笑氣可抑制福馬林所引起大白鼠的暫時性及強直性痛覺行為但無法抑制脊髓背角神經元的c-Fos蛋白質之表現

Nitrous Oxide Suppresses Tonic and Phasic Nociceptive Behaviors but not Formalin-induced c-Fos Expression in the Rat Spinal Cord Dorsal Horn

背景：本實驗目的在經由研究大白鼠對暫時性及強直性痛覺刺激的痛覺行為，以及福馬林引起脊髓背角神經元的Fos-like免疫反應，來了解未達麻醉濃度的笑氣的麻醉及止痛效果，並與halothane及fentanyl作比較。並且觀察受試大白鼠的本體感覺，神智狀態，以及運動功能，以了解大白鼠的行為反應。方法：本實驗分為暫時性疼痛組及強直性疼痛組。皆以雄性Sprague-Dawley大鼠，分為四組，各予以(1)生理食鹽水，(2)75％笑氣(0.5 MAC)，(3)0.5％ halothane(0.5 MAC)，(4)fentanyl 100μxg/kg之後，分別接受不同強度的二氧化碳雷射刺激（暫時性疼痛組），或50μl 2.5％福馬林皮下注射（強直性疼痛組）。所有強直性疼痛組的大鼠均在注射福馬林60分鐘後犧牲，進行免疫組織化學檢查，並且計算比較有Fos-like反應(Fos-LI)的神經元在脊髓背角各層的分布。結果：所有組別的受試大鼠皆保有正常的翻身反射，笑氣及halothane均明顯使大鼠的神智狀態及運動功能變差，表示在未達麻醉濃度時，這兩種藥物皆會導致中等程度的輕癱與鎮靜。但是兩種藥物均無法降低Fos-LI神經元數目。Fentanyl則會提高大鼠對熱痛覺刺激的閾值，減少福馬林引起的舔咬行為，並減少在脊髓背角之頸部中Fos-LI神經元的數目。結論：笑氣的止痛效果及型態，與已知止痛效果極微的halothane相同。由笑氣無法抑制強直性痛覺刺激所引起的生化反應看來，笑氣雖可以有效抑制過度痛覺行為，但無法抑制脊髓的敏感化。因此，就如同其他的吸入性麻醉藥物，笑氣所以能有效抑制痛覺行為主要是對所有行為反應的非選擇性抑制。

Background: The aim of this study was to investigate the anesthetic and analgesic effects of subanesthetic concentration of nitrous oxide and to compare these effects with halothane and fentanyl. Methods: The antinociceptive effects were assessed in male Sprague-Dawley rats by behavioral responses to phasic and tonic nociceptive stimulations and biochemical index of pain, formalin-induced Fos-like immunoreactivity (Fos-LI), in spinal cord dorsal horn. Neurological functions (proprioception, mental status and motor function) were monitored to determine whether or not behavioral responses were impaired by anesthetic action of the treatment. Four groups of rats treated with: (1) saline, (2) 75% nitrous oxide (0.5 MAC), (3) 0.5% halothane (0.5 MAC) and (4) fentanyl 100 μg/kg were subject either to graded intensity of CO2 laser stimulation (phasic pain) or s.c. injection of 50 μl 2.5% formalin (tonic pain) in two separate studies. All rats in the tonic pain study were killed for immunohistochemistry at 60 min after formalin injection. Maximal counts of Fos-LI labelled neurons in rat spinal cord dorsal horn were compared according to the laminar distribution. Results: We found that all rats exhibited normal righting reflexes regardless of whatever treatment. Nitrous oxide and halothane greatly impaired mental status and motor function, indicating that both agents could induce a modest degree of sedation and paresis at subanesthestic concentrations. Fentanyl increased the threshold level to noxious thermal stimulation, and reduced the formalin-induced licking/biting behaviors and the number of Fos-LI labelled neurons which are predominantly found in the neck of the dorsal horn. Nitrous oxide and halothane increased the thermal nociceptive threshold, suppressed licking/biting behavior in both early and late phases of the formalin test. Unlike fentanyl, nitrous oxide and halothane failed to suppress c-fos expression. The extent and pattern of nitrous oxide-induced antinociception was identical to halothane, which is known to have little or no analgesic effect. The lack of attenuated biochemical response to tonic pain stimulation may suggest that nitrous oxide fails to suppress spinal sensitization despite its potent inhibition on behavioral hyperalgesia. Conclusions: These findings suggest that, at the spinal level, subanesthetic concentration of nitrous oxide greatly attenuates nociceptive behaviors mainly due to a non-selective suppression of behavioral responses that are commonly associated with inhalation anesthestic drugs.