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Molecular Medicine

, Volume 19, Issue 1, pp 7–17 | Cite as

In Vivo Regulation of the μ Opioid Receptor: Role of the Endogenous Opioid Agents

  • Veronica Gonzalez-Nunez
  • Ada Jimenez González
  • Katherine Barreto-Valer
  • Raquel E. Rodríguez
Research Article

Abstract

It is well known that genotypic differences can account for the subject-specific responses to opiate administration. In this regard, the basal activity of the endogenous system (either at the receptor or ligand level) can modulate the effects of exogenous agonists as morphine and vice versa. The µ opioid receptor from zebrafish, dre-oprm1, binds endogenous peptides and morphine with similar affinities. Morphine administration during development altered the expression of the endogenous opioid propeptides proenkephalins and proopiomelanocortin. Treatment with opioid peptides (Met-enkephalin (Met-ENK), Met-enkephalin-Gly-Tyr (MEGY) and β-endorphin (β-END)) modulated dre-oprm1 expression during development. Knocking down the dre-oprm1 gene significantly modified the mRNA expression of the penk and pomc genes, thus indicating that oprm1 is involved in shaping penk and pomc expression. In addition, the absence of a functional oprm1 clearly disrupted the embryonic development, since proliferation was disorganized in the central nervous system of oprm1-morphant embryos: mitotic cells were found widespread through the optic tectum and were not restricted to the proliferative areas of the mid- and hindbrain. Transferase-mediated dUTP nick-end labeling (TUNEL) staining revealed that the number of apoptotic cells in the central nervous system (CNS) of morphants was clearly increased at 24-h postfertilization. These findings clarify the role of the endogenous opioid system in CNS development. Our results will also help unravel the complex feedback loops that modulate opioid activity and that may be involved in establishing a coordinated expression of both receptors and endogenous ligands. Further knowledge of the complex interactions between the opioid system and analgesic drugs will provide insights that may be relevant for analgesic therapy.

Notes

Acknowledgments

This work was supported by grants from the Spanish Ministry of Science and Education (SAF2010-18597) and from Consejeria de Sanidad, Junta de Castilla y León (SAN673/SA25/08 and B1039/SA25/10). The authors would like to thank G Valencia and G Arsequell for synthesizing the zebrafish MEGY peptide and its two analogs: (d-Ala2)-MEGY and (d-Ala2, Val5)-MEGY.

Supplementary material

10020_2013_1901007_MOESM1_ESM.pdf (337 kb)
Supplementary material, approximately 336 KB.

