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Opioid receptor heteromers in analgesia

  • Cristina M. Costantino (a1), Ivone Gomes (a1), Steven D. Stockton (a1) (a2), Maribel P. Lim (a1) and Lakshmi A. Devi (a1) (a2)...
Abstract

Opiates such as morphine and fentanyl, a major class of analgesics used in the clinical management of pain, exert their effects through the activation of opioid receptors. Opioids are among the most commonly prescribed and frequently abused drugs in the USA; however, the prolonged use of opiates often leads to the development of tolerance and addiction. Although blockade of opioid receptors with antagonists such as naltrexone and naloxone can lessen addictive impulses and facilitate recovery from overdose, systemic disruption of endogenous opioid receptor signalling through the use of these antagonistic drugs can have severe side effects. In the light of these challenges, current efforts have focused on identifying new therapeutic targets that selectively and specifically modulate opioid receptor signalling and function so as to achieve analgesia without the adverse effects associated with chronic opiate use. We have previously reported that opioid receptors interact with each other to form heteromeric complexes and that these interactions affect morphine signalling. Since chronic morphine administration leads to an enhanced level of these heteromers, these opioid receptor heteromeric complexes represent novel therapeutic targets for the treatment of pain and opiate addiction. In this review, we discuss the role of heteromeric opioid receptor complexes with a focus on mu opioid receptor (MOR) and delta opioid receptor (DOR) heteromers. We also highlight the evidence for altered pharmacological properties of opioid ligands and changes in ligand function resulting from the heteromer formation.

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Corresponding author
*Corresponding author: Lakshmi A. Devi, 1468, Madison Avenue, New York, NY 10029USA. E-mail: Lakshmi.devi@mssm.edu
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This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

1B.L. Kieffer (1995) Recent advances in molecular recognition and signal transduction of active peptides: receptors for opioid peptides. Cellular and Molecular Neurobiology 15, 615-635

2M. Waldhoer , S.E. Bartlett and J.L. Whistler (2004) Opioid receptors. Annual Review of Biochemistry 73, 953-990

3Y.L. Chen , P.Y. Law and H.H. Loh (2008) The other side of the opioid story: modulation of cell growth and survival signaling. Current Medicinal Chemistry 15, 772-778

4F.M. Filbey (2009) Marijuana craving in the brain. Proceedings of the National Academy of Sciences of the United States of America 106, 13016-13021

5H.W. Matthes (1996) Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene. Nature 383, 819-823

6B.L. Kieffer and C.J. Evans (2009) Opioid receptors: from binding sites to visible molecules in vivo. Neuropharmacology 56(Suppl. 1), 205-212

7N.J. Smith and G. Milligan (2010) Allostery at G protein-coupled receptor homo- and heteromers: uncharted pharmacological landscapes. Pharmacological Reviews 62, 701-725

8I. Gomes (2001) G protein coupled receptor dimerization: implications in modulating receptor function. Journal of Molecular Medicine (Berlin) 79, 226-242

9H. Satake and T. Sakai (2008) Recent advances and perceptions in studies of heterodimerization between G protein-coupled receptors. Protein and Peptide Letters 15, 300-308

10J. Gonzalez-Maeso (2011) GPCR oligomers in pharmacology and signaling. Molecular Brain 4, 20

11I. Gomes (2011) G protein-coupled receptor heteromerization: a role in allosteric modulation of ligand binding. Molecular Pharmacology 79, 1044-1052

12R. Rozenfeld and L.A. Devi (2011) Exploring a role for heteromerization in GPCR signalling specificity. Biochemical Journal 433, 11-18

13R. Rozenfeld and L.A. Devi (2010) Receptor heteromerization and drug discovery. Trends in Pharmacological Sciences 31, 124-130

14D. Williams and L.A. Devi (2010) Escorts take the lead molecular chaperones as therapeutic targets. Progress in Molecular Biology and Translational Sciences 91, 121-149

15S. Chakrabarti , N.J. Liu and A.R. Gintzler (2010) Formation of mu-/kappa-opioid receptor heterodimer is sex-dependent and mediates female-specific opioid analgesia. Proceedings of the National Academy of Sciences of the United States of America 107, 20115-20119

17R.B. Rothman and T.C. Westfall (1981) Allosteric modulation by leucine-enkephalin of [3H]naloxone binding in rat brain. European Journal of Pharmacology 72, 365-368

