5-HT1A Receptor Agonist Befiradol Reduces Fentanyl-induced Respiratory Depression, Analgesia, and Sedation in Rats. (February 2015)

• Record Type: Journal Article
• Authors: Ren, Jun; Ding, Xiuqing; Greer, John J.
• Is Part Of: Anesthesiology. Volume 122:Number 2(2015)
• Publication Date: 2015-02
• Subjects: Anesthesiology -- Periodicals; Anesthetics -- Periodicals; Anesthesia -- Periodicals; 617.9605
• DOI: 10.1097/ALN.0000000000000490
• Languages: English
• ISSNs: 0003-3022

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background:</title> <p>There is an unmet clinical need to develop a pharmacological therapy to counter opioid-induced respiratory depression without interfering with analgesia or behavior. Several studies have demonstrated that 5-HT<sub>1A</sub> receptor agonists alleviate opioid-induced respiratory depression in rodent models. However, there are conflicting reports regarding their effects on analgesia due in part to varied agonist receptor selectivity and presence of anesthesia. Therefore the authors performed a study in rats with befiradol (F13640 and NLX-112), a highly selective 5-HT<sub>1A</sub> receptor agonist without anesthesia.</p> </sec> <sec> <title>Methods:</title> <p>Respiratory neural discharge was measured using <italic>in vitro</italic> preparations. Plethysmographic recording, nociception testing, and righting reflex were used to examine respiratory ventilation, analgesia, and sedation, respectively.</p> </sec> <sec> <title>Results:</title> <p>Befiradol (0.2 mg/kg, n = 6) reduced fentanyl-induced respiratory depression (53.7 ± 5.7% of control minute ventilation 4 min after befiradol <italic>vs</italic>. saline 18.7 ± 2.2% of control, n = 9; <italic>P</italic> < 0.001), duration of analgesia (90.4 ± 11.6 min <italic>vs.</italic> saline 130.5 ± 7.8 min; <italic>P</italic> = 0.011), duration of sedation (39.8 ± 4 min <italic>vs</italic>. saline 58 ± 4.4 min; <italic>P</italic> = 0.013); and induced baseline hyperventilation, hyperalgesia, and "behavioral syndrome" in nonsedated rats. Further, the befiradol-induced alleviation of opioid-induced respiratory depression involves sites or mechanisms not functioning <italic>in vitro</italic> brainstem–spinal cord and medullary slice preparations.</p> </sec> <sec> <title>Conclusions:</title> <p>The reversal of opioid-induced respiratory depression and sedation by befiradol in adult rats was robust, whereas involved mechanisms are unclear. However, there were adverse concomitant decreases in fentanyl-induced analgesia and altered baseline ventilation, nociception, and behavior.</p> </sec> </abstract>