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Ligand-Directed Signaling at the Delta Opioid Receptor

Part of the Handbook of Experimental Pharmacology book series


Delta opioid receptors (δORs) regulate a number of physiological functions, and agonists for this receptor are being pursued for the treatment of mood disorders, chronic pain, and migraine. A major challenge to the development of these compounds is that, like many G-protein coupled receptors (GPCRs), agonists at the δOR can induce very different signaling and receptor trafficking events. This concept, known as ligand-directed signaling, functional selectivity, or biased agonism, can result in different agonists producing highly distinct behavioral consequences. In this chapter, we highlight the in vitro and in vivo evidence for ligand-directed signaling and trafficking at the δOR. A number of biological implications of agonist-directed signaling at the δOR have been demonstrated. Importantly, ligand-specific effects can impact both acute behavioral effects of delta agonists, as well as the long-term adaptations induced by chronic drug treatment. A better understanding of the specific signaling cascades that regulate these differential behavioral effects would help to guide rational drug design, ultimately resulting in δOR agonists with fewer adverse effects.


Pain Receptor trafficking Tolerance 



This work was supported by NIH-NIDA grants DA031243 and DA040688.


  1. Allouche S, Polastron J, Hasbi A, Homburger V, Jauzac P (1999) Differential G-protein activation by alkaloid and peptide opioid agonists in the human neuroblastoma cell line SK-N-BE. Biochem J 342(Pt 1):71–78CrossRefPubMedPubMedCentralGoogle Scholar
  2. Alongkronrusmee D, Chiang T, van Rijn RM (2016) Delta opioid pharmacology in relation to alcohol behaviors. In: Handbook of experimental pharmacology. doi:10.1007/164_2016_30 Google Scholar
  3. Alves ID, Salamon Z, Varga E, Yamamura HI, Tollin G, Hruby VJ (2003) Direct observation of G-protein binding to the human delta-opioid receptor using plasmon-waveguide resonance spectroscopy. J Biol Chem 278(49):48890–48897. doi:10.1074/jbc.M306866200 CrossRefPubMedGoogle Scholar
  4. Alves ID, Ciano KA, Boguslavski V, Varga E, Salamon Z, Yamamura HI, Hruby VJ, Tollin G (2004) Selectivity, cooperativity, and reciprocity in the interactions between the delta-opioid receptor, its ligands, and G-proteins. J Biol Chem 279(43):44673–44682. doi:10.1074/jbc.M404713200 CrossRefPubMedGoogle Scholar
  5. Audet N, Paquin-Gobeil M, Landry-Paquet O, Schiller PW, Pineyro G (2005) Internalization and Src activity regulate the time course of ERK activation by delta opioid receptor ligands. J Biol Chem 280(9):7808–7816. doi:10.1074/jbc.M411695200 CrossRefPubMedGoogle Scholar
  6. Audet N, Gales C, Archer-Lahlou E, Vallieres M, Schiller PW, Bouvier M, Pineyro G (2008) Bioluminescence resonance energy transfer assays reveal ligand-specific conformational changes within preformed signaling complexes containing delta-opioid receptors and heterotrimeric G proteins. J Biol Chem 283(22):15078–15088CrossRefPubMedPubMedCentralGoogle Scholar
  7. Audet N, Charfi I, Mnie-Filali O, Amraei M, Chabot-Dore AJ, Millecamps M, Stone LS, Pineyro G (2012) Differential association of receptor-Gbetagamma complexes with beta-arrestin2 determines recycling bias and potential for tolerance of delta opioid receptor agonists. J Neurosci 32(14):4827–4840. doi:10.1523/jneurosci.3734-11.2012 CrossRefPubMedGoogle Scholar
  8. Bosier B, Hermans E (2007) Versatility of GPCR recognition by drugs: from biological implications to therapeutic relevance. Trends Pharmacol Sci 28(8):438–446CrossRefPubMedGoogle Scholar
  9. Bradbury FA, Zelnik JC, Traynor JR (2009) G protein independent phosphorylation and internalization of the delta opioid receptor. J Neurochem 109(5):1526–1535CrossRefPubMedPubMedCentralGoogle Scholar
