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Current studies have indicated that donepezil as a cholinesterase inhibitor can attenuate morphine-induced tolerance. The present study aimed to evaluate the possible role of N -methyl- d -aspartate receptors (NMDARs), protein kinase C (PKC) and CaM-dependent kinase II (CaMKII) pathways in this effect. Female Wistar rats received daily morphine (10 mg/kg, i.p.) alone or in combination with donepezil (1.5 or 2 mg/kg, gavaged) for 14 days. The analgesic effect was assessed by Von-frey, hotplate and tail flick test. On the 15th day, the periaqueductal gray (PAG) and lumbar spinal cord of rats were dissected. Then, protein levels of NMDAR-NR1, NR2B, PKCγ and CaMKIIα were tested using Western blot method. The results showed that morphine tolerance was seen after 8–10 days of injection compared with control group, while daily co-administration of donepezil with morphine prolonged the occurrence of analgesic tolerance. Western blot showed that morphine significantly increased NR1, PKCγ and CaMKIIα expressions in PAG, and significantly increased PKCγ and CaMKIIα in spinal cord. In contrast, donepezil downregulated NR1 and PKCγ in PAG, and downregulated PKCγ and CaMKIIα in spinal cord. Moreover, donepezil alone activates NR1 and NR2B in spinal cord, which needs to be further studied. Thus, the present results suggest that the attenuation effects of donepezil on morphine tolerance are possibly mediated by preventing morphine-induced upregulations in NR1, PKCγ and CaMKIIα expressions. • Donepezil inhibits morphine-induced NR1 and PKCγ upregulation in PAG. • Donepezil inhibits morphine-induced PKCγ and CaMKIIα upregulation in spinal cord. • Donepezil alone activates NR1 and NR2B in spinal cord, which needs to be further studied. [ABSTRACT FROM AUTHOR]