Donepezil reverses buprenorphine-induced central respiratory depression in anesthetized rabbits.
Buprenorphine is a mixed opioid receptor agonist-antagonist used in acute and chronic pain management. Although this agent's analgesic effect increases in a dose-dependent manner, buprenorphine-induced respiratory depression shows a marked ceiling effect at higher doses, which is considered to be an indicator of safety. Nevertheless, cases of overdose mortality or severe respiratory depression associated with buprenorphine use have been reported. Naloxone can reverse buprenorphine-induced respiratory depression, but is slow-acting and unstable, meaning that new drug candidates able to specifically antagonize buprenorphine-induced respiratory depression are needed in order to enable maximal analgesic effect without respiratory depression. Acetylcholine is an excitatory neurotransmitter in central respiratory control. We previously showed that a long-acting acetylcholinesterase inhibitor, donepezil, antagonizes morphine-induced respiratory depression. We have now investigated how donepezil affects buprenorphine-induced respiratory depression in anesthetized, paralyzed, and artificially ventilated rabbits. We measured phrenic nerve discharge as an Index of respiratory rate and amplitude, and compared discharges following the injection of buprenorphine with discharges following the injection of donepezil. Buprenorphine-induced suppression of the respiratory rate and respiratory amplitude was antagonized by donepezil (78.4 +/- 4.8 %, 92.3% +/- 22.8 % of control, respectively). These findings indicate that systemically administered donepezil restores buprenorphine-induced respiratory depression in anesthetized rabbits.
Department of Anesthesiology, Clinical Care Medicine, Kanagawa Dental College, Kanagawa, Japan. shigekisakuraba@gmail.com
Shigeki
S
Sakuraba
Miki
M
Tsujita
Hirofumi
H
Arisaka
Junzo
J
Takeda
Kazuichi
K
Yoshida
Shun-Ichi
S
Kuwana
D000818:Animals; D002047:Buprenorphine / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D000077265:Donepezil; D007189:Indans / Q000494:pharmacology*; D008297:Male; D009292:Narcotic Antagonists; D010791:Phrenic Nerve / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology*; D011817:Rabbits; D012131:Respiratory Insufficiency / Q000139:chemically induced / Q000188:drug therapy
D002800:Cholinesterase Inhibitors; D007189:Indans; D009292:Narcotic Antagonists; D010880:Piperidines; D002047:Buprenorphine; D000077265:Donepezil