Endogenous Opioid Peptides: Comparison
Please note this is a comparison between Version 3 by Bruce Ren and Version 2 by Anna Abrimian.

There exist three main types of endogenous opioid peptides, enkephalins, dynorphins and β-endorphin, all of which are derived from their precursors. These endogenous opioid peptides act through opioid receptors, including mu opioid receptor (MOR), delta opioid receptor (DOR) and kappa opioid receptor (KOR), and play important roles not only in analgesia, but also many other biological processes such as reward, stress response, feeding and emotion. 

  • β-endorphin
  • dynorphin A
  • [Met]5Enkephalin-Arg6-Phe7
  • endormorphins
  • mu opioid receptor
  • MOR
  • OPRM1
  • alternative splicing
  • G protein
  • β-arrestin
  • biased signaling
Please wait, diff process is still running!

References

  1. Cox, B.M.; Opheim, K.E.; Teschemacher, H.; Goldstein, A. A peptide-like substance from pituitary that acts like morphine. 2. Purification and properties. Life Sci. 1975, 16, 1777–1782.
  2. Goldstein, A. Opioid peptides (endorphins) in pituitary and brain. Science 1976, 193, 1081–1086.
  3. Goldstein, A.; Tachibana, S.; Lowney, L.I.; Hunkapiller, M.; Hood, L. Dynorphin-(1-13), an extraordinarily potent opioid peptide. Proc. Natl. Acad. Sci. USA 1979, 76, 6666–6670.
  4. Birdsall, N.J.M.; Hulme, E.C. C-fragment of lipotropin has a high affinity for brain opiate receptors. Nature 1976, 260, 793–795.
  5. Pert, C.B.; Pasternak, G.W.; Snyder, S.H. Opiate agonists and antagonists discriminated by receptor binding in brain. Science 1973, 182, 1359–1361.
  6. Terenius, L. Stereospecific interaction between narcotic analgesics and a synaptic plasma membrane fraction of rat cerebral cortex. Acta Pharmacol. Toxicol. 1973, 32, 856.
  7. Simon, E.J.; Hiller, J.M.; Edelman, I. Stereospecific binding of the potent narcotic analgesice [3H]etorphine to rat-brain homogenate. Proc. Natl. Acad. Sci. USA 1973, 70, 1947–1949.
  8. Evans, C.J.; Keith, D.E., Jr.; Morrison, H.; Magendzo, K.; Edwards, R.H. Cloning of a delta opioid receptor by functional expression. Science 1992, 258, 1952–1955.
  9. Kieffer, B.L.; Befort, K.; Gaveriaux-Ruff, C.; Hirth, C.G. The d-opioid receptor: Isolation of a cDNA by expression cloning and pharmacological characterization. Proc. Natl. Acad. Sci. USA 1992, 89, 12048–12052.
  10. Chen, Y.; Mestek, A.; Liu, J.; Hurley, J.A.; Yu, L. Molecular cloning and functional expression of a m-opioid receptor from rat brain. Mol. Pharmacol. 1993, 44, 8–12.
  11. Eppler, C.M.; Hulmes, J.D.; Wang, J.-B.; Johnson, B.; Corbett, M.; Luthin, D.R.; Uhl, G.R.; Linden, J. Purification and partial amino acid sequence of a m opioid receptor from rat brain. J. Biol. Chem. 1993, 268, 26447–26451.
  12. Thompson, R.C.; Mansour, A.; Akil, H.; Watson, S.J. Cloning and pharmacological characterization of a rat m opioid receptor. Neuron 1993, 11, 903–913.
  13. Wang, J.B.; Imai, Y.; Eppler, C.M.; Gregor, P.; Spivak, C.E.; Uhl, G.R. μ opiate receptor: cDNA cloning and expression. Proc. Natl. Acad. Sci. USA 1993, 90, 10230–10234.
  14. Chen, Y.; Mestek, A.; Liu, J.; Yu, L. Molecular cloning of a rat kappa opioid receptor reveals sequence similarities to the m and d opioid receptors. Biochem. J. 1993, 295, 625–628.
