From the Department of Physiology, Neuroscience, and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada (J.R., X.D., J.J.G.); and the Alberta Innovates Health Sciences Foundation, Edmonton, Alberta, Canada (J.J.G.).
Anesthesiology. 2015 Feb;122(2):424-34. doi: 10.1097/ALN.0000000000000490.
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-HT1A 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-HT1A receptor agonist without anesthesia.
Respiratory neural discharge was measured using in vitro preparations. Plethysmographic recording, nociception testing, and righting reflex were used to examine respiratory ventilation, analgesia, and sedation, respectively.
Befiradol (0.2 mg/kg, n = 6) reduced fentanyl-induced respiratory depression (53.7 ± 5.7% of control minute ventilation 4 min after befiradol vs. saline 18.7 ± 2.2% of control, n = 9; P < 0.001), duration of analgesia (90.4 ± 11.6 min vs. saline 130.5 ± 7.8 min; P = 0.011), duration of sedation (39.8 ± 4 min vs. saline 58 ± 4.4 min; P = 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 in vitro brainstem-spinal cord and medullary slice preparations.
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.
开发一种既能对抗阿片类药物引起的呼吸抑制又不影响镇痛或行为的药理学治疗方法，存在未满足的临床需求。有几项研究表明，5-HT1A 受体激动剂可缓解啮齿动物模型中阿片类药物引起的呼吸抑制。然而，由于激动剂受体选择性的差异和麻醉的存在，它们对镇痛的影响存在相互矛盾的报告。因此，作者在使用 befiradol（F13640 和 NLX-112）的大鼠中进行了一项研究，befiradol 是一种高度选择性的 5-HT1A 受体激动剂，没有使用麻醉。
使用体外制剂测量呼吸神经放电。体积描记法记录、疼痛测试和翻正反射分别用于检查呼吸通气、镇痛和镇静。
befiradol（0.2mg/kg，n=6）降低了芬太尼引起的呼吸抑制（befiradol 后 4 分钟呼吸分钟通气量为对照的 53.7±5.7%，盐水为对照的 18.7±2.2%，n=9；P＜0.001）、镇痛持续时间（90.4±11.6min 与盐水 130.5±7.8min；P=0.011）、镇静持续时间（39.8±4min 与盐水 58±4.4min；P=0.013）；并在非镇静大鼠中诱导基础过度通气、痛觉过敏和“行为综合征”。此外，befiradol 缓解阿片类药物引起的呼吸抑制涉及体外脑干-脊髓和延髓切片制剂中不起作用的部位或机制。
befiradol 逆转成年大鼠阿片类药物引起的呼吸抑制和镇静作用强大，而涉及的机制尚不清楚。然而，芬太尼诱导的镇痛作用降低，以及基础通气、疼痛感知和行为改变。
