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


RESULTS
The 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.


CONCLUSIONS
In conclusion, we found that systemic administration of donepezil attenuated morphine-induced tolerance and apoptosis in the rat cerebral cortex and lumbar spinal cord.
Mozhdeh
M
Sharifipour
Esmaeal
E
Izadpanah
Bahram
B
Nikkhoo
Samad
S
Zare
Ali
A
Abdolmaleki
Katayoun
K
Hassanzadeh
Farshid
F
Moradi
Cellular and Molecular Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran. kambizhassanzadeh@gmail.com.
Kambiz
K
Hassanzadeh
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002490:Central Nervous System / Q000187:drug effects* / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D000077265:Donepezil; D004361:Drug Tolerance / Q000235:genetics*; D006801:Humans; D007189:Indans / Q000008:administration & dosage*; D009020:Morphine / Q000008:administration & dosage; D018696:Neuroprotective Agents / Q000008:administration & dosage; D059225:Nociception / Q000187:drug effects; D010147:Pain Measurement; D010880:Piperidines / Q000008:administration & dosage*; D051381:Rats; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology
D007189:Indans; D018696:Neuroprotective Agents; D010880:Piperidines; D009020:Morphine; D000077265:Donepezil