  15. Li, S.; Zhu, J.; Chen, C.; Chen, Y.-W.; Deriel, J.K.; Ashby, B.; Liu-Chen, L.-Y. Molecular cloning and expression of a rat kappa opioid receptor. Biochem. J. 1993, 295, 629–633.
  16. Meng, F.; Xie, G.-X.; Thompson, R.C.; Mansour, A.; Goldstein, A.; Watson, S.J.; Akil, H. Cloning and pharmacological characterization of a rat kappa opioid receptor. Proc. Natl. Acad. Sci. USA 1993, 90, 9954–9958.
  17. Pan, Y.X. Diversity and complexity of the mu opioid receptor gene: Alternative pre-mRNA splicing and promoters. DNA Cell Biol. 2005, 24, 736–750.
  18. Pasternak, G.W.; Pan, Y.X. Mu opioids and their receptors: Evolution of a concept. Pharmacol. Rev. 2013, 65, 1257–1317.
  19. Pasternak, G.W.; Childers, S.R.; Pan, Y.X. Emerging insights into mu opioid pharmacology. Handb. Exp. Pharmacol. 2020, 258, 89–125.
  20. Piltonen, M.; Parisien, M.; Gregoire, S.; Chabot-Dore, A.J.; Jafarnejad, S.M.; Berube, P.; Djambazian, H.; Sladek, R.; Geneau, G.; Willett, P.; et al. Alternative splicing of the delta-opioid receptor gene suggests existence of new functional isoforms. Mol. Neurobiol. 2019, 56, 2855–2869.
  21. Gavériaux-Ruff, C.; Peluso, J.; Befort, K.; Simonin, F.; Zilliox, C.; Kieffer, B.L. Detection of opioid receptor mRNA by RT-PCR reveals alternative splicing for the d- and kappa-opioid receptors. Mol. Brain Res. 1997, 48, 298–304.
  22. Belkowski, S.M.; Zhu, J.M.; Liu-Chen, L.Y.; Eisenstein, T.K.; Adler, M.W.; Rogers, T.J. Sequence of kappa-opioid receptor cDNA in the R1.1 thymoma cell line. J. Neuroimmunol. 1995, 62, 113–117.
  23. Alicea, C.; Belkowski, S.M.; Sliker, J.K.; Zhu, J.M.; Liu-Chen, L.Y.; Eisenstein, T.K.; Adler, M.W.; Rogers, T.J. Characterization of kappa-opioid receptor transcripts expressed by T cells and macrophages. J. Neuroimmunol. 1998, 91, 55–62.
  24. Beckett, A.H.; Casy, A.F. Synthetic analgesics: Sterochemical considerations. J. Pharm. Pharmacol. 1954, 6, 986–1001.
  25. Beckett, A.H.; Casy, A.F. Analgesics and their antagonists: Biochemical aspects and structure-activity relationships. Prog. Med. Chem. 1965, 4, 171–218.
  26. Portoghese, P.S. Stereochemical factors and receptor interactions associated with narcotic analgesics. J. Pharmacol. Sci. 1966, 55, 865–887.
  27. Janssen, P.A.H., Jr.; Schider, O.; Besendorf, L.; Pellmont, B. Diphenulpropylamines, morphinans. In Synthetic Analgesics Part I; Pergamon Press: New York, NY, USA, 1960.
  28. Janssen, P.A.H., Jr.; Schider, O.; Besendorf, L.; Pellmont, B. Diphenulpropylamine, morphinans. In Synthetic Analgesics Part II; Pergamon: New York, NY, USA, 1966.
  29. Jacobson, A.E.; Morrison, E.L.; Sargent, L.J. Analgesics. In Medicinal Chemistry (Part II); Burger, A., Ed.; Wiley Interscience: New York, NY, USA, 1970.
