Although certain regions of the brain are thought to be associated with waking, little is known about the precise mechanisms underlying arousal from general anesthesia. “It’s been a big black box,” says Elena M. Vazey, PhD, a senior postdoctoral fellow in the Department of Neurosciences.
In the March 11, 2014 issue of the Proceedings of the National Academy of Sciences, Vazey and Gary S. Aston-Jones, Ph.D., the William B. Murray SmartState™ Endowed Chair in Neuroscience, showed for the first time that a specific subset of norepinephrine neurons (Figure, green stain) in the locus coeruleus (LC) are a potent trigger for inducing arousal from isoflurane general anesthesia.1 The LC, the main site in the brain for the production of norepinephrine, governs responses to stress and panic and has been linked to the sleep-wake cycle.
Vazey and Aston-Jones were able to activate precisely the targeted norepinephrine neurons using DREADDs (Designer Receptors Exclusively Activated by a Designer Drug), a novel targeted genetic approach. The designer receptors (Figure, magenta stain) were delivered via an adeno-associated virus fitted with a promoter to target the norepinephrine neurons of the LC. The DREADDs and the designer drug clozapine-N-oxide (CNO) act together, the latter serving as a key to unlock the former. “You can essentially pop a pill to turn these designer receptors on or off,” explains Vazey.
By administering CNO to “turn on” the designer receptors and activate the targeted norepinephrine neurons, Vazey and Aston-Jones were able to awaken rats that had been anesthetized with isoflurane or to slow the induction of anesthesia. Administration of β or α-1 noradrenergic antagonists prevented arousal and increased the duration of anesthesia.
These findings challenge a prominent theory about how general anesthesia works. Proponents of the “membrane fluidity” theory speculate that the anesthetic agent acts broadly on the brain’s neurons by permeating their membranes. In contrast, Vazey and Aston-Jones showed that activating only a small fraction of neurons could have a very profound effect on anesthesia.
This study in an animal model could have implications for clinical practice. Patients with high levels of stress, such as those with anxiety disorders, have elevated levels of norepinephrine and so may be harder to anesthetize and more prone to remaining “lightly” sedated. In contrast, patients taking β-blockers for cardiovascular disease, which lower norepinephrine levels, may be very sensitive to anesthesia and slower to awaken. Providing a β-blocker before administering anesthesia in the former and selecting β-blockers that do not cross the blood-brain barrier in the latter could help offset these effects. Studies in humans will be needed to confirm the potential benefits of these clinical strategies.
Currently used primarily for research, DREADDs also have broad therapeutic potential because they make possible a manipulation of the brain that is much more focused and transient than that achieved by deep brain stimulation or transcranial magnetic stimulation. They could also provide a less invasive method than the currently used surgical resection for disabling the region of the brain in which an epileptic seizure originates.
1 Vazey EM, Aston-Jones G. Designer receptor manipulations reveal a role of the locus coeruleus noradrenergic system in isoflurane general anesthesia. Proc Natl Acad Sci USA. 2014 Mar 11;111(10):3859-3864.
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