Spinal and Systemic Action of the α2 Receptor Agonist Dexmedetomidine in Dogs: Antinociception and Carbon Dioxide Response
Spinal and Systemic Action of the α2 Receptor Agonist Dexmedetomidine in Dogs: Antinociception and Carbon Dioxide Response
复制标题
α2 受体激动剂右美托咪定对狗的脊柱和全身作用：镇痛和二氧化碳反应
作者：
M. Sabbe;J. Penning;G. Ozaki;T. Yaksh
背景：4aL2激动剂是脊椎分娩后的强效镇痛剂。本研究描述了在长期准备的犬鞘内、硬膜外、静脉和脑池内分娩后，右美托咪定的剂量依赖性抗伤害性作用和对呼吸功能的影响。方法：用慢性气管造口术准备犬，并训练其进行重复呼吸研究。然后，这些动物被准备好慢性腰椎鞘内、硬膜外或脑池内导管。结果：鞘内注射、硬膜外注射和静脉注射右旋美托咪定(剂量分别为1.80、10和15μg，达到皮肤抽搐最大效应的50%所需剂量)后，小鼠热性皮肤抽搐反应潜伏期和对机械挤压的缩爪反应均呈剂量依赖性增加，而脑室内注射右旋美托咪定(15μg)后则不明显，最大有效剂量持续约90分钟。脊髓效应没有伴随着对行为警觉性、运动功能或二氧化碳反应变化的影响。相反，静脉注射右美托咪定(1-10μg/kg)可引起剂量依赖性镇静，心率和呼吸频率显著减慢，对二氧化碳增加的反应减弱，持续约2小时。脑池内注射高达15μg对伤害性阈值和二氧化碳反应无影响，也未导致警觉性显著降低。静脉注射α2拮抗剂阿替帕唑(30~300μg/kg)可拮抗右美托咪定的上述作用，而阿片拮抗剂纳洛酮(30μg/kg)则不能拮抗右美托咪定的上述作用，而阿片受体拮抗剂阿替帕唑不能逆转舒芬太尼(50μg)的抗伤害作用或呼吸抑制作用，而这种作用可被纳洛酮逆转。结论：右美托咪定通过α2受体作用，在脊髓水平产生强大的抗伤害性作用，而药物的全身再分布导致催眠状态，具有显著的心肺效应。
Background:4aL2 Agonists are powerful analgesics after spinal delivery. The current work characterizes the dose-dependent antinociception and effects upon respiratory function of dexmedetomidine after intrathecal, epidural, intravenous, and intracisternal delivery in chronically prepared dogs. Methods:Dogs were prepared with chronic tracheostomies and trained to perform rebreathing studies. These animals were then prepared with chronic lumbar intrathecal, epidural, or intracisternal catheters. Results:A rapid dose-dependent increase in the thermal skin twitch response latency and paw withdrawal to mechanical pinch was observed after intrathecal, epidural, and intravenous dexmedetomidine (dose required to reach 50% of maximal effect for skin twitch = 1.8, 10, and 15 μg, respectively) but not after intracisternal dexmedetomidine (>15 μg), with the maximally effective dose lasting approximately 90 min. The spinal effect was unaccompanied by effects upon behavioral alertness, motor function, or changes in CO2 response. In contrast, intravenous dexmedetomidine (1–10 μg/kg) resulted in a dose-dependent sedation and a significant reduction in heart rate and respiratory rate and a diminished response to increased CO2, these effects lasting approximately 2 h. Intracisternal administration of up to 15 μg had no effect upon the nociceptive threshold, and CO2 response, and failed to result in a significant reduction in alertness. All of the effects of dexmedetomidine were antagonized by the α2-antagonist atipamezole (30–300 μg/kg, intravenous), but not by the opioid antagonist naloxone (30 μg/kg, intravenous), while atipamezole did not reverse the antinociceptive or respiratory depressant actions of intravenous sufentanil (50 μg), effects which were reversible by naloxone. Conclusions:Dexmedetomidine, acting through an α2-receptor, produces a powerful antinociceptive effect, mediated at the spinal level, while systemic redistribution of the drug leads to a hypnotic state with significant cardiorespiratory effects.