  30. Martin, W.R. Opioid antagonists. Pharmacol. Rev. 1967, 19, 463–521.
  31. Martin, W.R.; Eades, C.G.; Thompson, J.A.; Huppler, R.E.; Gilbert, P.E. The effects of morphine and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J. Pharmacol. Exp. Ther. 1976, 197, 517–532.
  32. Hughes, J.; Smith, T.W.; Kosterlitz, H.W.; Fothergill, L.A.; Morgan, B.A.; Morris, H.R. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature 1975, 258, 577–579.
  33. Pasternak, G.W.; Goodman, R.; Snyder, S.H. An endogenous morphine like factor in mammalian brain. Life Sci. 1975, 16, 1765–1769.
  34. Terenius, L.; Wahlstrom, A. Search for an endogenous ligand for the opiate receptor. Acta Physiol. Scand. 1975, 94, 74–81.
  35. Pert, C.B.; Snyder, S.H. Properties of opiate-receptor binding in rat brain. Proc. Natl. Acad. Sci. USA 1973, 70, 2243–2247.
  36. Pasternak, G.W.; Snyder, S.H. Opiate receptor binding: Enzymatic treatments and discrimination between agonists and antagonists. Mol. Pharmacol. 1975, 11, 735–744.
  37. Wilson, H.A.; Pasternak, G.W.; Snyder, S.H. Differentiation of opiate agonist and antagonist receptor binding by protein-modifying reagants. Nature 1975, 256, 448–450.
  38. Snyder, S.H.; Maurty, S. Opiate Receptor Mechanisms; MIT Press: Boston, MA, USA, 1975.
  39. Li, C.H.; Chung, D.; Doneen, B.A. Isolation, characterization and opiate activity of beta-endorphin from human pituitary glands. Biochem. Biophys. Res. Commun. 1976, 72, 1542–1547.
  40. Berezniuk, I.F.; John, L.D. Endogenous opioids. In The Opiate Receptors; Pasternak, G.W., Ed.; Springer: New York, NY, USA, 2011; pp. 93–120.
  41. Zhang, S.; Tong, Y.; Tian, M.; Dehaven, R.N.; Cortesburgos, L.; Mansson, E.; Simonin, F.; Kieffer, B.; Yu, L. Dynorphin A as a potential endogenous ligand for four members of the opioid receptor gene family. J. Pharmacol. Exp. Ther. 1998, 286, 136–141.
  42. Fricker, L.D.; Margolis, E.B.; Gomes, I.; Devi, L.A. Five decades of research on opioid peptides: current knowledge and unanswered questions. Mol. Pharmacol. 2020, 98, 96–108.
  43. Zadina, J.E.; Hackler, L.; Ge, L.J.; Kastin, A.J. A potent and selective endogenous agonist for the m-opiate receptor. Nature 1997, 386, 499–502.
  44. Fichna, J.; Janecka, A.; Costentin, J.; Do Rego, J.C. The endomorphin system and its evolving neurophysiological role. Pharmacol. Rev. 2007, 59, 88–123.
  45. Emery, M.A.; Akil, H. Endogenous opioids at the intersection of opioid addiction, pain, and depression: The search for a precision medicine approach. Annu. Rev. Neurosci. 2020, 43, 355–374.
  46. Bodnar, R.J. Endogenous opiates and behavior: 2018. Peptides 2020, 132, 170348.
  47. Gianoulakis, C. Endogenous opioids and addiction to alcohol and other drugs of abuse. Curr. Top. Med. Chem. 2009, 9, 999–1015.
  48. Trigo, J.M.; Martin-Garcia, E.; Berrendero, F.; Robledo, P.; Maldonado, R. The endogenous opioid system: A common substrate in drug addiction. Drug Alcohol Depend. 2010, 108, 183–194.
  49. Pecina, M.; Karp, J.F.; Mathew, S.; Todtenkopf, M.S.; Ehrich, E.W.; Zubieta, J.K. Endogenous opioid system dysregulation in depression: Implications for new therapeutic approaches. Mol. Psychiatry 2019, 24, 576–587.
