Stabilization of morphine tolerance with long-term dosing: Association with selective upregulation of mu-opioid receptor splice variant mRNAs Journal Article


Authors: Xu, J.; Faskowitz, A. J.; Rossi, G. C.; Xu, M.; Lu, Z.; Pan, Y. X.; Pasternak, G. W.
Article Title: Stabilization of morphine tolerance with long-term dosing: Association with selective upregulation of mu-opioid receptor splice variant mRNAs
Abstract: Chronic morphine administration is associated with the development of tolerance, both clinically and in animal models. Many assume that tolerance is a continually progressive response to chronic opioid dosing. However, clinicians have long appreciated the ability to manage cancer pain in patients for months on stable opioid doses, implying that extended dosing may eventually result in a steady state in which the degree of tolerance remains constant despite the continued administration of a fixed morphine dose. Preclinical animal studies have used short-term paradigms, typically a week or less, whereas the clinical experience is based upon months of treatment. Chronic administration of different fixed morphine doses produced a progressive increase in the ED50 that peaked at 3 wk in mice, consistent with prior results at shorter times. Continued morphine dosing beyond 3 wk revealed stabilization of the level of tolerance for up to 6 wk with no further increase in the ED50. The degree of tolerance at all time pointswas dependent upon the dose ofmorphine. The mRNA levels for the various mu opioid receptor splice variantswere assessed to determine whether stabilization of morphine tolerance was associated with changes in their levels. After 6 wk of treatment, mRNA levels of the variants increased as much as 300-fold for selected variants in specific brain regions. These findings reconcile preclinical and clinical observations regarding the development of morphine tolerance.
Keywords: controlled study; nonhuman; treatment duration; mouse; mus; clinical assessment; animal experiment; animal model; genetic variability; animalia; messenger rna; rat; alternative rna splicing; upregulation; morphine; opioid; analgesia; mu opiate receptor; brain region; receptor gene; drug stability; morphine tolerance; clinical observation; chronic drug administration; opiate receptor; short course therapy; mor-1; splice variant; pharmacological parameters; human; male; article
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 112
Issue: 1
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2015-01-06
Start Page: 279
End Page: 284
Language: English
DOI: 10.1073/pnas.1419183112
PROVIDER: scopus
PMCID: PMC4291645
PUBMED: 25535370
DOI/URL:
Notes: Export Date: 2 February 2015 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Yingxian Pan
    113 Pan
  2. Zhigang Lu
    11 Lu
  3. Gavril W Pasternak
    312 Pasternak
  4. Ming Ming Xu
    34 Xu
  5. Jin   Xu
    51 Xu