Although micro
opioid receptor (MOR) agonists are used for treatment of most types of
pain, a recent study has suggested that the sensitivity of
bone cancer pain to systemic
morphine was lower than that of inflammatory
pain. However, the reasons for this have remained unclear. In this study, MOR expression and the
analgesic effects of
morphine in a
bone cancer model were compared with those in an inflammatory
pain model. A
bone cancer pain model and an inflammatory
pain model were made by implantation of
sarcoma cells into the intramedullary space of the femur and hind-paw injection of complete
Freund's adjuvant (CFA), respectively. In a behavioral study,
sarcoma-implanted mice showed flinching behavior of magnitude comparable to that induced by CFA injection. The flinching behavior of
sarcoma-implanted mice was less sensitive to intrathecal
morphine than that of CFA-injected mice. Western blot analysis showed that MOR expression in the dorsal root ganglion (DRG) ipsilateral to
sarcoma implantation was significantly reduced, while that in the DRG ipsilateral to CFA injection was increased. In
sarcoma-implanted mice, the percentage of MOR-positive DRG neuronal profiles was lower than that in control mice (30.3% vs. 45.2%). In particular, MOR expression was reduced among
calcitonin gene-related peptide- and transient receptor potential vanilloid subfamily 1-positive DRG neuronal profiles, which are considered to be involved in the generation of
bone cancer pain (from 61.5% to 41.5% and from 72.1% to 48.4%, respectively). These results suggest that down-regulation of MOR in the distinct populations of DRG neurons contributes to the fact that higher doses of
morphine are needed to produce
analgesia in
bone cancer as compared with those used in non-malignant inflammatory situations.