Guo T Z, Poree L, Golden W, Stein J, Fujinaga M, Maze M
Anesthesiology Service, Department of Veterans Affairs, Palo Alto, California, USA.
Anesthesiology. 1996 Oct;85(4):846-52. doi: 10.1097/00000542-199610000-00020.
Despite nearly 150 years of clinical use, the mechanism(s) of action of nitrous oxide (N2O) remains in doubt. In some but not all studies the analgesic properties of N2O can be attenuated by opiate receptor antagonists. The purported mechanism for the opiate antagonistic effect relates to the finding that N2O increases supraspinal levels of endogenous opiates, although this finding has been disputed. Based on the observations that (1) N2O promotes the release of catecholamines, including the endogenous alpha 2 adrenergic agonist norepinephrine, and (2) that descending noradrenergic inhibitory pathways are activated by opioid analgesics, this study sought to determine whether alpha 2 adrenergic receptors are involved in the antinociceptive action of nitrous oxide.
Institutional approval was obtained for the study. Rats breathed 70% N2O and 30% O2 in an enclosed chamber. After a 30-min exposure, significant antinociception was indicated by an increase in the latency response to a noxious stimulus (tail-flick latency). The tail-flick latency was tested in rats exposed to 70% N2O after either systemic or regional (intrathecal or intracerebroventricular) injections with either competitive (atipamezole; yohimbine) or noncompetitive (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) alpha 2 adrenoceptor antagonists, or the opiate receptor antagonist naloxone.
When administered systemically, both the opiate (naloxone) and alpha 2 adrenoceptor antagonists (atipamezole, yohimbine, and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) blocked the enhanced tail-flick latency response to N2O-Naloxone administered intracerebroventricularly, but not intrathecally, blocked the enhanced tail-flick latency response to N2O. Conversely, atipamezole administered intrathecally, but not intracerebroventricularly, blocked the enhanced tail-flick latency response to N2O.
These data suggest that both supraspinal opiate and spinal alpha 2 adrenoceptors play a mediating role in the antinociceptive response to N2O in rats. A possible mechanism may involve a descending inhibitory noradrenergic pathway that may be activated by opiate receptors in the periaqueductal gray region of the brain stem in the rat after exposure to N2O.
尽管一氧化二氮（N₂O）已临床应用近150年，但其作用机制仍存在疑问。在一些但并非所有研究中，阿片受体拮抗剂可减弱N₂O的镇痛特性。阿片拮抗作用的所谓机制与以下发现有关，即N₂O可提高内源性阿片类物质的脊髓上水平，尽管这一发现存在争议。基于以下观察结果：（1）N₂O促进儿茶酚胺的释放，包括内源性α₂肾上腺素能激动剂去甲肾上腺素；（2）下行去甲肾上腺素能抑制通路可被阿片类镇痛药激活，本研究旨在确定α₂肾上腺素能受体是否参与一氧化二氮的抗伤害感受作用。
本研究获得了机构批准。大鼠在封闭舱内吸入70% N₂O和30% O₂。暴露30分钟后，对有害刺激（甩尾潜伏期）的反应潜伏期增加表明有显著的抗伤害感受作用。在全身或局部（鞘内或脑室内）注射竞争性（阿替美唑；育亨宾）或非竞争性（N - 乙氧羰基 - 2 - 乙氧基 - 1,2 - 二氢喹啉）α₂肾上腺素能受体拮抗剂或阿片受体拮抗剂纳洛酮后，对暴露于70% N₂O的大鼠进行甩尾潜伏期测试。
全身给药时，阿片（纳洛酮）和α₂肾上腺素能受体拮抗剂（阿替美唑、育亨宾和N - 乙氧羰基 - 2 - 乙氧基 - 1,2 - 二氢喹啉）均阻断了对N₂O增强的甩尾潜伏期反应。脑室内注射纳洛酮可阻断对N₂O增强的甩尾潜伏期反应，但鞘内注射则不能。相反，鞘内注射阿替美唑可阻断对N₂O增强的甩尾潜伏期反应，但脑室内注射则不能。
这些数据表明，脊髓上阿片受体和脊髓α₂肾上腺素能受体在大鼠对N₂O的抗伤害感受反应中均起介导作用。一种可能的机制可能涉及下行抑制性去甲肾上腺素能通路，该通路可能在大鼠暴露于N₂O后被脑干导水管周围灰质区域的阿片受体激活。
