The role of the central histaminergic system in emergence from propofol anesthesia in rats model

Abstract

The mechanisms of emergence from general anesthesia remain to be elucidated. Recent studies indicate that the central histaminergic system plays a critical role in maintaining wakefulness. In addition, the neural pathways that regulate the wake-sleep cycle are involved in general anesthesia. In this study, we determined the role of the central histaminergic system in emergence from propofol anesthesia using microinjections and single-unit recordings in rats. All rats were implanted with unilateral guide cannulae or bilateral cannulae. Return of righting reflex could be used as an index of recovery of consciousness in rats. Neuronal activity was collected. The placement of the injection cannulae and/or microelectrodes was verified in coronal sections (10 µm) cut with a cryostat microtome. Animals with incorrect placements were removed from this study. The neuronal activity was subjected to an off-line clustering analysis (K-means) using the Plexon Off-line Sorter to identify one or more individual units recorded from the same electrode from each other and noise. We found intracerebroventricular (icv) microinjections of histamine decreased the emergence time in a dose-dependent manner and had an excitatory effect on the firing activity of medial prefrontal cortex (mPFC) neurons, while the decrease of emergence time was completely reversed by the pre-treatment with triprolidine (80 µg/5 µL) but not cimetidine (100 µg/5 µL). Moreover, the presumed histaminergic neurons fired in a state-dependent manner, and there was a dramatic increase in firing activity before regain of righting reflex. Furthermore, bidirectional manipulations of emergence were achieved through the microinjection of gamma-aminobutyric acid (GABA) (10 µg/side) and a potent H3 receptor inverse agonist ciproxifan (1 µg/side) into the posterior hypothalamus, where the tuberomammillary nucleus (TMN) resides. Combine the behavioral and neurophysiologic evidence, the central histaminergic system promotes emergence from propofol anesthesia in rats. Our findings suggest an important role of the central histaminergic system in a broader field of state transitions, such as emergence from propofol anesthesia.