Dawson Cecilia, Ma Daqing, Chow Andre, Maze Mervyn
Department of Anaesthetics and Intensive Care, Imperial College London, London, United Kingdom.
Anesthesiology. 2004 Apr;100(4):894-904. doi: 10.1097/00000542-200404000-00020.
Nitrous oxide and dexmedetomidine are thought to mediate analgesia (antinociception in a noncommunicative organism) via alpha 2B- and alpha 2A-adrenergic receptor subtypes within the spinal cord, respectively. Nitrous oxide and dexmedetomidine exert diametrically opposite effects on neuronal activity within the locus ceruleus, a pivotal site for modulation of analgesia. Because of these differences, the authors explored whether the two analgesics in combination would provide satisfactory analgesia.
The analgesic effects of nitrous oxide and dexmedetomidine given both intraperitoneally and intrathecally were evaluated using the tail-flick latency test in rats. For investigation of the interaction, rats were pretreated with dexmedetomidine, either intraperitoneally or intrathecally, immediately before nitrous oxide exposure such that peak antinociceptive effects of each drug coincided. For assessment of the effect on tolerance, dexmedetomidine was administered as tolerance to nitrous oxide developed. Expression of c-Fos was used to assess neuronal activity in the locus ceruleus.
Nitrous oxide and dexmedetomidine increased tail-flick latency with an ED50 (mean +/- SEM) of 55.0 +/- 2.2% atm for nitrous oxide, 27.6 +/- 5.1 for microg/kg intraperitoneal dexmedetomidine, and 2.9 +/- 0.1 microg for intrathecal dexmedetomidine. Combinations of systemically administered dexmedetomidine and nitrous oxide produced an additive analgesic interaction; however, neuraxially administered dexmedetomidine interacted synergistically with nitrous oxide. Tolerance to nitrous oxide was reversed by coadministration of dexmedetomidine. Prazosin, the alpha 1-/alpha 2B-adrenoceptor antagonist, attenuated the analgesic effect of nitrous oxide and prevented dexmedetomidine-induced reversal of tolerance to nitrous oxide. Nitrous oxide-induced increase of neuronal activity in the locus ceruleus was reversed by dexmedetomidine.
The synergistic analgesic interaction between nitrous oxide and dexmedetomidine within the spinal cord is obscured by a supraspinal antagonism when dexmedetomidine is administered systemically in the pretolerant state. After tolerance to nitrous oxide develops, supraspinal functional antagonism no longer obtains exposing the synergistic action at the level of the spinal cord, which expresses itself as a reversal of the tolerant state. The authors speculate that the addition of dexmedetomidine to nitrous oxide is likely to provide enhanced and more durable analgesia in settings in which nitrous oxide is currently used alone (e.g., labor and dental surgery).
氧化亚氮和右美托咪定被认为分别通过脊髓内的α2B -和α2A -肾上腺素能受体亚型介导镇痛作用（非交流生物体中的抗伤害感受）。氧化亚氮和右美托咪定对蓝斑核内的神经元活动产生截然相反的影响，蓝斑核是调节镇痛的关键部位。由于存在这些差异，作者探讨了两种镇痛药联合使用是否能提供满意镇痛效果。
采用大鼠甩尾潜伏期试验评估腹腔内和鞘内给予氧化亚氮和右美托咪定的镇痛效果。为研究相互作用，在氧化亚氮暴露前即刻腹腔内或鞘内给予右美托咪定预处理大鼠，使每种药物的抗伤害感受峰值效应同时出现。为评估对耐受性的影响，在氧化亚氮耐受性形成时给予右美托咪定。采用c - Fos表达评估蓝斑核内的神经元活动。
氧化亚氮和右美托咪定均增加甩尾潜伏期，氧化亚氮的半数有效剂量（ED50，均值±标准误）为55.0±2.2%大气压，腹腔内给予右美托咪定的ED50为27.6±5.1μg/kg，鞘内给予右美托咪定的ED50为2.9±0.1μg。全身给予右美托咪定与氧化亚氮联合产生相加性镇痛相互作用；然而，鞘内给予右美托咪定与氧化亚氮产生协同相互作用。右美托咪定与氧化亚氮联合给药可逆转对氧化亚氮的耐受性。α1 -/α2B -肾上腺素能受体拮抗剂哌唑嗪减弱氧化亚氮的镇痛作用，并阻止右美托咪定诱导的对氧化亚氮耐受性的逆转。氧化亚氮诱导的蓝斑核内神经元活动增加被右美托咪定逆转。
当在预耐受状态下全身给予右美托咪定时，脊髓内氧化亚氮与右美托咪定之间的协同镇痛相互作用被脊髓上的拮抗作用掩盖。在对氧化亚氮产生耐受性后，脊髓上的功能拮抗作用不再存在，暴露了脊髓水平的协同作用，表现为耐受状态的逆转。作者推测，在目前单独使用氧化亚氮的情况下（如分娩和牙科手术），将右美托咪定添加到氧化亚氮中可能会提供增强且更持久的镇痛效果。
