期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：1
页码：279-284
DOI：10.1073/pnas.1419183112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceMany assume that morphine tolerance is a continually progressive response, based mainly upon preclinical studies typically lasting a week or less. Yet, clinicians have long appreciated the ability to manage cancer pain in patients with stable opioid doses for months, implying that extended dosing may eventually stabilize the level of tolerance. To reconcile these differences, we examined tolerance over 6 wk and show that extended morphine dosing leads to progressive tolerance for 3 wk that then stabilizes for up to 6 wk and is associated with increases in the abundance of mu opioid receptor splice variant mRNA levels of as much as 300-fold. 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 points was dependent upon the dose of morphine. The mRNA levels for the various mu opioid receptor splice variants were 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.