18N.M. Lee and A.P. Smith (1980) A protein-lipid model of the opiate receptor. Life Sciences 26, 1459-1464

19J.A. Lord (1977) Endogenous opioid peptides: multiple agonists and receptors. Nature 267, 495-499

21R.W. Barrett and J.L. Vaught (1982) The effects of receptor selective opioid peptides on morphine-induced analgesia. European Journal of Pharmacology 80, 427-430

22J.L. Vaught , R.B. Rothman and T.C. Westfall (1982) Mu and delta receptors: their role in analgesia in the differential effects of opioid peptides on analgesia. Life Sciences 30, 1443-1455

23L. Gendron (2006) Morphine and pain-related stimuli enhance cell surface availability of somatic delta-opioid receptors in rat dorsal root ganglia. Journal of Neuroscience 26, 953-962

26Y. Zhu (1999) Retention of supraspinal delta-like analgesia and loss of morphine tolerance in delta opioid receptor knockout mice. Neuron 24, 243-252

27B.L. Kieffer and C. Gaveriaux-Ruff (2002) Exploring the opioid system by gene knockout. Progress in Neurobiology 66, 285-306

28S.K. Billa , Y. Xia and J.A. Moron (2010) Disruption of morphine-conditioned place preference by a delta2-opioid receptor antagonist: study of mu-opioid and delta-opioid receptor expression at the synapse. European Journal of Neuroscience 32, 625-631

31W. Walwyn (2009) Delta receptors are required for full inhibitory coupling of mu-receptors to voltage-dependent Ca(2+) channels in dorsal root ganglion neurons. Molecular Pharmacology 76, 134-143

32P.Y. Chengm , L.Y. Liu-Chen and V.M. Pickel (1997) Dual ultrastructural immunocytochemical labeling of mu and delta opioid receptors in the superficial layers of the rat cervical spinal cord. Brain Research 778, 367-380

33H. Wang and M.W. Wessendorf (1999) Mu- and delta-opioid receptor mRNAs are expressed in spinally projecting serotonergic and nonserotonergic neurons of the rostral ventromedial medulla. Journal of Comparative Neurology 404, 183-196

34I. Gomes (2004) A role for heterodimerization of mu and delta opiate receptors in enhancing morphine analgesia. Proceedings of the National Academy of Sciences of the United States of America 101, 5135-5139

36S.R. George (2000) Oligomerization of mu- and delta-opioid receptors. Generation of novel functional properties. Journal of Biological Chemistry 275, 26128-26135

38G. Scherrer (2009) Dissociation of the opioid receptor mechanisms that control mechanical and heat pain. Cell 137, 1148-1159

39H.B. Wang (2010) Coexpression of delta- and mu-opioid receptors in nociceptive sensory neurons. Proceedings of the National Academy of Sciences of the United States of America 107, 13117-13122

40G. Scherrer (2006) Knockin mice expressing fluorescent delta-opioid receptors uncover G protein-coupled receptor dynamics in vivo. Proceedings of the National Academy of Sciences of the United States of America 103, 9691-9696

41H.B. Wang (2008) Distinct subcellular distribution of delta-opioid receptor fused with various tags in PC12 cells. Neurochemical Research 33, 2028-2034

42F.M. Decaillot (2008) Cell surface targeting of mu-delta opioid receptor heterodimers by RTP4. Proceedings of the National Academy of Sciences of the United States of America 105, 16045-16050

43P.Y. Law (2005) Heterodimerization of mu- and delta-opioid receptors occurs at the cell surface only and requires receptor-G protein interactions. Journal of Biological Chemistry 280, 11152-11164

44V. Chaipatikul (2003) Rescuing the traffic-deficient mutants of rat mu-opioid receptors with hydrophobic ligands. Molecular Pharmacology 64, 32-41

45R.K. Stumm (2004) Neuronal types expressing mu- and delta-opioid receptor mRNA in the rat hippocampal formation. Journal of Comparative Neurology 469, 107-118

46S.Q. He (2011) Facilitation of mu-opioid receptor activity by preventing delta-opioid receptor-mediated codegradation. Neuron 69, 120-131

47R. Rozenfeld and L.A. Devi (2007) Receptor heterodimerization leads to a switch in signaling: beta-arrestin2-mediated ERK activation by mu-delta opioid receptor heterodimers. FASEB Journal 21, 2455-2465