References

  1. 1.
    Comb M, Seeburg PH, Adelman J, Eiden L, Herbert E. (1982) Primary structure of the human Met- and Leu-enkephalin precursor and its mRNA. Nature. 295:663–6.CrossRefPubMedGoogle Scholar
  2. 2.
    Gubler U, Seeburg P, Hoffman BJ, Gage LP, Udenfriend S. (1982) Molecular cloning establishes proenkephalin as precursor of enkephalincontaining peptides. Nature. 295:206–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Chang AC, Cochet M, Cohen SN. (1980) Structural organization of human genomic DNA encoding the pro-opiomelanocortin peptide. Proc. Natl. Acad. Sci. U. S. A. 77:4890–4.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Corbett AD, Henderson G, McKnight AT, Paterson SJ. (2006) 75 years of opioid research: the exciting but vain quest for the Holy Grail. Br. J. Pharmacol. 147 (Suppl 1):S153–62.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Mansour A, Hoversten MT, Taylor LP, Watson SJ, Akil H. (1995) The cloned mu, delta and kappa receptors and their endogenous ligands: evidence for two opioid peptide recognition cores. Brain Res. 700:89–98.CrossRefPubMedGoogle Scholar
  6. 6.
    Borgland SL, Connor M, Osborne PB, Furness JB, Christie MJ. (2003) Opioid agonists have different efficacy profiles for G protein activation, rapid desensitization, and endocytosis of muopioid receptors. J. Biol. Chem. 278:18776–84.CrossRefPubMedGoogle Scholar
  7. 7.
    Matthes HW, et al. (1996) Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioidreceptor gene. Nature. 383:819–23.CrossRefPubMedGoogle Scholar
  8. 8.
    Zhu Y, et al. (1999) Retention of supraspinal delta-like analgesia and loss of morphine tolerance in delta opioid receptor knockout mice. Neuron. 24:243–52.CrossRefPubMedGoogle Scholar
  9. 9.
    Hauser KF, McLaughlin PJ, Zagon IS. (1987) Endogenous opioids regulate dendritic growth and spine formation in developing rat brain. Brain Res. 416:157–61.CrossRefPubMedGoogle Scholar
  10. 10.
    Zagon IS, McLaughlin PJ. (1987) Endogenous opioid systems regulate cell proliferation in the developing rat brain. Brain Res. 412:68–72.CrossRefPubMedGoogle Scholar
  11. 11.
    Zagon IS, Verderame MF, McLaughlin PJ. (2002) The biology of the opioid growth factor receptor (OGFr). Brain Res. Brain Res. Rev. 38:351–76.CrossRefPubMedGoogle Scholar
  12. 12.
    Jansson LM, Velez M, Harrow C. (2009) The opioid-exposed newborn: assessment and pharmacologic management. J. Opioid. Manag. 5:47–55.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Kim E, et al. (2006) Mu- and kappa-opioids induce the differentiation of embryonic stem cells to neural progenitors. J. Biol. Chem. 281:33749–60.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hahn JW, etal. (2010) Mu and kappa opioids modulate mouse embryonic stem cell-derived neural progenitor differentiation via MAP kinases. J. Neurochem. 112:1431–41.CrossRefPubMedGoogle Scholar
  15. 15.
    Narita M, et al. (2006) Role of delta-opioid receptor function in neurogenesis and neuroprotection. J. Neurochem. 97:1494–505.CrossRefPubMedGoogle Scholar
  16. 16.
    Gonzalez-Nunez V, Rodriguez RE. (2009) The zebrafish: a model to study the endogenous mechanisms of pain. ILAR J. 50:373–86.CrossRefPubMedGoogle Scholar
  17. 17.
    de Velasco EM, Law PY, Rodriguez RE. (2009) Mu opioid receptor from the zebrafish exhibits functional characteristics as those of mammalian mu opioid receptor. Zebrafish. 6:259–68.CrossRefGoogle Scholar
  18. 18.
    Gonzalez Nunez V, Gonzalez Sarmiento R, Rodriguez RE. (2003) Characterization of zebrafish proenkephalin reveals novel opioid sequences. Brain Res. Mol. Brain Res. 114:31–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Gonzalez-Nunez V, Gonzalez-Sarmiento R, Rodriguez RE. (2003) Identification of two proopiomelanocortin genes in zebrafish (Danio rerio). Brain Res. Mol. Brain Res. 120:1–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Gonzalez-Nunez V, Toth G, Rodriguez RE. (2007) Endogenous heptapeptide Met-enkephalin-Gly-Tyr binds differentially to duplicate delta opioid receptors from zebrafish. Peptides. 28:2340–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Gonzalez-Nunez V, Marron Fernandez de Velasco E, Arsequell G, Valencia G, Rodriguez RE. (2007) Identification of dynorphin a from zebrafish: a comparative study with mammalian dynorphin A. Neuroscience. 144:675–84.CrossRefPubMedGoogle Scholar
  22. 22.
    Kimmel CB, Ballard WW, Kimmel SR, Ullmann B, Schilling TF. (1995) Stages of embryonic development of the zebrafish. Dev. Dyn. 203:253–310.CrossRefPubMedGoogle Scholar
  23. 23.
    European Parliament; Council of the EU. (2010) Directive 2010/63/UE of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes. Off. J. European Union. 53:L 276/33–79.Google Scholar
  24. 24.
    (2005) 17344: REAL DECRETO 1201/2005, de 10 de octubre, sobre proteccion de los animales utilizados para experimentacion y otros fines cientificos. Boletin Oficial del Estado (BOE). 252:34367–34391 252.Google Scholar
  25. 25.
