (Pubitemid 29466162)
90. Simonin F, Slowe S, Becker JA, et al. Analysis of [3H]bremazocine binding in single and combinatorial opioid receptor knockout mice. Eur J Pharmacol 2001; 414: 189-95 (Pubitemid 32181885)
91. Wei LN, Loh HH. Transcriptional and epigenetic regulation of opioid receptor genes: present and future. Annu Rev Pharmacol Toxicol 2011; 51: 75-97
92. Black DL. Mechanisms of alternative pre-messenger RNA splicing. Annu Rev Biochem 2003; 72: 291-336 (Pubitemid 36930448)
93. Matlin AJ, Clark F, Smith CW. Understanding alternative splicing: towards a cellular code. Nat Rev Mol Cell Biol 2005; 6: 386-98 (Pubitemid 40637856)
94. Tanowitz M, Hislop JN, von Zastrow M. Alternative splicing determines the post-endocytic sorting fate of G-protein-coupled receptors. J Biol Chem 2008; 283: 35614-21
95. Zimprich A, Simon T, Höllt V. Cloning and expression of an isoform of the rat mu opioid receptor (rMOR1B) which differs in agonist induced desensitization from rMOR1. FEBS Lett 1995; 359: 142-6
96. Xu J, Xu M, Rossi GC, Pasternak GW, Pan YX. Identification and characterization of seven new exon 11-associated splice variants of the rat mu opioid receptor gene, OPRM1. Mol Pain 2011; 7: 9
97. Pan YX, Xu J, Mahurter L, Bolan E, Xu M, Pasternak GW. Generation of the mu opioid receptor (MOR-1) protein by three new splice variants of the Oprm gene. Proc Natl Acad Sci USA 2001; 98: 14084-9 (Pubitemid 33116028)
98. Pan YX. Diversity and complexity of the mu opioid receptor gene: alternative pre-mRNA splicing and promoters. DNA Cell Biol 2005; 24: 736-50
99. Pan YX, Xu J, Xu M, Rossi GC, Matulonis JE, Pasternak GW. Involvement of exon 11-associated variants of the mu opioid receptor MOR-1 in heroin, but not morphine, actions. Proc Natl Acad Sci USA 2009; 106: 4917-22
100. Schuller AG, King MA, Zhang J, et al. Retention of heroin and morphine-6 beta-glucuronide analgesia in a new line of mice lacking exon 1 of MOR-1. Nat Neurosci 1999; 2: 151-6 (Pubitemid 30491315)
101. Jordan BA, Devi LA. G-protein-coupled receptor heterodimeriza-tion modulates receptor function. Nature 1999; 399: 697-700 (Pubitemid 29289066)
102. George SR, Fan T, Xie Z, et al. Oligomerization of mu-and delta-opioid receptors. Generation of novel functional properties. J Biol Chem 2000; 275: 26128-35
103. Cvejic S, Devi LA. Dimerization of the delta opioid receptor: implication for a role in receptor internalization. J Biol Chem 1997; 272: 26959-64 (Pubitemid 27452648)
104. Ramsay D, Kellett E, McVey M, Rees S, Milligan G. Homo-and hetero-oligomeric interactions between G-protein-coupled receptors in living cells monitored by two variants of biolumi-nescence resonance energy transfer (BRET): hetero-oligomers between receptor subtypes form more efficiently than between less closely related sequences. Biochem J 2002; 365: 429-40 (Pubitemid 36135314)
105. McVey M, Ramsay D, Kellett E, et al. Monitoring receptor oligo-merization using time-resolved fluorescence resonance energy transfer and bioluminescence resonance energy transfer. The human delta-opioid receptor displays constitutive oligomeriza-tion at the cell surface, which is not regulated by receptor occupancy. J Biol Chem 2001; 276: 14092-9
