Vanini Giancarlo, Nemanis Kriste, Baghdoyan Helen A, Lydic Ralph
Department of Anesthesiology, University of Michigan, 7433 Medical Science Building I, 1150 West Medical Center Drive, Ann Arbor, MI, 48109-5615, USA.
Eur J Neurosci. 2014 Jul;40(1):2264-73. doi: 10.1111/ejn.12571. Epub 2014 Mar 27.
The oral part of the pontine reticular formation (PnO) contributes to the regulation of sleep, anesthesia and pain. The role of PnO γ-aminobutyric acid (GABA) in modulating these states remains incompletely understood. The present study used time to loss and time to resumption of righting response (LoRR and RoRR) as surrogate measures of loss and resumption of consciousness. This study tested three hypotheses: (i) pharmacologically manipulating GABA levels in rat PnO alters LoRR, RoRR and nociception; (ii) propofol decreases GABA levels in the PnO; and (iii) inhibiting GABA synthesis in the PnO blocks hyperalgesia caused by sleep deprivation. Administering a GABA synthesis inhibitor [3-mercaptopropionic acid (3-MPA)] or a GABA uptake inhibitor [nipecotic acid (NPA)] into rat PnO significantly altered LoRR caused by propofol. 3-MPA significantly decreased LoRR for propofol (-18%). NPA significantly increased LoRR during administration of propofol (36%). Neither 3-MPA nor NPA altered RoRR following cessation of propofol or isoflurane delivery. The finding that LoRR was decreased by 3-MPA and increased by NPA is consistent with measures showing that extracellular GABA levels in the PnO were decreased (41%) by propofol. Thermal nociception was significantly decreased by 3-MPA and increased by NPA, and 3-MPA blocked the hyperalgesia caused by sleep deprivation. The results demonstrate that GABA levels in the PnO regulate the time for loss of consciousness caused by propofol, extend the concept that anesthetic induction and emergence are not inverse processes, and suggest that GABAergic transmission in the PnO mediates hyperalgesia caused by sleep loss.
脑桥网状结构的口部区域（PnO）参与睡眠、麻醉和疼痛的调节。PnO中γ-氨基丁酸（GABA）在调节这些状态中的作用仍未完全明确。本研究使用翻正反射消失时间和恢复时间（LoRR和RoRR）作为意识消失和恢复的替代指标。本研究检验了三个假设：（i）药理学调控大鼠PnO中的GABA水平会改变LoRR、RoRR和痛觉感受；（ii）丙泊酚降低PnO中的GABA水平；（iii）抑制PnO中的GABA合成可阻断睡眠剥夺引起的痛觉过敏。向大鼠PnO注射GABA合成抑制剂[3-巯基丙酸（3-MPA）]或GABA摄取抑制剂[哌啶酸（NPA）]可显著改变丙泊酚引起的LoRR。3-MPA显著缩短丙泊酚诱导的LoRR（-18%）。NPA显著延长丙泊酚给药期间的LoRR（36%）。丙泊酚或异氟烷停止给药后，3-MPA和NPA均未改变RoRR。3-MPA降低LoRR而NPA增加LoRR这一结果与丙泊酚使PnO细胞外GABA水平降低（41%）的测量结果一致。3-MPA显著降低热痛觉感受，而NPA使其增加，且3-MPA阻断了睡眠剥夺引起的痛觉过敏。结果表明，PnO中的GABA水平调节丙泊酚引起的意识消失时间，拓展了麻醉诱导和苏醒并非相反过程的概念，并提示PnO中的GABA能传递介导了睡眠剥夺引起的痛觉过敏。
