A new pharmacological role for donepezil: attenuation of morphine-induced tolerance and apoptosis in rat central nervous system

Abstract

BackgroundTolerance to the analgesic effect of opioids is a pharmacological phenomenon that occurs after their prolonged administration. It has been shown that morphine-induced tolerance is associated with apoptosis in the central nervous system and neuroprotective agents which prevented apoptosis signaling could attenuate tolerance to the analgesic effects. On the other hand donepezil, an acetylcholinesterase inhibitor, has been reported to have neuroprotective effects. Therefore in this study, the effect of systemic administration of donepezil on morphine-induced tolerance and apoptosis in the rat cerebral cortex and lumbar spinal cord was evaluated. Various groups of rats received morphine (ip) and different doses of donepezil (0, 0.5, 1, 1.5 mg/kg/day). Nociception was assessed using tail flick apparatus. Tail flick latency was recorded when the rat shook its tail. For apoptosis assay other groups of rats received the above treatment and apoptosis was evaluated by in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method.ResultsThe results showed that administration of donepezil (0.5, 1, 1.5 mg/kg, ip) delayed the morphine tolerance for 9, 12 and 17 days, respectively. Furthermore pretreatment injection of donepezil attenuated the number of apoptotic cells in the cerebral cortex and lumbar spinal cord compared to the control group.ConclusionIn conclusion, we found that systemic administration of donepezil attenuated morphine-induced tolerance and apoptosis in the rat cerebral cortex and lumbar spinal cord.

The Cholinergic System as a Treatment Target for Opioid Use Disorder

“…Regarding effects on analgesia, both donepezil or rivastigmine increased morphine’s acute analgesic effects [138]. Donepezil, rivastigmine and scopolamine each attenuated the development of tolerance to morphine’s analgesic effects [134, 138, 139]. In contrast, mecamylamine did not affect tolerance to morphine’s analgesic effects [126].…”

Early single Aspirin-triggered Lipoxin blocked morphine anti-nociception tolerance through inhibiting NALP1 inflammasome: Involvement of PI3k/Akt signaling pathway

“…First, sustained morphine incubation on primary cultured neurons precludes the involvement of glia cells in the development of tolerance regardless of the intimate interfaces or crosstalk between neurons and glia in this process (Chen et al, 2012b). Second, there is concern about chronic morphine-induced neurotoxicity and neuronal apoptosis both in vivo and in vitro (Mao et al, 2002b;Sharifipour et al, 2014;Svensson et al, 2008). Although the final concentration used in our study was the most commonly used dose in in vitro experiments, cultures derived from different tissues with different treatment paradigms or even during different developmental stages might respond differently to certain stimulants (Ma et al, 2001).…”

Present and Future Pharmacological Treatments for Opioid Addiction

“…Cholinesterase inhibitors, currently used to treat Alzheimer's disease, including donepezil, rivastigmine, and galantamine, increase cholinergic activity and can be potential therapeutic targets in opioid abuse and dependence treatments [132]. Preclinical models have demonstrated that these cholinesterase inhibitors prevented morphine tolerance and attenuated the acquisition and expression of morphine CPP [133].…”