  10. Brandt MR, Furness MS, Rice KC, Fischer BD, Negus SS (2001) Studies of tolerance and dependence with the delta-opioid agonist SNC80 in rhesus monkeys responding under a schedule of food presentation. J Pharmacol Exp Ther 299(2):629–637PubMedGoogle Scholar
  11. Broom DC, Jutkiewicz EM, Folk JE, Traynor JR, Rice KC, Woods JH (2002a) Convulsant activity of a non-peptidic delta-opioid receptor agonist is not required for its antidepressant-like effects in Sprague-Dawley rats. Psychopharmacology (Berl) 164(1):42–48CrossRefGoogle Scholar
  12. Broom DC, Nitsche JF, Pintar JE, Rice KC, Woods JH, Traynor JR (2002b) Comparison of receptor mechanisms and efficacy requirements for delta-agonist-induced convulsive activity and antinociception in mice. J Pharmacol Exp Ther 303(2):723–729CrossRefPubMedGoogle Scholar
  13. Cahill CM, Walwyn W, Taylor AM, Pradhan AA, Evans CJ (2016) Allostatic mechanisms of opioid tolerance beyond desensitization and downregulation. Trends Pharmacol Sci 37(11):963–976. doi:10.1016/j.tips.2016.08.002 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Charfi I, Audet N, Bagheri Tudashki H, Pineyro G (2015) Identifying ligand-specific signalling within biased responses: focus on delta opioid receptor ligands. Br J Pharmacol 172(2):435–448. doi:10.1111/bph.12705 CrossRefPubMedGoogle Scholar
  15. Charles A, Pradhan AA (2016) Delta-opioid receptors as targets for migraine therapy. Curr Opin Neurol 29(3):314–319. doi:10.1097/wco.0000000000000311 CrossRefPubMedGoogle Scholar
  16. Chiang T, Sansuk K, van Rijn RM (2015) Beta-arrestin 2 dependence of delta opioid receptor agonists is correlated with alcohol intake. Br J Pharmacol. doi:10.1111/bph.13374
  17. Chu Sin Chung P, Boehrer A, Stephan A, Matifas A, Scherrer G, Darcq E, Befort K, Kieffer BL (2014) Delta opioid receptors expressed in forebrain GABAergic neurons are responsible for SNC80-induced seizures. Behav Brain Res 278C:429–434. doi:10.1016/j.bbr.2014.10.029 Google Scholar
  18. Chung PC, Boehrer A, Stephan A, Matifas A, Scherrer G, Darcq E, Befort K, Kieffer BL (2015) Delta opioid receptors expressed in forebrain GABAergic neurons are responsible for SNC80-induced seizures. Behav Brain Res 278:429–434. doi:10.1016/j.bbr.2014.10.029 CrossRefPubMedGoogle Scholar
  19. Comer SD, Hoenicke EM, Sable AI, McNutt RW, Chang KJ, De Costa BR, Mosberg HI, Woods JH (1993) Convulsive effects of systemic administration of the delta opioid agonist BW373U86 in mice. J Pharmacol Exp Ther 267(2):888–895PubMedGoogle Scholar
  20. Costa-Neto CM, Parreiras ESLT, Bouvier M (2016) A pluridimensional view of biased agonism. Mol Pharmacol 90(5):587–595. doi:10.1124/mol.116.105940 CrossRefPubMedGoogle Scholar
  21. Do Carmo GP, Folk JE, Rice KC, Chartoff E, Carlezon WA Jr, Negus SS (2009) The selective non-peptidic delta opioid agonist SNC80 does not facilitate intracranial self-stimulation in rats. Eur J Pharmacol 604(1–3):58–65CrossRefPubMedGoogle Scholar
  22. Fenalti G, Giguere PM, Katritch V, Huang XP, Thompson AA, Cherezov V, Roth BL, Stevens RC (2014) Molecular control of delta-opioid receptor signalling. Nature 506(7487):191–196. doi:10.1038/nature12944 CrossRefPubMedPubMedCentralADSGoogle Scholar
  23. Filliol D, Ghozland S, Chluba J, Martin M, Matthes HW, Simonin F, Befort K, Gaveriaux-Ruff C, Dierich A, LeMeur M, Valverde O, Maldonado R, Kieffer BL (2000) Mice deficient for delta- and mu-opioid receptors exhibit opposing alterations of emotional responses. Nat Genet 25(2):195–200CrossRefPubMedGoogle Scholar
  24. Galandrin S, Oligny-Longpre G, Bouvier M (2007) The evasive nature of drug efficacy: implications for drug discovery. Trends Pharmacol Sci 28(8):423–430CrossRefPubMedGoogle Scholar
