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The Molecular Mechanisms of Cellular Tolerance to δ-Opioid Agonists

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Acta Biologica Hungarica volume 54, pages203–218(2003)Cite this article

Abstract

Chronic treatment with δ-opioid agonists, similar to other agonist drugs, causes tolerance. Tolerance is a complex adaptation process that consists of multiple, cellular and neural-system adaptations. Cellular tolerance to δ-opioid agonists involves feedback-regulation of the function, concentration, and localization of the δ-opioid receptors (receptor desensitization) as well as of intracellular effectors (functional desensitization). We are using a recombinant Chinese hamster ovary cell line expressing the human δ-opioid receptors (hDOR/CHO) to investigate the molecular mechanisms of cellular tolerance We found that the structurally distinct δ-opioid agonists mediate receptor down-regulation by different mechanisms. Thus, truncation of the last 35 C-terminal amino acids of the hDOR completely abolished DPDPE, but not SNC 80-mediated receptor down-regulation. In addition, down-regulation of the wild type-, and the truncated hDORs exhibited different inhibitor sensitivity-profile. Chronic δ-opioid agonist treatment also causes functional desensitization of forskolin-stimulated cAMP formation and cAMP overshoot in the hDOR/CHO cells. We have demonstrated that chronic SNC 80 treatment also causes concurrent phosphorylation of the adenylyl cyclase (AC) VI isoenzyme hDOR/CHO cells. Both AC superactivation and AC VI phosphorylation were SNC 80 dose-dependent, naltrindole-sensitive, and exhibited similar time course-, and protein kinase inhibitor-sensitivity profile. We hypothesize that phosphorylation of AC VI plays an important role in δ-opioid agonist-mediated AC superactivation in hDOR/CHO cells.

References

  1. 1.

    Afify, E. A., Law, P. Y., Riedl, M., Elde, R., Loh, H. H. (1998) Role of carboxyl terminus of μ and δ opioid receptor in agonist-induced down-regulation. Mol. Brain Res. 54, 24–34.

    CAS  PubMed  Google Scholar 

  2. 2.

    Ammer, H., Schulz, R. (1997) Enhanced stimulatory adenylyl cyclase signaling during opioid dependence is associated with a reduction in palmitoylated Gsα. Mol. Pharmacol. 52, 993–999.

    CAS  PubMed  Google Scholar 

  3. 3.

    Bayewitch, M. L., Nevo, I., Avidor-Reiss, T., Levy, R., Simmonds, W. F., Vogel, Z. (2000) Alterations in detergent solubility of heterotrimeric G proteins after chronic activation of Gi/o-coupled receptors: Changes in detergent solubility are in correlation with onset of adenylyl cyclase superac-tivation. Mol. Pharmacol. 57, 820–825.

    CAS  PubMed  Google Scholar 

  4. 4.

    Belcheva, M. M., Szűcs, M., Wang, D., Sadee, W., Coscia, C. J. (2001) Mu opioid receptor-mediated ERK activation involves calmodulin dependent EGF receptor transactivation. J. Biol. Chem. 276, 33847–33853.

    CAS  PubMed  Google Scholar 

  5. 5.

    Belcheva, M. M., Coscia, C. J. (2002) Diversity of G protein-coupled receptor signaling pathways to ERK/MAP kinase. Neurosignals 11, 34–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Bohm, S. K., Grady, E. F., Bunett, N. W. (1997) Regulatory mechanisms that modulate signaling by G protein-coupled receptors. Biochem. J. 322, 1–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Chakrabarti, S., Wang, L., Tang, W.-J., Gintzler, A. R. (1998) Chronic morphine augments adenylyl cyclase phosphorylation: relevance to altered signaling during tolerance/dependence. Mol. Pharmacol. 54, 949–953.

    CAS  PubMed  Google Scholar 

  8. 8.

    Chaturvedi, K., Bandari, P., Chinen, N., Howells, R. D. (2001) Proteasome involvement in agonist-induced down-regulation of the μ and δ-opioid receptors. J. Biol. Chem. 276, 12345–12352.

    CAS  PubMed  Google Scholar 

  9. 9.

    Cvejic, S., Trapaidze, N., Cyr, C., Devi, L. A. (1996) Thr353, located within the COOH-terminal tail of the δ opiate receptor, is involved in receptor down-regulation. J. Biol. Chem. 271, 4073–4079.

