Involvement of Enhanced Gene Expression of Anti-Opioid Systems in Morphine Tolerance and Dependence

  • Akira Yoshida
  • Makoto Inoue
  • Hiroshi Ueda
Part of the Advances in Behavioral Biology book series (ABBI, volume 53)


Chronic morphine application induces such side effects as tolerance and physical dependence, which have been speculated to be developed through neuronal plasticity of the central nervous system. Based on the assumption that the reduction of morphine analgesia during chronic treatment is mediated through anti-opioid systems in brain, several attempts have been done to characterize morphine analgesic tolerance by use of blocking agents for anti-opioid systems.1 Glutamaterigic system using NMD A receptor (NMDAR) was the first to be demonstrated as an anti-opioid system to develop morphine tolerance and dependence.2 On the other hand, nociceptin/orphanin FQ (N/OFQ) was discovered to be an endogenous ligand for opioid receptor-like orphan receptor, ORL1, which is now called NOPR.3, 4 From the initial pharmacological studies N/OFQ has been reported to be an anti-opioid peptide.5, 6 Using this idea, we have firstly clarified that N/OFQ system through NOPR is also involved in the development of morphine tolerance and dependence, by use of NOPR-/- mice, which lack the gene encoding NOPR.7, 8 However, as it is often observed that knock-out mice develop some compensatory changes during development and growth, we have studied the involvement of NOPR in such mechanisms by use of specific antagonist (J-113397).9 Here, we report the characterization and their possible molecular mechanisms of both NMDAR and NOPR systems involved in the development of morphine tolerance and dependence.


NMDA Receptor Ventral Tegmental Area Morphine Tolerance Morphine Analgesia Rostral Ventromedial Medulla 
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  1. 1.
    J. M. Mitchell, A. I. Basbaum and H. L. Fields, A locus and mechanism of action for associative morphine tolerance, Nat Neurosci 3(1), 47–53. (2000).PubMedCrossRefGoogle Scholar
  2. 2.
    K. A. Trujillo and H. Akil, Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801, Science 251(4989), 85–87. (1991).PubMedCrossRefGoogle Scholar
  3. 3.
    J. C. Meunier, C. Mollereau, L. Toll, C. Suaudeau, C. Moisand, P. Alvinerie, J. L. Butour, J. C. Guillemot, P. Ferrara, B. Monsarrat and et al., Isolation and structure of the endogenous agonist of opioid receptor- like ORL1 receptor, Nature 377(6549), 532–535. (1995).PubMedCrossRefGoogle Scholar
  4. 4.
    R. K. Reinscheid, H. P. Nothacker, A. Bourson, A. Ardati, R. A. Henningsen, J. R. Bunzow, D. K. Grandy, H. Langen, F. J. Monsma, Jr. and O. Civelli, Orphanin FQ: a neuropeptide that activates an opioidlike G protein- coupled receptor, Science 270(5237), 792–794. (1995).PubMedCrossRefGoogle Scholar
  5. 5.
    J. H. Tian, W. Xu, Y. Fang, J. S. Mogil, J. E. Grisel, D. K. Grandy and J. S. Han, Bidirectional modulatory effect of orphanin FQ on morphine-induced analgesia: antagonism in brain and potentiation in spinal cord of the rat, Br J Pharmacol 120(4), 676–680. (1997).PubMedCrossRefGoogle Scholar
  6. 6.
    M. M. Heinricher, S. McGaraughty and D. K. Grandy, Circuitry underlying antiopioid actions of orphanin FQ in the rostral ventromedial medulla, J Neurophysiol 78(6), 3351–3358. (1997).PubMedGoogle Scholar
  7. 7.
    H. Ueda, T. Yamaguchi, S. Tokuyama, M. Inoue, M. Nishi and H. Takeshima, Partial loss of tolerance liability to morphine analgesia in mice lacking the nociceptin receptor gene, Neurosci Lett 237(2–3), 136–138. (1997).PubMedCrossRefGoogle Scholar
  8. 8.
    H. Ueda, M. Inoue, H. Takeshima and Y. Iwasawa, Enhanced spinal nociceptin receptor expression develops morphine tolerance and dependence, J Neurosci 20(20), 7640–7647. (2000).PubMedGoogle Scholar
  9. 9.
    H. Kawamoto, S. Ozaki, Y. Itoh, M. Miyaji, S. Arai, H. Nakashima, T. Kato, H. Ohta and Y. Iwasawa, Discovery of the first potent and selective small molecule opioid receptor-like (ORL1) antagonist: 1- [(3R, 4R)-1 -cyclooctylmethyl-3- hydroxymethyl-4-piperidyl]-3-ethyl-1, 3-dihydro-2H-benzimidazol-2-one (J-113397), J Med Chem 42(25), 5061–5063. (1999).PubMedCrossRefGoogle Scholar
  10. 10.
    M. Zimmermann, Ethical guidelines for investigations of experimental pain in conscious animals, Pain 16(2), 109–110. (1983).PubMedCrossRefGoogle Scholar
  11. 11.
    H. Ueda, M. Inoue and T. Matsumoto, Protein kinase C-mediated inhibition of mu-opioid receptor internalization and its involvement in the development of acute tolerance to peripheral mu-agonist analgesia, J Neurosci 21(9), 2967–2973. (2001).PubMedGoogle Scholar
  12. 12.
    Y Kushima, C. Nishio, T. Nonomura and H. Hatanaka, Effects of nerve growth factor and basic fibroblast growth factor on survival of cultured septal cholinergic neurons from adult rats, Brain Res 598(1–2), 264–270. (1992).PubMedCrossRefGoogle Scholar
  13. 13.
    G. Tezel and M. B. Wax, The mechanisms of hsp27 antibody-mediated apoptosis in retinal neuronal cells, J Neurosci 20(10), 3552–3562. (2000).PubMedGoogle Scholar

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© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Akira Yoshida
  • Makoto Inoue
  • Hiroshi Ueda
    • 1
  1. 1.Department of Molecular Pharmacology and NeuroscienceNagasaki University School of Pharmaceutical SciencesNagasakiJapan

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