Diabetic neuropathy (DN) is a common complication of diabetes mellitus and is associated with structural changes in the nerves. Nerve damage happen as a result of many factors including metabolic disorders, oxidative and nitrosative stress, changes in the blood vessels that supply the peripheral nerves and changes in ion channel expression in peripheral fibres. However, the molecular basis for DN is poorly understood. Adenosine monophosphate activated protein kinase (AMPK) has been shown to regulate the activity of some kinases including protein kinase B (AKT), mitogen-activated protein kinases (MAPK) and mammalian target of rapamycin complex 1 (mTORC1) that represent important signalling pathways modulating the function of peripheral nociceptive neurons. Donepezil can activate AMPK and exerts neuroprotective effects. Diabetic mice showed reduced expression of p-AMPK in sciatic nerves with consequent activation of AKT/MAPK/4EBP1. In addition, a significant upregulation of the N-Methyl-D-aspartate (NMDA) receptors in spinal cord of diabetic mice was observed. Therefore, Donepezil could be a potential pharmacological agent for management of DN.