  50. Charbogne, P.; Kieffer, B.L.; Befort, K. 15 years of genetic approaches in vivo for addiction research: Opioid receptor and peptide gene knockout in mouse models of drug abuse. Neuropharmacology 2014, 76 Pt B, 204–217.
  51. Drolet, G.; Dumont, E.C.; Gosselin, I.; Kinkead, R.; Laforest, S.; Trottier, J.F. Role of endogenous opioid system in the regulation of the stress response. Prog. Neuropsychopharmacol. Biol. Psychiatry 2001, 25, 729–741.
  52. Zimmer, A.; Valjent, E.; Konig, M.; Zimmer, A.M.; Robledo, P.; Hahn, H.; Valverde, O.; Maldonado, R. Absence of delta-9-tetrahydrocannabinol dysphoric effects in dynorphin-deficient mice. J. Neurosci. Off. J. Soc. Neurosci. 2001, 21, 9499–9505.
  53. Konig, M.; Zimmer, A.M.; Steiner, H.; Holmes, P.V.; Crawley, J.N.; Brownstein, M.J.; Zimmer, A. Pain responses, anxiety and aggression in mice deficient in pre-proenkephalin. Nature 1996, 383, 535–538.
  54. Yaswen, L.; Diehl, N.; Brennan, M.B.; Hochgeschwender, U. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nat. Med. 1999, 5, 1066–1070.
  55. Rubinstein, M.; Mogil, J.S.; Japon, M.; Chan, E.C.; Allen, R.G.; Low, M.J. Absence of opioid stress-induced analgesia in mice lacking beta-endorphin by site-directed mutagenesis. Proc. Natl. Acad. Sci. USA 1996, 93, 3995–4000.
  56. Appleyard, S.M.; Hayward, M.; Young, J.I.; Butler, A.A.; Cone, R.D.; Rubinstein, M.; Low, M.J. A role for the endogenous opioid beta-endorphin in energy homeostasis. Endocrinology 2003, 144, 1753–1760.
  57. Mogil, J.S.; Kest, B.; Sadowski, B.; Belknap, J.K. Differential genetic mediation of sensitivity to morphine in genetic models of opiate antinociception: Influence of nociceptive assay. J. Pharmacol. Exp. Ther. 1996, 276, 532–544.
  58. Reith, M.E.A.; Sershen, H.; Vadasz, C.; Lajtha, A. Strain differences in opiate receptors in mouse brain. Eur. J. Pharmacol. 1981, 74, 377–380.
  59. Baron, A.; Shuster, L.; Elefterhiou, B.E.; Bailey, D.W. Opiate receptors in mice: Genetic differences. Life Sci. 1975, 17, 633–640.
  60. Pick, C.G.; Nejat, R.; Pasternak, G.W. Independent expression of two pharmacologically distinct supraspinal mu analgesic systems in genetically different mouse strains. J. Pharmacol. Exp. Ther. 1993, 2265, 166–171.
  61. Chang, A.; Emmel, D.W.; Rossi, G.C.; Pasternak, G.W. Methadone analgesia in morphine-insensitive CXBK mice. Eur. J. Pharmacol. 1998, 351, 189–191.
  62. Pasternak, G.W.; Childers, S.R.; Snyder, S.H. Naloxazone, long-acting opiate antagonist: Effects in intact animals and on opiate receptor binding in vitro. J. Pharmacol. Exp. Ther. 1980, 214, 455–462.
  63. Pasternak, G.W.; Childers, S.R.; Snyder, S.H. Opiate analgesia: Evidence for mediation by a subpopulation of opiate receptors. Science 1980, 208, 514–516.
  64. Hazum, E.; Chang, K.J.; Cuatrescasas, P.; Pasternak, G.W. Naloxazone irreversibility inhibits the high affinity binding of [124I]D-ala2-D-leu5-enkephalin. Life Sci. 1981, 29, 843–851.
