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 CO 2 . In the other experiment, apneic threshold PaCO 2 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.

M3-receptor activation counteracts opioid-mediated apneusis, but the apneusis per se is not necessarily related to an impaired M3 mechanism in rats

“…In conclusion, our results are consistent with previous reports showing interaction between opioidergic and cholinergic mechanisms in respiration in experimental animals (Berkenbosch et al, 1994;Bourke et al, 1984;Sakuraba et al, 2009;Tsujita et al, 2007;Weinstock et al, 1981) and in human subjects (Snir-Mor et al, 1983). Naloxone not only counteracts morphine-induced side effects but also inhibits morphine-induced analgesia (Bowdle, 1998).…”

“…Moreover, the central chemosensitive area is proposed to be one of the sites of opioid action, because morphine decreases the sensitivity of hypercapnic response and because an antagonist of opioid receptors, naloxone, augments the respiratory neuronal response to CO 2 (Shook et al, 1990;Yeadom and Kitchen, 1989). It is reported that the opioid-induced respiratory depression is recovered by anticholinesterases, physostigmine (Berkenbosch et al, 1994;Bourke et al, 1984;Weinstock et al, 1980Weinstock et al, , 1981 and donepezil (Sakuraba et al, 2009;Tsujita et al, 2007). These findings raise a possibility that opioids negatively interact with the CO 2 -sensitive cholinergic transmission, presumably by depression of acetylcholine (ACh) release (Trouth et al, 1993).…”

Donepezil reverses buprenorphine-induced central respiratory depression in anesthetized rabbits

“…The experimental procedure has been described in detail elsewhere (Kuwana and Natsui, 1981;Okada et al 2004;Tsujita et al 2007). Briefly, 15 healthy rabbits (Japanese White, male, Sankyo laboratory, Tokyo, Japan) 2.35 ± 0.08 kg (1.98-2.97 kg) were anesthetized by intraperitoneal administration of 10 mg/kg ketamine (Sankyo Pharmaceutical, Tokyo, Japan) followed by intravenous administration of 40 mg/kg chloralose and 200 mg/kg urethane (Wako Pure Chemical, Osaka, Japan).…”

“…In our previous study, it was shown that donepezil, a long-acting synthetic drug widely used for Alzheimer's disease (Rho and Lipson, 1997), can reverse morphineinduced respiratory depression (Tsujita et al, 2007).…”

Donepezil: It is time to replace physostigmine in Anesthesiology

“…It appears to improve sedation and fatigue in patients receiving opioids for cancer pain and prevents the addictive effect of morphine. Also it might enhance the analgesic effect of morphine because spinal Ach enhances the analgesic effect of systemic morphine [6].…”