The latest study from a Massachusetts General Hospital (MGH)/Massachusetts Institute of Technology (MIT) team investigating the mechanisms underlying general anesthesia finds that stimulating a specific group of neurons in mice produces signs of arousal -- including getting on their feet and walking -- even as the animals continue to receive the anesthetic drug isoflurane. In addition to developing ways to actively reverse anesthetic-induced unconsciousness, the findings may someday help improve treatment of conditions such as coma or opioid overdose.
"There currently are no ways to actively wake someone from general anesthesia, and understanding the mechanisms that promote arousal could help us develop therapies to treat other low-arousal conditions, such as traumatic brain injury," says Norman Taylor, MD, PhD, of the MGH Department of Anesthesia, Critical Care and Pain Medicine, lead author of the report published online in the Proceedings of the National Academy of Sciences. "Finding one set of neurons that is able to produce such a powerful arousing effect changes the way we think about recovery from anesthesia and possibly coma as well."
Taylor is part of a team led by Emery Brown, MD, PhD, of the MGH Department of Anesthesia, Critical Care and Pain Medicine and the MIT Department of Brain and Cognitive Sciences, that has been investigating both how general anesthesia induces unconsciousness and ways of reversing the effects. Several previous studies led by Ken Solt, MD, MGH Department of Anesthesia, the senior author of the current study, found that stimulant drugs such as methylphenidate and amphetamine could restore consciousness to animals continuing to receive general anesthetics. A paper in the August 2014 issue of Anesthesiology found that stimulating the ventral tegmental area (VTA), a brain region that releases the neurotransmitter dopamine, also could arouse anesthetized rats.
Since the electrical stimulation used in the 2014 study can activate all adjacent neurons, the current study used optogenetics, a method of activating specific populations of neurons by means of light, to target only dopamine-responsive neurons in the VTA. Every one of six mice engineered to express a light-responsive protein in dopamine neurons showed signs of arousal -- including moving, standing up and walking -- in response to pulses of light delivered to the VTA, even while they continued to receive isoflurane. Use of an agent that blocks signaling by the D1 receptor -- one of five dopamine receptors -- prevented the arousal response to light stimulation, indicated that dopamine signaling was responsible for counteracting anesthetic effects. EEG readings taken during optogenetic stimulation of the VTA showed patterns similar but not identical to those of unanesthetized animals.
"We now need to study whether the activation of dopamine neurons can help in coma-like states," says Taylor, who is an instructor in Anesthesia at Harvard Medical School. "One of the effects of dopamine neuron stimulation we observed was increased respiratory rate, which may have implications for treating the sedating effects of medications such as opioids and provide insight into how to save the lives of more overdose patients."
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In addition to Solt and Brown, the co-authors of the PNAS paper are Christa Van Dort, PhD, Jonathan Kenny, JunZhu Pei, Jennifer Guidera, Ksenia Vlasov, and Justin Lee, of both the MGH Department of Anesthesia, Critical Care and Pain Medicine and the MIT Department of Brain and Cognitive Sciences; and Edward Boyden, PhD, MIT Brain and Cognitive Sciences. Support for the study includes National Institutes of Health grants TR01 GM104948 and T32 GM07592.
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School.
The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals, earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."
Journal
Proceedings of the National Academy of Sciences