    Committee for the Update of the Guide for the Care and Use of Laboratory Animals, Institute for Laboratory Animal Research, Division on Earth and Life Studies, National Research Council of the National Academies. (2011) Guide for the Care and Use of Laboratory Animals. 8th edition. Washington (DC): National Academies Press. [cited 2013 Jan 30]. Available from: https://doi.org/oacu.od.nih.gov/regs/Google Scholar
  26. 26.
    Cheng Y, Prusoff WH. (1973) Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem. Pharmacol. 22:3099–108.CrossRefPubMedGoogle Scholar
  27. 27.
    Gonzalez-Nunez V, Nocco V, Budd A. (2010) Characterization of drCol 15a1b: a novel component of the stem cell niche in the zebrafish retina. Stem Cells. 28:1399–411.CrossRefPubMedGoogle Scholar
  28. 28.
    Pfaffl MW, Horgan GW, Dempfle L. (2002) Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res. 30:e36.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Rodriguez RE, et al. (2000) Characterization of ZFOR1, a putative delta-opioid receptor from the teleost zebrafish (Danio rerio). Neurosci. Lett. 288:207–10.CrossRefPubMedGoogle Scholar
  30. 30.
    Pinal-Seoane N, et al. (2006) Characterization of a new duplicate delta-opioid receptor from zebrafish. J. Mol. Endocrinol. 37:391–403.CrossRefPubMedGoogle Scholar
  31. 31.
    Bojnik E, et al. (2011) Phylogenetic diversity and functional efficacy of the C-terminally expressed heptapeptide unit in the opioid precursor polypeptide proenkephalin A. Neuroscience. 178:56–67.CrossRefPubMedGoogle Scholar
  32. 32.
    Bradford CS, Walthers EA, Stanley DJ, Baugh MM, Moore FL. (2006) Delta and mu opioid receptors from the brain of a urodele amphibian, the rough-skinned newt Taricha granulosa: cloning, heterologous expression, and pharmacological characterization. Gen. Comp. Endocrinol. 146:275–90.CrossRefPubMedGoogle Scholar
  33. 33.
    Hao S, Hu J, Fink DJ. (2009) Transgene-mediated enkephalin expression attenuates signs of naloxone-precipitated morphine withdrawal in rats with neuropathic pain. Behav. Brain Res. 197:84–9.CrossRefPubMedGoogle Scholar
  34. 34.
    Vats ID, et al. (2009) Endogenous peptide: Metenkephalin-Arg-Phe, differently regulate expression of opioid receptors on chronic treatment. Neuropeptides. 43:355–62.CrossRefPubMedGoogle Scholar
  35. 35.
    Fang Y, Kelly MJ, Ronnekleiv OK. (1998) Proopiomelanocortin (POMC) mRNA expression: distribution and region-specific down-regulation by chronic morphine in female guinea pig hypothalamus. Brain Res. Mol. Brain Res. 55:1–8.CrossRefPubMedGoogle Scholar
  36. 36.
    Nieto MM, Wilson J, Cupo A, Roques BP, Noble F. (2002) Chronic morphine treatment modulates the extracellular levels of endogenous enkephalins in rat brain structures involved in opiate dependence: a microdialysis study. J. Neurosci. 22:1034–41.CrossRefPubMedGoogle Scholar
  37. 37.
    Turchan J, Lason W, Budziszewska B, Przewlocka B. (1997) Effects of single and repeated morphine administration on the prodynorphin, proenkephalin and dopamine D2 receptor gene expression in the mouse brain. Neuropeptides. 31:24–8.CrossRefPubMedGoogle Scholar
  38. 38.
    Yukhananov RY, Handa RJ. (1997) Effect of morphine on proenkephalin gene expression in the rat brain. Brain Res. Bull. 43:349–56.CrossRefPubMedGoogle Scholar
  39. 39.
    Gieryk A, Ziolkowska B, Solecki W, Kubik J, Przewlocki R. (2010) Forebrain PENK and PDYN gene expression levels in three inbred strains of mice and their relationship to genotype-dependent morphine reward sensitivity. Psychopharmacology (Berl.). 208:291–300.CrossRefPubMedGoogle Scholar
  40. 40.
    Sanchez-Cardoso P, et al. (2007) Modulation of the endogenous opioid system after morphine self-administration and during its extinction: a study in Lewis and Fischer 344 rats. Neuropharmacology. 52:931–48.CrossRefPubMedGoogle Scholar
  41. 41.
    Kieffer BL, Gaveriaux-Ruff C. (2002) Exploring the opioid system by gene knockout. Prog. Neurobiol. 66:285–306.CrossRefPubMedGoogle Scholar
  42. 42.
    Takasaki Y, Wolff RA, Chien GL, van Winkle DM. (1999) Met5-enkephalin protects isolated adult rabbit cardiomyocytes via delta-opioid receptors. Am. J. Physiol. 277:H2442–50.PubMedGoogle Scholar
  43. 43.
    Reyes BA, et al. (2012) Opiate agonist-induced redistribution of Wntless, a mu-opioid receptor interacting protein, in rat striatal neurons. Exp. Neurol. 233:205–13.CrossRefPubMedGoogle Scholar
  44. 44.
    McLaughlin PJ, Verderame MF, Hankins JL, Zagon IS. (2007) Overexpression of the opioid growth factor receptor downregulates cell proliferation of human squamous carcinoma cells of the head and neck. Int. J. Mol. Med. 19:421–8.PubMedGoogle Scholar

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Authors and Affiliations

  • Veronica Gonzalez-Nunez
    • 1
    • 2
  • Ada Jimenez González
    • 1
    • 2
  • Katherine Barreto-Valer
    • 1
    • 2
  • Raquel E. Rodríguez
    • 1
    • 2
  1. 1.Department of Biochemistry and Molecular Biology, Faculty of Medicine, Instituto de Neurociencias de Castilla y León (INCyL)University of SalamancaSalamancaSpain
  2. 2.Institute of Biomedical Research of Salamanca (IBSAL)SalamancaSpain

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