  65. Hahn, E.F.; Carroll-Buatti, M.; Pasternak, G.W. Irreversible opiate agonists and antagonists: The 14-hydroxydihydromorphinone azines. J. Neurosci. 1982, 2, 572–576.
  66. Pasternak, G.W. Multiple morphine and enkephalin receptors: Biochemical and pharmacological aspects. In Stress-Induced Analgesia; Kelly, D., Ed.; New York Academy of Sciences: New York, NY, USA, 1986; pp. 130–139.
  67. Pasternak, G.W. Incomplete cross tolerance and multiple mu opioid peptide receptors. Trends Pharmacol. Sci. 2001, 22, 67–70.
  68. Christensen, C.B.; Jorgensen, L.N. Morphine-6-glucuronide has high affinity for the opioid receptor. Pharmacol. Toxicol. 1987, 60, 75–76.
  69. Pasternak, G.W.; Bodnar, R.J.; Clark, J.A.; Inturrisi, C.E. Morphine-6-glucuronide, a potent mu agonist. Life Sci. 1987, 41, 2845–2849.
  70. Paul, D.; Standifer, K.M.; Inturrisi, C.E.; Pasternak, G.W. Pharmacological characterization of morphine-6b-glucuronide, a very potent morphine metabolite. J. Pharmacol. Exp. Ther. 1989, 251, 477–483.
  71. Schuller, A.G.P.; King, M.A.; Zhang, J.W.; Bolan, E.; Pan, Y.X.; Morgan, D.J.; Chang, A.; Czick, M.E.; Unterwald, E.M.; Pasternak, G.W.; 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, 151–156.
  72. Zhou, X.E.; He, Y.; de Waal, P.W.; Gao, X.; Kang, Y.; Van Eps, N.; Yin, Y.; Pal, K.; Goswami, D.; White, T.A.; et al. Identification of phosphorylation codes for arrestin recruitment by g protein-coupled receptors. Cell 2017, 170, 457–469.e413.
  73. Bolan, E.A.; Pan, Y.X.; Pasternak, G.W. Functional analysis of MOR-1 splice variants of the mouse mu opioid receptor gene Oprm. Synapse 2004, 51, 11–18.
  74. Pasternak, D.A.; Pan, L.; Xu, J.; Yu, R.; Xu, M.M.; Pasternak, G.W.; Pan, Y.X. Identification of three new alternatively spliced variants of the rat mu opioid receptor gene: Dissociation of affinity and efficacy. J. Neurochem. 2004, 91, 881–890.
  75. Pan, Y.X.; Xu, J.; Bolan, E.; Moskowitz, H.S.; Xu, M.; Pasternak, G.W. Identification of four novel exon 5 splice variants of the mouse mu-opioid receptor gene: Functional consequences of C-terminal splicing. Mol. Pharmacol. 2005, 68, 866–875.
  76. Pan, L.; Xu, J.; Yu, R.; Xu, M.M.; Pan, Y.X.; Pasternak, G.W. Identification and characterization of six new alternatively spliced variants of the human mu opioid receptor gene, Oprm. Neuroscience 2005, 133, 209–220.
  77. Xu, J.; Xu, M.; Bolan, E.; Gilbert, A.K.; Pasternak, G.W.; Pan, Y.X. Isolating and characterizing three alternatively spliced mu opioid receptor variants: mMOR-1A, mMOR-1O, and mMOR-1P. Synapse 2014, 68, 144–152.
  78. Pan, Y.X.; Xu, J.; Bolan, E.; Chang, A.; Mahurter, L.; Rossi, G.; Pasternak, G.W. Isolation and expression of a novel alternatively spliced mu opioid receptor isoform, MOR-1F. FEBS Letters 2000, 466, 337–340.
  79. Pan, Y.X.; Xu, J.; Mahurter, L.; Xu, M.; Gilbert, A.K.; Pasternak, G.W. Identification and characterization of two new human mu opioid receptor splice variants, hMOR-1O and hMOR-1X. Biochem. Biophys. Res. Commun. 2003, 301, 1057–1061.
