In vivo imaging of nitrous oxide-induced changes in cerebral activation during noxious heat stimuli

Background: Although previous studies have provided some insight into the pharmacologic aspects of nitrous oxide analgesia, the neural circuits mediating its antinociceptive effect remain relatively unexplored. Positron emission tomography was used in nine volunteers to identify the loci of nitrous oxide-modulated cerebral responses to a peripheral noxious stimulus. Methods: Nitrous oxide-pain interactions were studied by comparing regional cerebral blood flow responses to a 48°C tonic heat stimulus, applied to each volunteer's left forearm, during room air inhalation with those obtained while 20% nitrous oxide was administered. Two cerebral blood flow scans were obtained with the ¹⁵O-water technique during each condition. Locations of specific regional activation related to pain, and nitrous oxide, were identified using the statistical parametric mapping method, with a significance level of P < 0.01. Pain was rated by visual analog scale and the values were compared using Wilcoxon rank sum analysis. Results: Pain produced cerebral activation in the contralateral thalamus, anterior cingulate, and supplementary motor area. Adding nitrous oxide during pain stimulation abolished activation in these areas but was associated with activation in the contralateral infralimbic and orbitofrontal cortices. In parallel, mean visual analog scale scores decreased significantly from 67 ± 4 (SEM) to 54 ± 5 (P < 0.05). Conclusions: Nitrous oxide, at 20% concentration, appears to modulate pain processing in the brain's medial pain system, and also activates the infralimbic and orbitofrontal cortices. The potential contribution of the affected brain areas to nitrous oxide analgesia is discussed.