    CAS  PubMed  Google Scholar 

  10. 10.

    Crain, S. M., Shen, S.-F. (1998) Modulation of opioid analgesia, tolerance and dependence by Gs-coupled, GM1 ganglioside-regulated opioid receptor functions. Trends Pharmacol. Sci. 19, 358–365.

    CAS  PubMed  Google Scholar 

  11. 11.

    Cussack, D., Newman- Tancredi, A., Pasteau, V., Millan, M. J. (1999) Human dopamine D3 receptors mediate MAP kinase activation via PI-3-kinase and an atypical protein kinase C dependent mechanism. Mol. Pharmacol. 56, 1025–1030.

    Google Scholar 

  12. 12.

    Fukuda, K., Kato, S., Morikawa, H., Shoda, T., Mori, K. (1996) Functional coupling of δ, μ, and K-opioid receptors to MAP kinase and arachidonate release in Chinese hamster ovary cells. J. Neurochem. 67, 1309–1316.

    CAS  PubMed  Google Scholar 

  13. 13.

    Hicke, L. (1997) Ubiquitin-dependent internalization and down-regulation of plasma membrane proteins. The FASEB J. 11, 1215–1234.

    CAS  PubMed  Google Scholar 

  14. 14.

    Hosohata, Y., Varga, E. V., Stropova, D., Li, X., Knapp, R. J., Hruby, V. J., Rice, K. C., Nagase, H., Roeske, W. R., Yamamura, H. I. (2001) Mutation W284L of the human delta opioid receptor reveals agonist specific receptor conformations for G protein activation. Life Sci. 68, 22–33, 2001.

    Google Scholar 

  15. 15.

    Kieffer, B. L., Evans, C. J. (2002) Opioid tolerance - in search of the holy grail. Cell 108, 587–590.

    CAS  PubMed  Google Scholar 

  16. 16.

    Knapp, R. J., Malatynska, E., Fang, L., Li, X., Babin, E., Nguyen, M., Santoro, G., Varga, E. V, Hruby, V J., Roeske, W. R., Yamamura, H. I. (1994) Identification of a human delta opioid receptor: cloning and expression. Life Sci. 54, PL463–465.

    CAS  PubMed  Google Scholar 

  17. 17.

    Kramer, H. K., Simon, E. J. (1999) Role of protein kinase C in agonist-induced μ-opioid receptor down-regulation: II. Activation and involvement of the α, ε and ξ isoforms of PKC. J. Neurochem. 72, 594–604.

    CAS  PubMed  Google Scholar 

  18. 18.

    Law, P.-Y, Louie, A. K., Loh, H. H. (1985) Effect of pertussis toxin treatment on the down-regulation of opiate receptors in neuroblastoma x glioma NG108-15 hybrid cells. J. Biol. Chem. 260, 14818–14822.

    CAS  PubMed  Google Scholar 

  19. 19.

    Law, P.-Y, Loh, H. H. (1993) Delta opioid receptor activates cAMP phosphodiesterase activities in neuroblastoma x glioma NG108-15 hybrid cells. Mol. Pharmacol. 43, 684–693.

    CAS  PubMed  Google Scholar 

  20. 20.

    Law, P.-Y, Wong, Y. H., Loh, H. H. (1999) Mutational analysis of the structure and function of opioid receptors. Biopolymers 51, 440–457.

    CAS  PubMed  Google Scholar 

  21. 21.

    Maestri-El Kouhen, O., Wang, G., Solberg, J., Erickson, L. J., Law, P.-Y., Loh, H. H. (2000) Hierarchical phosphorylation of δ-opioid receptor regulates agonist-induced receptor desensitization and internalization. J. Biol. Chem. 275, 36659–36664.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Malatynska, E., Wang, Y., Knapp, R. J., Waite, S., Calderon, S., Rice, K., Hruby, V. J., Yamamura, H. I., Roeske, W. R. (1996) Human delta opioid receptor: Functional studies on stably transfected Chinese hamster ovary cells after acute and chronic treatment with the selective nonpeptidic agonist SNC-80. J. Pharmacol. Exp. Ther. 278, 1083–1094.

    CAS  Google Scholar 

  23. 23.

    Mellman, I. (1996) Endocytosis and molecular sorting. Ann. Rev. Cell. Dev. Biol. 12, 575–592.