  80. Xu, J.; Lu, Z.; Narayan, A.; Le Rouzic, V.P.; Xu, M.; Hunkele, A.; Brown, T.G.; Hoefer, W.F.; Rossi, G.C.; Rice, R.C.; et al. Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine. J. Clin. Investig. 2017, 127, 1561–1573.
  81. Narayan, A.; Hunkele, A.; Xu, J.; Bassoni, D.L.; Pasternak, G.W.; Pan, Y.X. Mu opioids induce biased signaling at the full-length seven transmembrane C-terminal splice variants of the mu opioid receptor gene, Oprm1. Cell Mol. Neurobiol. 2020.
  82. Koch, T.; Schulz, S.; Schroder, H.; Wolf, R.; Raulf, E.; Hollt, V. Carboxyl-terminal splicing of the rat mu opioid receptor modulates agonist-mediated internalization and receptor resensitization. J. Biol. Chem. 1998, 273, 13652–13657.
  83. Abbadie, C.; Pasternak, G.W. Differential in vivo internalization of MOR-1 and MOR-1C by morphine. Neuroreport 2001, 12, 3069–3072.
  84. Tanowitz, M.; Hislop, J.N.; von Zastrow, M. Alternative splicing determines the post-endocytic sorting fate of G-protein-coupled receptors. J. Biol. Chem. 2008, 283, 35614–35621.
  85. Xu, J.; Faskowitz, A.J.; Rossi, G.C.; Xu, M.; Lu, Z.; Pan, Y.X.; Pasternak, G.W. Stabilization of morphine tolerance with long-term dosing: Association with selective upregulation of mu-opioid receptor splice variant mRNAs. Proc. Natl. Acad. Sci. USA 2015, 112, 279–284.
  86. Xu, J.; Lu, Z.; Xu, M.; Rossi, G.C.; Kest, B.; Waxman, A.R.; Pasternak, G.W.; Pan, Y.X. Differential expressions of the alternatively spliced variant mRNAs of the micro opioid receptor gene, OPRM1, in brain regions of four inbred mouse strains. PLoS ONE 2014, 9, e111267.
  87. Abbadie, C.; Pan, Y.X.; Pasternak, G.W. Differential distribution in rat brain of mu opioid receptor carboxy terminal splice variants MOR-1C-like and MOR-1-like immunoreactivity: Evidence for region-specific processing. J. Comp. Neurol. 2000, 419, 244–256.
  88. Abbadie, C.; Pan, Y.-X.; Drake, C.T.; Pasternak, G.W. Comparative immunhistochemical distributions of carboxy terminus epitopes from the mu opioid receptor splice variants MOR-1D, MOR-1 and MOR-1C in the mouse and rat central nervous systems. Neuroscience 2000, 100, 141–153.
  89. Brown, T.G.; Xu, J.; Hurd, Y.L.; Pan, Y.X. Dysregulated expression of the alternatively spliced variant mRNAs of the mu opioid receptor gene, OPRM1, in the medial prefrontal cortex of male human heroin abusers and heroin self-administering male rats. J. Neurosci. Res. 2020.
  90. Dever, S.M.; Xu, R.; Fitting, S.; Knapp, P.E.; Hauser, K.F. Differential expression and HIV-1 regulation of mu-opioid receptor splice variants across human central nervous system cell types. J. Neurovirol. 2012, 18, 181–190.
  91. Dever, S.M.; Costin, B.N.; Xu, R.; El-Hage, N.; Balinang, J.; Samoshkin, A.; O’Brien, M.A.; McRae, M.; Diatchenko, L.; Knapp, P.E.; et al. Differential expression of the alternatively spliced OPRM1 isoform mu-opioid receptor-1K in HIV-infected individuals. AIDS 2014, 28, 19–30.
  92. Liu, X.Y.; Liu, Z.C.; Sun, Y.G.; Ross, M.; Kim, S.; Tsai, F.F.; Li, Q.F.; Jeffry, J.; Kim, J.Y.; Loh, H.H.; et al. Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids. Cell 2011, 147, 447–458.
