A brain-targeted ampakine compound protects against opioid-induced respiratory depression.

Abstract

The use of opioid drugs for pain relief can induce life-threatening respiratory depression. Although naloxone effectively counteracts opioid-induced respiratory depression, it diminishes the efficacy of analgesia. Our studies indicate that ampakines, in particular, a brain-targeted compound XD-8-17C, are able to reverse respiratory depression without affecting analgesia at relatively low doses. Mice and rats were subcutaneously or intravenously injected with the opioid agonist TH-030418 to induce moderate or severe respiratory depression. XD-8-17C was intravenously administered before or after TH-030418. The effect of XD-8-17C on opioid-induced respiratory depression was evaluated in terms of the opioid-induced acute death rate, arterial blood gas analysis and pulmonary function tests. In addition, the hot-plate test was conducted to investigate whether XD-8-17C influenced opioid-induced analgesia. Pre-treatment with XD-8-17C significantly reduced opioid-induced acute death, and increased the median lethal dose of TH-030418 by 4.7-fold. Blood gas analysis and pulmonary function tests demonstrated that post-treatment with XD-8-17C alleviated respiratory depression, as indicated by restoration of arterial blood gas (pO2, sO2, cK+) and lung function parameters (respiratory frequency, minute ventilation) to the normal range. The hot-plate test showed that XD-8-17C had no impact on the antinociceptive efficacy of morphine. The ability of XD-8-17C to reverse opioid-induced respiratory depression has the potential to increase the safety and convenience of opioid treatment. These findings contribute to the discovery of novel therapeutic agents that protect against opioid-induced respiratory depression without loss of analgesia.

• Authors: Wei Dai, Dian Xiao, Xiang Gao, Xin-Bo Zhou, Tong-Yu Fang, Zheng Yong, Rui-Bin Su
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 809 Pg. 122-129 (Aug 15 2017) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 28502631 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Analgesics, Opioid
• Oxadiazoles

Topics

• Analgesics, Opioid (adverse effects)
• Animals
• Blood Gas Analysis
• Brain (drug effects, metabolism)
• Female
• Male
• Mice
• Oxadiazoles (pharmacology, therapeutic use)
• Rats
• Respiratory Insufficiency (blood, chemically induced, drug therapy)