Effects Of Donepezil On Morphine Analgesia And Tolerance In Rats With Cancer-induced Bone Pain

Objective:According to statistics,about 60-80%of patients with advanced cancer have suffered from varying degrees of pain,approximately 30%of which have suffered from persistent severe pain.Primary bone tumor or bone metastases are the most common causes for cancer pain.Although there are various methods applying to treat cancer-induced bone pain,morphine is still the gold standard for the clinic treatment of severe cancer pain.The chronic use of morphine leads to the development of tolerance to their analgesic effects,which seriously hampers the use of morphine in clinic.Some studies have shown that donepezil provides anti-apoptotic effects associated with the prevention of morphine tolerance to the analgesic effect.However,there is no relevant study about the effects of donepezil in morphine-tolerant rats with cancer-induced bone pain reported until now.In this study,we aim to observe the characteristic of morphine tolerance model in rats with cancer-induced bone pain induced by Walker256 breast cancer cell and investigate the effects of donepezil on morphine analgesia and tolerance in rats with cancer-induced bone pain.Methods:The 36 female Wistar rats,weighing 160-200g,were randomly divided into 6 groups(n=6 each):sham group(S),chronic morphine tolerance group(M),bone cancer pain group(B),bone cancer pain+morphine tolerance group(BM),bone cancer pain+morphine tolerance+low dose donepezil group(BMD1),bone cancer pain+morphine tolerance+high dose donepezil group(BMD1.5).The 10?L Walker 256 breast cancer cells(11×05)were injected into left tibial bone marrow cavity of rats to induce cancer-induced bone pain.M group were injected lO?L normal saline instead.Morphine tolerance was induced by subcutaneous(s.c.)injection of morphine(10mg/kg,twice a day)for 14 consecutive days,starting from the 15th day after operation in M,BM,BMD1,BMD1.5 groups.From the 15th day after operation,intragastrical(i.g.)donepezil(1mg/kg or 1.5mg/kg)was administered once a day for 14 consecutive days in BMD1,BMD1.5 groups respectively.The paw withdrawal thresholds(PWT)and thermal withdrawal latency(TWL)were measured before operation and at day 3,6,9,12,15,17,19,21,23,25,27 after operation.The degree of bone destruction was assessed by X-ray film at day 14 after operation.Results:At day 9 and 12 after the cancer cells were inoculated,PWT in group B,group BM,group BMDl,group BMD1.5 were significantly decreased compared with those in group S and group M(P<0.05).After taking an X-ray of left tibial bone of rats at day 14 after operation,we found bone destruction in group B.At day 19 after operation(administration of morphine for 5 consecutive days),the PWT and TWL in group BM decreased to baseline,at day 21 after operation,the PWT,TWL and MPE in group M decreased to baseline.At day 15 after operation,the MPE in group BMD1.5 were significantly lower than those in group BM(P<0.01).At day 27 after operation,the MPE in group BMD1 decreased to the same level of the group BM(P>0.05).However,the MPE in group BMD1.5 were significantly higher than those in group BM during the whole experiment period(p<0.05 or p<0.01).Conclusion:With the subcutaneous injection of morphine(10mg/kg)for 5 consecutive days in rats with bone cancer pain,the morphine-tolerant rats with cancer-induced bone pain model can be established.Donepezil enhance acute antinociceptive effects of morphine.The combination of morphine and donepezil can delay the development of morphine tolerance in rats with bone cancer pain.