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

• Published in: European journal of pharmacology Vol. 809; pp. 122 - 129
• Main Authors: Dai, Wei, Xiao, Dian, Gao, Xiang, Zhou, Xin-Bo, Fang, Tong-Yu, Yong, Zheng, Su, Rui-bin
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.08.2017
• Subjects: AMPA receptor; Ampakine; Analgesics, Opioid - adverse effects; Animals; Blood Gas Analysis; Brain - drug effects; Brain - metabolism; Female; Male; Mice; Opioid-induced respiratory depression; Oxadiazoles - pharmacology; Oxadiazoles - therapeutic use; Prodrugs; Rats; Respiratory Insufficiency - blood; Respiratory Insufficiency - chemically induced; Respiratory Insufficiency - drug therapy; Morphine hydrochloride (PubChem CID: 5464110); AMPA receptor; Naloxone hydrochloride dihydrate (PubChem CID: 20112022); Prodrugs; Ampakine; Opioid-induced respiratory depression; Hydroxypropyl-β-cyclodextrin (PubChem CID: 44134771)
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2017.05.025

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.