title: Antagonism of morphine-induced central respiratory depression by donepezil in the anesthetized rabbit.
abstract: Morphine is often used in cancer pain and postoperative analgesic management but induces respiratory depression. Therefore, there is an ongoing search for drug candidates that can antagonize morphine-induced respiratory depression but have no effect on morphine-induced analgesia. Acetylcholine is an excitatory neurotransmitter in central respiratory control and physostigmine antagonizes morphine-induced respiratory depression. However, physostigmine has not been applied in clinical practice because it has a short action time, among other characteristics. We therefore asked whether donepezil (a long-acting acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease) can antagonize morphine-induced respiratory depression. Using the anesthetized rabbit as our model, we measured phrenic nerve discharge as an index of respiratory rate and amplitude. We compared control indices with discharges after the injection of morphine and after the injection of donepezil. Morphine-induced depression of respiratory rate and respiratory amplitude was partly antagonized by donepezil without any effect on blood pressure and end-tidal C02. In the other experiment, apneic threshold PaC02 was also compared. Morphine increased the phrenic nerve apnea threshold but this was antagonized by donepezil. These findings indicate that systemically administered donepezil partially restores morphine-induced respiratory depression and morphine-deteriorated phrenic nerve apnea threshold in the anesthetized rabbit.
authors.affiliation: Department of Anesthesiology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Tsujita
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sakuraba
authors.forename: Junya
authors.initials: J
authors.lastname: Kuribayashi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hosokawa
authors.forename: Eiki
authors.initials: E
authors.lastname: Hatori
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Okada
authors.forename: Masanori
authors.initials: M
authors.lastname: Kashiwagi
authors.forename: Junzo
authors.initials: J
authors.lastname: Takeda
authors.forename: Shun-Ichi
authors.initials: S
authors.lastname: Kuwana
mesh_terms: D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003864:Depression, Chemical; D000077265:Donepezil; D007189:Indans / Q000494:pharmacology*; D008297:Male; D009020:Morphine / Q000037:antagonists & inhibitors*; D010791:Phrenic Nerve / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D011817:Rabbits; D012119:Respiration / Q000187:drug effects*
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D009020:Morphine; D000077265:Donepezil