    CAS  Google Scholar 

  24. 24.

    Menard, L., Ferguson, S. S. G., Zhang, J., Lin, F.-T., Lefkowitz, R. J., Caron, M. G., Barak, L. S. (1997) Synergistic regulation of ß2-adrenergic receptor sequestration: Intracellular complement of ß-adrenergic receptor kinase and ß-arrestin determine kinetics of internalization. Mol. Pharmacol. 51, 800–808.

    CAS  PubMed  Google Scholar 

  25. 25.

    Morris, A. J., Malbon, C. C. (1999) Physiological regulation of G protein linked signaling. Physiol. Rev. 79, 1373–1430.

    CAS  PubMed  Google Scholar 

  26. 26.

    Murray, S. R., Evans, C. J., von Zastrow, M. (1998) Phosphorylation is not required for dynamin-dependent endocytosis of a truncated mutant opioid receptor. J. Biol. Chem. 273, 24987–24996.

    CAS  PubMed  Google Scholar 

  27. 27.

    Okura, T., Cowell, S. M., Varga, E. V., Burkey, T. H., Roeske, W. R., Hruby, V. J., Yamamura, H. I. (2000) Differential down-regulation of the human delta-opioid receptor by SNC80 and [D-Pen2, D-Pen5]enkephalin. Eur. J. Pharmacol. 387, R11–13.

    CAS  PubMed  Google Scholar 

  28. 28.

    Okura, T., Varga, E. V., Hosohata, Y, Navratilova, E., Cowell, S. M., Rice, K., Nagase, H., Hruby, V. J., Roeske, W. R., Yamamura, H. I. (2003) Agonist-specific down-regulation of the human delta-opioid receptor. Eur J. Pharmacol. 459, 9–16.

    CAS  PubMed  Google Scholar 

  29. 29.

    Pei, G., Kieffer, B. L., Lefkowitz, R. J., Freedman, R. D. (1995) Agonist-dependent phosphorylation of the mouse 5-opioid receptor: Involvement of G protein-coupled receptor kinases but not protein kinase C. Mol. Pharmacol. 48, 173–178.

    CAS  PubMed  Google Scholar 

  30. 30.

    Quock, R. M., Burkey, T. H., Varga, E. V, Hosohata, Y, Hosohata, K., Cowell, S. M., Slate, C. A., Ehlert, F. J., Roeske, W. R., Yamamura, H. I. (1999) The 5-opioid receptor: molecular pharmacology, signal transduction, and the determination of drug efficacy. Pharmacol. Rev. 51, 503–532.

    CAS  PubMed  Google Scholar 

  31. 31.

    Rapaka, R. S., Porreca, F. (1991) Development of delta opioid peptides as non-addicting analgesics. Pharm. Res. 8, 1–8.

    CAS  PubMed  Google Scholar 

  32. 32.

    Rivera, M., Ginzler, A. R. (1998) Differential effect of chronic morphine on mRNA encoding adeny-lyl cyclase isoforms: relevance to physiological sequela of tolerance/dependence. Mol. Brain Res. 54, 165–169.

    CAS  PubMed  Google Scholar 

  33. 33.

    Rubenzik, M., Varga, E. V, Stropova, D., Roeske, W. R, Yamamura, H. I. (2001) Expression of α-transducin in Chinese hamster ovary cells stably transfected with the human 5-opioid receptor attenuates agonist-induced adenylyl cyclase superactivation. Mol. Pharmacol. 60, 1076–1082.

    CAS  PubMed  Google Scholar 

  34. 34.

    Sharma, S. K., Klee, W. A., Nirenberg, M. (1975) Dual regulation of adenylyl cyclase accounts for narcotic dependence and tolerance. Proc. Natl. Acad. Sci. USA 72, 3092–3096.

    CAS  PubMed  Google Scholar 

  35. 35.

    Tan, C. M., Kelvin, D. J., Litchfield, D. W., Ferguson, S. S. G., Feldman, R. D. (2001) Tyrosine kinase-mediated serine phosphorylation of adenylyl cyclase. Biochemistry 40, 1702–1709.

    CAS  PubMed  Google Scholar 

  36. 36.

    Thomas, J. M., Hoffman, B. B. (1996) Isoform-specific sensitization of adenylyl cyclase activity by prior activation of inhibitory receptors: Role of ßy subunits in transducing enhanced activity of the type VI isoform. Mol. Pharmacol. 49, 907–914.