  25. Gallantine EL, Meert TF (2005) A comparison of the antinociceptive and adverse effects of the mu-opioid agonist morphine and the delta-opioid agonist SNC80. Basic Clin Pharmacol Toxicol 97(1):39–51CrossRefPubMedGoogle Scholar
  26. He X, Sandhu HK, Yang Y, Hua F, Belser N, Kim DH, Xia Y (2013) Neuroprotection against hypoxia/ischemia: delta-opioid receptor-mediated cellular/molecular events. Cell Mol Life Sci 70(13):2291–2303. doi:10.1007/s00018-012-1167-2 CrossRefPubMedGoogle Scholar
  27. Henry AG, White IJ, Marsh M, von Zastrow M, Hislop JN (2011) The role of ubiquitination in lysosomal trafficking of delta-opioid receptors. Traffic 12(2):170–184CrossRefPubMedGoogle Scholar
  28. Hruby VJ, Alves I, Cowell S, Salamon Z, Tollin G (2010) Use of plasmon waveguide resonance (PWR) spectroscopy for examining binding, signaling and lipid domain partitioning of membrane proteins. Life Sci 86(15–16):569–574. doi:10.1016/j.lfs.2009.02.027 CrossRefPubMedGoogle Scholar
  29. Hudzik TJ, Howell A, Payza K, Cross AJ (2000) Antiparkinson potential of delta-opioid receptor agonists. Eur J Pharmacol 396(2–3):101–107CrossRefPubMedGoogle Scholar
  30. Husain S, Abdul Y, Potter DE (2012) Non-analgesic effects of opioids: neuroprotection in the retina. Curr Pharm Des 18(37):6101–6108CrossRefPubMedGoogle Scholar
  31. Jutkiewicz EM, Baladi MG, Folk JE, Rice KC, Woods JH (2006) The convulsive and electroencephalographic changes produced by nonpeptidic delta-opioid agonists in rats: comparison with pentylenetetrazol. J Pharmacol Exp Ther 317(3):1337–1348CrossRefPubMedGoogle Scholar
  32. Kenakin T (2004) Principles: receptor theory in pharmacology. Trends Pharmacol Sci 25(4):186–192CrossRefPubMedGoogle Scholar
  33. Kenakin TP (2012) Biased signalling and allosteric machines: new vistas and challenges for drug discovery. Br J Pharmacol 165(6):1659–1669CrossRefPubMedPubMedCentralGoogle Scholar
  34. Lagerstrom MC, Schioth HB (2008) Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat Rev Drug Discov 7(4):339–357CrossRefPubMedGoogle Scholar
  35. Lecoq I, Marie N, Jauzac P, Allouche S (2004) Different regulation of human delta-opioid receptors by SNC-80 [(+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenz yl]-N,N-diethylbenzamide] and endogenous enkephalins. J Pharmacol Exp Ther 310(2):666–677CrossRefPubMedGoogle Scholar
  36. Marie N, Lecoq I, Jauzac P, Allouche S (2003) Differential sorting of human delta-opioid receptors after internalization by peptide and alkaloid agonists. J Biol Chem 278(25):22795–22804CrossRefPubMedGoogle Scholar
  37. Maslov LN, Naryzhnaia NV, Tsibulnikov SY, Kolar F, Zhang Y, Wang H, Gusakova AM, Lishmanov YB (2013) Role of endogenous opioid peptides in the infarct size-limiting effect of adaptation to chronic continuous hypoxia. Life Sci 93(9–11):373–379. doi:10.1016/j.lfs.2013.07.018 CrossRefPubMedGoogle Scholar
  38. Mittal N, Roberts K, Pal K, Bentolila LA, Fultz E, Minasyan A, Cahill C, Pradhan A, Conner D, DeFea K, Evans C, Walwyn W (2013) Select G-protein-coupled receptors modulate agonist-induced signaling via a ROCK, LIMK, and beta-arrestin 1 pathway. Cell Rep 5(4):1010–1021. doi:10.1016/j.celrep.2013.10.015 CrossRefPubMedGoogle Scholar
  39. Molinari P, Vezzi V, Sbraccia M, Gro C, Riitano D, Ambrosio C, Casella I, Costa T (2010) Morphine-like opiates selectively antagonize receptor-arrestin interactions. J Biol Chem 285(17):12522–12535CrossRefPubMedPubMedCentralGoogle Scholar
  40. Moon HE, Cavalli A, Bahia DS, Hoffmann M, Massotte D, Milligan G (2001) The human delta opioid receptor activates G(i1)alpha more efficiently than G(o1)alpha. J Neurochem 76(6):1805–1813CrossRefPubMedGoogle Scholar