48R. Rozenfeld (2007) An emerging role for the delta opioid receptor in the regulation of mu opioid receptor function. Scientific World Journal 7, 64-73

49L.M. Bohn (1999) Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science 286, 2495-2498

51T. Trang (2003) Spinal administration of lipoxygenase inhibitors suppresses behavioural and neurochemical manifestations of naloxone-precipitated opioid withdrawal. British Journal of Pharmacology 140, 295-304

52R.J. Lefkowitz (1998) Mechanisms of beta-adrenergic receptor desensitization and resensitization. Advances in Pharmacology 42, 416-420

53L. He (2002) Regulation of opioid receptor trafficking and morphine tolerance by receptor oligomerization. Cell 108, 271-282

55E.J. Nestler (2001) Molecular basis of long-term plasticity underlying addiction. Nature Reviews. Neuroscience 2, 119-128

56A.K. Finn and J.L. Whistler (2001) Endocytosis of the mu opioid receptor reduces tolerance and a cellular hallmark of opiate withdrawal. Neuron 32, 829-839

57J.S. Guan (2005) Interaction with vesicle luminal protachykinin regulates surface expression of delta-opioid receptors and opioid analgesia. Cell 122, 619-631

58T.S. Shippenberg , V.I. Chefer and A.C. Thompson (2009) Delta-opioid receptor antagonists prevent sensitization to the conditioned rewarding effects of morphine. Biological Psychiatry 65, 169-174

59D.J. Daniels (2005) Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series. Proceedings of the National Academy of Sciences of the United States of America 102, 19208-19213

60N.R. Lenard (2007) Absence of conditioned place preference or reinstatement with bivalent ligands containing mu-opioid receptor agonist and delta-opioid receptor antagonist pharmacophores. European Journal of Pharmacology 566, 75-82

61N.R. Lenard and S.C. Roerig (2005) Development of antinociceptive tolerance and physical dependence following morphine i.c.v. infusion in mice. European Journal of Pharmacology 527, 71-76

62K. Ren and R. Dubner (2002) Descending modulation in persistent pain: an update. Pain 100, 1-6

63F. Porreca , M.H. Ossipov and G.F. Gebhart (2002) Chronic pain and medullary descending facilitation. Trends in Neurosciences 25, 319-325

64I. Sora (1997) Opiate receptor knockout mice define mu receptor roles in endogenous nociceptive responses and morphine-induced analgesia. Proceedings of the National Academy of Sciences of the United States of America 94, 1544-1549

65I. Bushlin , R. Rozenfeld and L.A. Devi (2010) Cannabinoid–opioid interactions during neuropathic pain and analgesia. Current Opinion in Pharmacology 10, 80-86

66P. Robledo (2008) Advances in the field of cannabinoid–opioid cross-talk. Addiction Biology 13, 213-224

67J.P. Chen (1990) Delta 9-tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamine efflux in nucleus accumbens of conscious, freely-moving rats as measured by intracerebral microdialysis. Psychopharmacology (Berlin) 102, 156-162

68G. Tanda , F.E. Pontieri and G. Di Chiara (1997) Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism. Science 276, 2048-2050

69D.L. Cichewicz and E.A. McCarthy (2003) Antinociceptive synergy between delta(9)-tetrahydrocannabinol and opioids after oral administration. Journal of Pharmacology and Experimental Therapeutics 304, 1010-1015

71I. Reche , J.A. Fuentes , M. Ruiz-Gayo (1996) Potentiation of delta 9-tetrahydrocannabinol-induced analgesia by morphine in mice: involvement of mu- and kappa-opioid receptors. European Journal of Pharmacology 318, 11-16

72M. Navarro (1998) CB1 cannabinoid receptor antagonist-induced opiate withdrawal in morphine-dependent rats. Neuroreport 9, 3397-3402

73O. Valverde (2001) Delta9-tetrahydrocannabinol releases and facilitates the effects of endogenous enkephalins: reduction in morphine withdrawal syndrome without change in rewarding effect. European Journal of Neuroscience 13, 1816-1824

75G. Vela , M. Ruiz-Gayo and J.A. Fuentes (1995) Anandamide decreases naloxone-precipitated withdrawal signs in mice chronically treated with morphine. Neuropharmacology 34, 665-668

76C. Ledent (1999) Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 283, 401-404

78A. Castane (2003) Cannabinoid withdrawal syndrome is reduced in double mu and delta opioid receptor knockout mice. European Journal of Neuroscience 17, 155-159