    CAS  PubMed  Google Scholar 

  37. 37.

    Trapaidze, N., Keith, D. E., Cvejic, S., Evans, C. J., Devi, L. A. (1996) Sequestration of the 5-opioid receptor, role of the C terminus in agonist-mediated internalization. J. Biol. Chem. 271, 29279–29286.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Vanderah, T. W., Ossipov, M. H., Lai, J., Malan, T. P. Jr., Porreca, F. (2001) Mechanisms of opioid-induced pain and antinociceptive tolerance: descending facilitation and spinal dynorphin. Pain 92, 5–9.

    CAS  PubMed  Google Scholar 

  39. 39.

    van Vliet, B. J., DeVries, T. J., Wardeh, G., Mulder, A. H., Schoffelmeer, A. N. M. (1991) ώ-Opioid receptor-regulated adenylate cyclase activity in primary cultures of rat striatal neurons upon chronic morphine exposure. Eur. J. Pharmacol. 208, 105–111.

    PubMed  Google Scholar 

  40. 40.

    Varga, E. V., Stropova, D., Rubenzik, M. K., Wang, M., Landsman, R. S., Roeske, W. R., Yamamura, H. I. (1998) Identification of adenylyl cyclase isoenzymes in CHO and B82 cells. Eur. J. Pharmacol. 348, R1–2.

    CAS  PubMed  Google Scholar 

  41. 41.

    Varga, E. V., Stropova, D., Rubenzik, M. K., Waite, S. L., Roeske, W. R., Yamamura, H. I. (1999) Phosphorylation of adenylyl cyclase VI upon chronic δ-opioid receptor stimulation. Eur. J. Pharmacol. 364, R1–2.

    CAS  PubMed  Google Scholar 

  42. 42.

    Varga, E. V., Rubenzik M. K., Grife, V., Sugiyama, M., Stropova, D., Roeske, W. R., Yamamura, H. I. (2002) Involvement of Raf-1 in chronic delta-opioid receptor agonist-mediated adenylyl cyclase superactivation. Eur. J. Pharmacol. 451, 101–103.

    CAS  PubMed  Google Scholar 

  43. 43.

    Varga, E. V., Rubenzik, M. K., Stropova, D., Sugiyama, M., Grife, V., Hruby, V. J., Rice, K. C., Roeske, W. R., Yamamura, H. I. (2003) Converging protein kinase pathways mediate adenylyl cyclase superactivation upon chronic δ-opioid agonist treatment, J. Pharmacol. Exp. Ther. (in press).

    Google Scholar 

  44. 44.

    Whistler, J. L., Chuang, H.-H., Chu, P., Jan, L.-Y., von Zastrow, M. (1999) Functional dissociation of ώ opioid receptor signaling and endocytosis: Implications for the biology of opiate tolerance and addiction. Neuron 23, 737–749.

    CAS  PubMed  Google Scholar 

  45. 45.

    Williams, J. T., Christie, M. J., Manzoni, O. (2001) Cellular and synaptic adaptations mediating opioid dependence. Physiol. Rev. 81, 299–343.

    CAS  PubMed  Google Scholar 

  46. 46.

    Zhao, J., Pei, G., Huang, Y. L., Zhong, F. M., Ma, L. (1997) Carboxyl terminus of delta opioid receptor is required for agonist-dependent receptor phosphorylation. Biochem. Biophys. Res. Commun. 238, 71–76.

    CAS  PubMed  Google Scholar 

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  1. Department of Pharmacology and the Sarver Heart Center, The University of Arizona, Health Sciences Center, Tucson, Arizona, USA

    Eva V. Varga

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  1. Eva V. Varga
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Correspondence to Eva V. Varga.

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Dedicated to Professor Maria Wollemann on the occasion of her 80th birthday.

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Varga, E.V. The Molecular Mechanisms of Cellular Tolerance to δ-Opioid Agonists. BIOLOGIA FUTURA 54, 203–218 (2003). https://doi.org/10.1556/ABiol.54.2003.2.9

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Keywords

  • Human δ-opioid receptor
  • cellular tolerance
  • receptor down-regulation
  • adenylyl cyclase superactivation
  • adenylyl cyclase phosphorylation