Donepezil attenuates the development of morphine tolerance in rats with cancer-induced bone pain: The role of cortical N-methyl-D-aspartate receptors

Cancer-induced bone pain (CIBP), which is associated with poor quality of life, is most commonly treated using opioids. However, long-term use of morphine for analgesia induces tolerance and can diminish the treatment's effectiveness. The mechanisms that underlie morphine tolerance have been reported to be related to the inflammation of the nervous system and hyperactivation of N-methyl-D-aspartate receptors (NMDARs). Donepezil is an anti-inflammatory and neuroprotective drug that is thought to alleviate morphine tolerance. In this study, we aimed to investigate the effect of three different dosages of donepezil (1, 1.5 and 2 mg/kg) on morphine tolerance in rats with CIBP, and the possible involvement of donepezil-mediated NMDAR subunit 1 (NR1). We found that donepezil can prolong the analgesic efficacy of morphine and delay the development of chronic morphine tolerance. Furthermore, continuous morphine injection increased the expression of NR1, and this was suppressed by co-administration with donepezil using both western blotting and immunofluorescence. Our findings demonstrate that donepezil has the potential to attenuate morphine tolerance, possibly by inhibiting NR1 activity in the cortex.