79D. Vigano (2005) Molecular mechanisms involved in the asymmetric interaction between cannabinoid and opioid systems. Psychopharmacology (Berlin) 182, 527-536

80T. Rubino (1997) Chronic treatment with a synthetic cannabinoid CP-55,940 alters G-protein expression in the rat central nervous system. Brain Research. Molecular Brain Research 44, 191-197

81S. Gonzalez (2002) Chronic exposure to morphine, cocaine or ethanol in rats produced different effects in brain cannabinoid CB(1) receptor binding and mRNA levels. Drug and Alcohol Dependence 66, 77-84

82S. Gonzalez (2003) Region-dependent changes in endocannabinoid transmission in the brain of morphine-dependent rats. Addiction Biology 8, 159-166

83S.N. Thorat and H.N. Bhargava (1994) Evidence for a bidirectional cross-tolerance between morphine and delta 9-tetrahydrocannabinol in mice. European Journal of Pharmacology 260, 5-13

84J. Romero (1998) Time-course of the cannabinoid receptor down-regulation in the adult rat brain caused by repeated exposure to delta9-tetrahydrocannabinol. Synapse 30, 298-308

85G. Lim , S. Wang and J. Mao (2005) Central glucocorticoid receptors modulate the expression of spinal cannabinoid receptors induced by chronic morphine exposure. Brain Research 1059, 20-27

86C. Salio (2001) CB1-cannabinoid and mu-opioid receptor co-localization on postsynaptic target in the rat dorsal horn. Neuroreport 12, 3689-3692

88A.G. Hohmann and M. Herkenham (2000) Localization of cannabinoid CB(1) receptor mRNA in neuronal subpopulations of rat striatum: a double-label in situ hybridization study. Synapse 37, 71-80

89V.M. Pickel (2004) Compartment-specific localization of cannabinoid 1 (CB1) and mu-opioid receptors in rat nucleus accumbens. Neuroscience 127, 101-112

91M. Herkenham (1991) Neuronal localization of cannabinoid receptors in the basal ganglia of the rat. Brain Research 547, 267-274

92A. Mansour (1988) Anatomy of CNS opioid receptors. Trends in Neurosciences 11, 308-314

94C. Rios , I. Gomes and L.A. Devi (2006) mu opioid and CB1 cannabinoid receptor interactions: reciprocal inhibition of receptor signaling and neuritogenesis. British Journal of Pharmacology 148, 387-395

95M. Hojo (2008) mu-Opioid receptor forms a functional heterodimer with cannabinoid CB1 receptor: electrophysiological and FRET assay analysis. Journal of Pharmacological Sciences 108, 308-319

96A. Korzh (2008) Modulation of extracellular signal-regulated kinase (ERK) by opioid and cannabinoid receptors that are expressed in the same cell. Brain Research 1189, 23-32

97V. Rubovitch , M. Gafni and Y. Sarne (2004) The involvement of VEGF receptors and MAPK in the cannabinoid potentiation of Ca2+ flux into N18TG2 neuroblastoma cells. Brain Research. Molecular Brain Research 120, 138-144

98M. Shapira , M. Gafni and Y. Sarne (1998) Independence of, and interacEtions between, cannabinoid and opioid signal transduction pathways in N18TG2 cells. Brain Research 806, 26-35

101F. Berrendero (2003) Cannabinoid receptor and WIN 55 212-2-stimulated [35S]-GTPgammaS binding in the brain of mu-, delta- and kappa-opioid receptor knockout mice. European Journal of Neuroscience 18, 2197-2202

102L. Uriguen (2005) Kappa- and delta-opioid receptor functional activities are increased in the caudate putamen of cannabinoid CB1 receptor knockout mice. European Journal of Neuroscience 22, 2106-2110

103R. Rozenfeld (2012) Receptor heteromerization expands the repertoire of cannabinoid signaling in rodent neurons. PLoS One 7, e29239

104S. Narang (2008) Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. Journal of Pain 9, 254-264

106Y.X. Pan , E. Bolan and G.W. Pasternak (2002) Dimerization of morphine and orphanin FQ/nociceptin receptors: generation of a novel opioid receptor subtype. Biochemical and Biophysical Research Communications 297, 659-663

107D. Wang (2005) Opioid receptor homo- and heterodimerization in living cells by quantitative bioluminescence resonance energy transfer. Molecular Pharmacology 67, 2173-2184

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