  41. Morse M, Sun H, Tran E, Levenson R, Fang Y (2013) Label-free integrative pharmacology on-target of opioid ligands at the opioid receptor family. BMC Pharmacol Toxicol 14:17. doi:10.1186/2050-6511-14-17 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Nagi K, Charfi I, Pineyro G (2015) Kir3 channels undergo arrestin-dependant internalization following delta opioid receptor activation. Cell Mol Life Sci. doi:10.1007/s00018-015-1899-x
  43. Negus SS, Butelman ER, Chang KJ, DeCosta B, Winger G, Woods JH (1994) Behavioral effects of the systemically active delta opioid agonist BW373U86 in rhesus monkeys. J Pharmacol Exp Ther 270(3):1025–1034PubMedGoogle Scholar
  44. Negus SS, Gatch MB, Mello NK, Zhang X, Rice K (1998) Behavioral effects of the delta-selective opioid agonist SNC80 and related compounds in rhesus monkeys. J Pharmacol Exp Ther 286(1):362–375PubMedGoogle Scholar
  45. Perrine SA, Hoshaw BA, Unterwald EM (2006) Delta opioid receptor ligands modulate anxiety-like behaviors in the rat. Br J Pharmacol 147(8):864–872CrossRefPubMedPubMedCentralGoogle Scholar
  46. Pierce KL, Premont RT, Lefkowitz RJ (2002) Seven-transmembrane receptors. Nat Rev Mol Cell Biol 3(9):639–650CrossRefPubMedGoogle Scholar
  47. Poole DP, Pelayo JC, Scherrer G, Evans CJ, Kieffer BL, Bunnett NW (2011) Localization and regulation of fluorescently labeled delta opioid receptor, expressed in enteric neurons of mice. Gastroenterology 141(3):982–991CrossRefPubMedPubMedCentralGoogle Scholar
  48. Por ED, Bierbower SM, Berg KA, Gomez R, Akopian AN, Wetsel WC, Jeske NA (2012) Beta-Arrestin-2 desensitizes the transient receptor potential vanilloid 1 (TRPV1) channel. J Biol Chem 287(44):37552–37563. doi:10.1074/jbc.M112.391847 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Pradhan AA, Becker JA, Scherrer G, Tryoen-Toth P, Filliol D, Matifas A, Massotte D, Gaveriaux-Ruff C, Kieffer BL (2009) In vivo delta opioid receptor internalization controls behavioral effects of agonists. PLoS One 4(5):e5425CrossRefPubMedPubMedCentralADSGoogle Scholar
  50. Pradhan AA, Walwyn W, Nozaki C, Filliol D, Erbs E, Matifas A, Evans C, Kieffer BL (2010) Ligand-directed trafficking of the delta-opioid receptor in vivo: two paths toward analgesic tolerance. J Neurosci 30(49):16459–16468CrossRefPubMedPubMedCentralGoogle Scholar
  51. Pradhan AA, Befort K, Nozaki C, Gaveriaux-Ruff C, Kieffer BL (2011) The delta opioid receptor: an evolving target for the treatment of brain disorders. Trends Pharmacol Sci 32(10):581–590CrossRefPubMedPubMedCentralGoogle Scholar
  52. Pradhan AA, Smith ML, Kieffer BL, Evans CJ (2012) Ligand-directed signalling within the opioid receptor family. Br J Pharmacol 167(5):960–969CrossRefPubMedPubMedCentralGoogle Scholar
  53. Pradhan AA, Smith ML, Zyuzin J, Charles A (2014) Delta-opioid receptor agonists inhibit migraine-related hyperalgesia, aversive state and cortical spreading depression in mice. Br J Pharmacol 171(9):2375–2384. doi:10.1111/bph.12591 CrossRefPubMedPubMedCentralGoogle Scholar
  54. Pradhan AA, Perroy J, Walwyn WM, Smith ML, Vicente-Sanchez A, Segura L, Bana A, Kieffer BL, Evans CJ (2016) Agonist-specific recruitment of arrestin isoforms differentially modify delta opioid receptor function. J Neurosci 36(12):3541–3551. doi:10.1523/jneurosci.4124-15.2016 CrossRefPubMedPubMedCentralGoogle Scholar
  55. Rajagopal S, Rajagopal K, Lefkowitz RJ (2010) Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nat Rev Drug Discov 9(5):373–386CrossRefPubMedPubMedCentralGoogle Scholar
  56. Reiter E, Ahn S, Shukla AK, Lefkowitz RJ (2012) Molecular mechanism of beta-arrestin-biased agonism at seven-transmembrane receptors. Annu Rev Pharmacol Toxicol 52:179–197CrossRefPubMedGoogle Scholar
  57. Rice FL, Xie JY, Albrecht PJ, Acker E, Bourgeois J, Navratilova E, Dodick DW, Porreca F (2016) Anatomy and immunochemical characterization of the non-arterial peptidergic diffuse dural innervation of the rat and Rhesus monkey: implications for functional regulation and treatment in migraine. Cephalalgia. doi:10.1177/0333102416677051