  93. Liu, X.Y.; Ginosar, Y.; Yazdi, J.; Hincker, A.; Chen, Z.F. Cross-talk between human spinal cord mu-opioid receptor 1y isoform and gastrin-releasing peptide receptor mediates opioid-induced scratching behavior. Anesthesiology 2019, 131, 381–391.
  94. Pan, Y.X.; Xu, J.; Xu, M.; Rossi, G.C.; Matulonis, J.E.; Pasternak, G.W. 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, 4917–4922.
  95. Grinnell, S.G.; Ansonoff, M.; Marrone, G.F.; Lu, Z.; Narayan, A.; Xu, J.; Rossi, G.; Majumdar, S.; Pan, Y.X.; Bassoni, D.L.; et al. Mediation of buprenorphine analgesia by a combination of traditional and truncated mu opioid receptor splice variants. Synapse 2016, 70, 395–407.
  96. Majumdar, S.; Grinnell, S.; Le, R.V.; Burgman, M.; Polikar, L.; Ansonoff, M.; Pintar, J.; Pan, Y.X.; Pasternak, G.W. Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects. Proc. Natl. Acad. Sci. USA 2011, 108, 19778–19783.
  97. Wieskopf, J.S.; Pan, Y.X.; Marcovitz, J.; Tuttle, A.H.; Majumdar, S.; Pidakala, J.; Pasternak, G.W.; Mogil, J.S. Broad-spectrum analgesic efficacy of IBNtxA is mediated by exon 11-associated splice variants of the mu-opioid receptor gene. Pain 2014.
  98. Xu, J.; Xu, M.; Brown, T.; Rossi, G.C.; Hurd, Y.L.; Inturrisi, C.E.; Pasternak, G.W.; Pan, Y.X. Stabilization of the mu-opioid receptor by truncated single transmembrane splice variants through a chaperone-like action. J. Biol. Chem. 2013, 288, 21211–21227.
  99. Zhang, T.; Xu, J.; Pan, Y.X. A truncated six transmembrane splice variant MOR-1g enhances expression of the full-length seven transmembrane mu-opioid receptor through heterodimerization. Mol. Pharmacol. 2020, 98, 518–527.
  100. Pan, Y.X.; Xu, J.; Bolan, E.; Abbadie, C.; Chang, A.; Zuckerman, A.; Rossi, G.; Pasternak, G.W. Identification and characterization of three new alternatively spliced mu-opioid receptor isoforms. Mol. Pharmacol. 1999, 56, 396–403.
  101. Manglik, A.; Kruse, A.C.; Kobilka, T.S.; Thian, F.S.; Mathiesen, J.M.; Sunahara, R.K.; Pardo, L.; Weis, W.I.; Kobilka, B.K.; Granier, S. Crystal structure of the mu-opioid receptor bound to a morphinan antagonist. Nature 2012, 485, 321–326.
  102. Huang, W.J.; Manglik, A.; Venkatakrishnan, A.J.; Laeremans, T.; Feinberg, E.N.; Sanborn, A.L.; Kato, H.E.; Livingston, K.E.; Thorsen, T.S.; Kling, R.C.; et al. Structural insights into mu-opioid receptor activation. Nature 2015, 524, 315.
  103. Sim, L.J.; Selley, D.E.; Childers, S.R. In vitro autoradiography of receptor-activated G proteins in rat brain by agonist-stimulated guanylyl 5′-[gamma-[35S]thio]triphosphate binding. Proc. Natl. Acad. Sci. USA 1995, 92, 7242–7246.
  104. Childers, S.R. Opioid receptor-coupled second messenger systems. Life Sci. 1991, 48, 1991–2003.
  105. Abbadie, C.; Gultekin, S.H.; Pasternak, G.W. Immunohistochemical localization of the carboxy terminus of the novel mu opioid receptor splice variant MOR-1C within the human spinal cord. Neuroreport 2000, 11, 1953–1957.