106. Gomes I, Jordan BA, Gupta A, Trapaidze N, Nagy V, Devi LA. Het-erodimerization of mu and delta opioid receptors: a role in opiate synergy. J Neurosci 2000; 20: RC110
107. van Rijn RM, Whistler JL, Waldhoer M. Opioid-receptor-heteromer-specific trafficking and pharmacology. Curr Opin Pharmacol 2010; 10: 73-9
108. Chakrabarti S, Liu NJ, Gintzler AR. Formation of mu-/ kappa-opioid receptor heterodimer is sex-dependent and mediates female-specific opioid analgesia. Proc Natl Acad Sci USA 2010; 107: 20115-9
109. Pan YX, Bolan E, Pasternak GW. Dimerization of morphine and orphanin FQ/nociceptin receptors: generation of a novel opioid receptor subtype. Biochem Biophys Res Commun 2002; 297: 659-63
110. Wang HL, Hsu CY, Huang PC, et al. Heterodimerization of opioid receptor-like 1 and mu-opioid receptors impairs the potency of micro receptor agonist. J Neurochem 2005; 92: 1285-94
111. Evans RM, You H, Hameed S, et al. Heterodimerization of ORL1 and opioid receptors and its consequences for N-type calcium channel regulation. J Biol Chem 2010; 285: 1032-40
112. Chakrabarti S, Regec A, Gintzler AR. Biochemical demonstration of mu-opioid receptor association with Gsalpha: enhancement following morphine exposure. Brain Res Mol Brain Res 2005; 135: 217-24 (Pubitemid 40602413)
113. Connor M, Christie MD. Opioid receptor signalling mechanisms. Clin Exp Pharmacol Physiol 1999; 26: 493-9 (Pubitemid 29309619)
114. Crain SM, Shen KF. Modulation of opioid analgesia, tolerance and dependence by Gs-coupled, GM1 ganglioside-regulated opioid receptor functions. Trends Pharmacol Sci 1998; 19: 358-65 (Pubitemid 28458832)
115. Smart D, Smith G, Lambert DG. mu-Opioid receptor stimulation of inositol (1,4,5)trisphosphate formation via a pertussis toxin-sensitive G protein. J Neurochem 1994; 62: 1009-14
116. 2+ from intra-cellular stores, in undifferentiated NG108-15 cells. J Neurochem 1996; 66: 1462-7
117. Whistler JL, von Zastrow M. Morphine-activated opioid receptors elude desensitization by beta-arrestin. Proc Natl Acad Sci USA 1998; 95: 9914-9 (Pubitemid 28415269)
118. Ramsay D, Carr IC, Pediani J, et al. High-affinity interactions between human alpha1A-adrenoceptor C-terminal splice variants produce homo-and heterodimers but do not generate the alpha1L-adrenoceptor. Mol Pharmacol 2004; 66: 228-39 (Pubitemid 38989479)
119. Kenakin T. Functional selectivity through protean and biased agonism: who steers the ship? Mol Pharmacol 2007; 72: 1393-401 (Pubitemid 350146075)
120. Evans BA, Sato M, Sarwar M, Hutchinson DS, Summers RJ. Ligand-directed signalling at beta-adrenoceptors. Br J Pharmacol 2010; 159: 1022-38
121. Chu J, Zheng H, Zhang Y, Loh HH, Law PY. Agonist-dependent mu-opioid receptor signaling can lead to heterologous desensitization. Cell Signal 2010; 22: 684-96
122. Zheng H, Chu J, Zhang Y, Loh HH, Law PY. Modulating {micro}-opioid receptor phosphorylation switches agonist-dependent signaling as reflected in PKC{epsilon} activation and dendritic spine stability. J Biol Chem 2011; 286: 12724-33
123. Pradhan AA, Walwyn W, Nozaki C, et al. Ligand-directed trafficking of the d-opioid receptor in vivo: two paths toward analgesic tolerance. J Neurosci 2010; 30: 16459-68
124. Brain SD, Grant AD. Vascular actions of calcitonin gene-related peptide and adrenomedullin. Physiol Rev 2004; 84: 903-34 (Pubitemid 38823770)