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 ED 50 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 ED 50 . 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.analgesia | opiate receptor | opioid | splice variant | MOR-1 P reclinical studies have established that tolerance progressively increases over time (1). 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 stable despite the continued administration of a fixed morphine dose (2, 3). However, the animal studies used short-term opioid exposure, which differs from the clinical experience, where patients are often treated on steady opioid doses for many months. In an effort to reconcile these divergent observations, we extended morphine treatment of mice for up to 6 wk and determined morphine ED 50 values and changes in mRNA levels of the splice variants of the mu-opioid receptor gene Oprm1 in a range of brain regions.Morphine tolerance is a complex response involving many processes (3). Blockade of the NMDA/nitric oxide cascade provided the first evidence that tolerance could be minimized and/or reversed pharmacologically (4-13). Morphine tolerance also can be prevented with delta-opioid receptor antagonists (14, 15) by antisense down-regulation of the delta-opioid receptor (16) and in a delta-opioid receptor KO mouse (17,18). A number of cellular factors have been implicated, including desensitization and trafficking (19-21). Even dispositional factors influence tolerance (22-26). Chronic morphine up-regulates the expression of P-glycoprotein and multidrug resistant-...