  106. Smith, J.S.; Lefkowitz, R.J.; Rajagopal, S. Biased signalling: From simple switches to allosteric microprocessors. Nat. Rev. Drug Discov. 2018, 17, 243–260.
  107. Raehal, K.M.; Schmid, C.L.; Groer, C.E.; Bohn, L.M. Functional selectivity at the mu-opioid receptor: Implications for understanding opioid analgesia and tolerance. Pharmacol. Rev. 2011, 63, 1001–1019.
  108. Schmid, C.L.; Kennedy, N.M.; Ross, N.C.; Lovell, K.M.; Yue, Z.Z.; Morgenweck, J.; Cameron, M.D.; Bannister, T.D.; Bohn, L.M. Bias factor and therapeutic window correlate to predict safer opioid analgesics. Cell 2017, 171, 1165.
  109. Grim, T.W.; Acevedo-Canabal, A.; Bohn, L.M. Toward directing opioid receptor signaling to refine opioid therapeutics. Biol. Psychiatry 2020, 87, 15–21.
  110. Turnaturi, R.; Chiechio, S.; Salerno, L.; Rescifina, A.; Pittala, V.; Cantarella, G.; Tomarchio, E.; Parenti, C.; Pasquinucci, L. Progress in the development of more effective and safer analgesics for pain management. Eur. J. Med. Chem. 2019, 183, 111701.
  111. Zhao, X.; Jones, A.; Olson, K.R.; Peng, K.; Wehrman, T.; Park, A.; Mallari, R.; Nebalasca, D.; Young, S.W.; Xiao, S.H. A homogeneous enzyme fragment complementation-based beta-arrestin translocation assay for high-throughput screening of G-protein-coupled receptors. J. Biomol. Screen. 2008, 13, 737–747.
  112. Kroeze, W.K.; Sassano, M.F.; Huang, X.P.; Lansu, K.; McCorvy, J.D.; Giguere, P.M.; Sciaky, N.; Roth, B.L. PRESTO-Tango as an open-source resource for interrogation of the druggable human GPCRome. Nat. Struct. Mol. Biol. 2015, 22, 362–369.
  113. Bertrand, L.; Parent, S.; Caron, M.; Legault, M.; Joly, E.; Angers, S.; Bouvier, M.; Brown, M.; Houle, B.; Menard, L. The BRET2/arrestin assay in stable recombinant cells: A platform to screen for compounds that interact with G protein-coupled receptors (GPCRS). J. Recept. Signal. Transduct. Res. 2002, 22, 533–541.
  114. Hamdan, F.F.; Audet, M.; Garneau, P.; Pelletier, J.; Bouvier, M. High-throughput screening of G protein-coupled receptor antagonists using a bioluminescence resonance energy transfer 1-based beta-arrestin2 recruitment assay. J. Biomol. Screen. 2005, 10, 463–475.
  115. Barak, L.S.; Ferguson, S.S.; Zhang, J.; Caron, M.G. A beta-arrestin/green fluorescent protein biosensor for detecting G protein-coupled receptor activation. J. Biol. Chem. 1997, 272, 27497–27500.
  116. Dixon, A.S.; Schwinn, M.K.; Hall, M.P.; Zimmerman, K.; Otto, P.; Lubben, T.H.; Butler, B.L.; Binkowski, B.F.; Machleidt, T.; Kirkland, T.A.; et al. NanoLuc complementation reporter optimized for accurate measurement of protein interactions in cells. ACS Chem. Biol. 2016, 11, 400–408.
  117. Kenakin, T.; Watson, C.; Muniz-Medina, V.; Christopoulos, A.; Novick, S. A simple method for quantifying functional selectivity and agonist bias. ACS Chem. Neurosci. 2012, 3, 193–203.
  118. Van der Westhuizen, E.T.; Breton, B.; Christopoulos, A.; Bouvier, M. Quantification of ligand bias for clinically relevant beta2-adrenergic receptor ligands: Implications for drug taxonomy. Mol. Pharmacol. 2014, 85, 492–509.
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