  58. Richard-Lalonde M, Nagi K, Audet N, Sleno R, Amraei M, Hogue M, Balboni G, Schiller PW, Bouvier M, Hebert TE, Pineyro G (2013) Conformational dynamics of Kir3.1/Kir3.2 channel activation via delta-opioid receptors. Mol Pharmacol 83(2):416–428. doi:10.1124/mol.112.081950 CrossRefPubMedPubMedCentralGoogle Scholar
  59. Rowan MP, Szteyn K, Doyle AP, Gomez R, Henry MA, Jeske NA (2014) Beta-arrestin-2-biased agonism of delta opioid receptors sensitizes transient receptor potential vanilloid type 1 (TRPV1) in primary sensory neurons. Mol Pain 10:50. doi:10.1186/1744-8069-10-50 CrossRefPubMedPubMedCentralGoogle Scholar
  60. Saitoh A, Kimura Y, Suzuki T, Kawai K, Nagase H, Kamei J (2004) Potential anxiolytic and antidepressant-like activities of SNC80, a selective delta-opioid agonist, in behavioral models in rodents. J Pharmacol Sci 95(3):374–380CrossRefPubMedGoogle Scholar
  61. Saitoh A, Yoshikawa Y, Onodera K, Kamei J (2005) Role of delta-opioid receptor subtypes in anxiety-related behaviors in the elevated plus-maze in rats. Psychopharmacology (Berl) 182(3):327–334CrossRefGoogle Scholar
  62. Salamon Z, Cowell S, Varga E, Yamamura HI, Hruby VJ, Tollin G (2000) Plasmon resonance studies of agonist/antagonist binding to the human delta-opioid receptor: new structural insights into receptor-ligand interactions. Biophys J 79(5):2463–2474. doi:10.1016/s0006-3495(00)76489-7 CrossRefPubMedPubMedCentralGoogle Scholar
  63. Salamon Z, Hruby VJ, Tollin G, Cowell S (2002) Binding of agonists, antagonists and inverse agonists to the human delta-opioid receptor produces distinctly different conformational states distinguishable by plasmon-waveguide resonance spectroscopy. J Pept Res 60(6):322–328CrossRefPubMedGoogle Scholar
  64. Sanchez-Blazquez P, Garzon J (1998) Delta opioid receptor subtypes activate inositol-signaling pathways in the production of antinociception. J Pharmacol Exp Ther 285(2):820–827PubMedGoogle Scholar
  65. Scherrer G, Tryoen-Toth P, Filliol D, Matifas A, Laustriat D, Cao YQ, Basbaum AI, Dierich A, Vonesh JL, Gaveriaux-Ruff C, Kieffer BL (2006) Knockin mice expressing fluorescent delta-opioid receptors uncover G protein-coupled receptor dynamics in vivo. Proc Natl Acad Sci U S A 103(25):9691–9696CrossRefPubMedPubMedCentralADSGoogle Scholar
  66. Sorkin A, von Zastrow M (2009) Endocytosis and signalling: intertwining molecular networks. Nat Rev Mol Cell Biol 10(9):609–622CrossRefPubMedPubMedCentralGoogle Scholar
  67. Tudashki HB, Robertson DN, Schiller PW, Pineyro G (2014) Endocytic profiles of delta-opioid receptor ligands determine the duration of rapid but not sustained cAMP responses. Mol Pharmacol 85(1):148–161. doi:10.1124/mol.113.089003 CrossRefPubMedPubMedCentralGoogle Scholar
  68. van Rijn RM, Brissett DI, Whistler JL (2010) Dual efficacy of delta opioid receptor-selective ligands for ethanol drinking and anxiety. J Pharmacol Exp Ther 335(1):133–139CrossRefPubMedPubMedCentralGoogle Scholar
  69. van Rijn RM, Brissett DI, Whistler JL (2012) Distinctive modulation of ethanol place preference by delta opioid receptor-selective agonists. Drug Alcohol Depend 122(1–2):156–159. doi:10.1016/j.drugalcdep.2011.09.024 CrossRefPubMedGoogle Scholar
  70. Vicente-Sanchez A, Segura L, Pradhan AA (2016) The delta opioid receptor tool box. Neuroscience 338:145–159. doi:10.1016/j.neuroscience.2016.06.028 CrossRefPubMedGoogle Scholar

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© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of PsychiatryUniversity of Illinois at ChicagoChicagoUSA
  2. 2.Department of PsychiatryUICChicagoUSA

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