Methods in enzymology
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Optogenetics and chemogenetics provide the ability to modulate neurons in a type- and region-specific manner. These powerful techniques are useful to test hypotheses regarding the neural circuit mechanisms of general anesthetic end points such as hypnosis and analgesia. ⋯ Optogenetics provides precise temporal control of neuronal firing with light pulses, whereas chemogenetics provides the ability to modulate neuronal firing for several hours with the single administration of a designer drug. This chapter provides an overview of neuronal targeting and experimental strategies and highlights the important advantages and disadvantages of each technique.
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Methods in enzymology · Jan 2018
Xenon Anesthesia and CT: Noninvasive Measures of Brain Anesthetic Concentration.
The existence of a barrier between anesthetic behavioral state transitions has been observed across phyla, but demonstrating that such a barrier exists and is not a pharmacokinetic artifact has not yet been possible in humans. Such an investigation requires temporally precise information regarding the brain concentration of anesthetic in order to demonstrate the specific pharmacokinetic-pharmacodynamic mismatch that is hysteresis. We propose a method to noninvasively determine brain tissue anesthetic concentration using computerized tomography and the radiopaque gaseous anesthetic xenon. Such a technique can be used to investigate pharmacokinetic-pharmacodynamic mismatches in humans.
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Methods in enzymology · Jan 2018
Anesthetic Drug Discovery and Development: A Case Study of Novel Etomidate Analogs.
All currently available general anesthetic agents possess potentially lethal side effects requiring their administration by highly trained clinicians. Among these agents is etomidate, a highly potent imidazole-based intravenous sedative-hypnotic that deleteriously suppresses the synthesis of adrenocortical steroids in a manner that is both potent and persistent. We developed two distinct strategies to design etomidate analogs that retain etomidate's potent hypnotic activity, but produce less adrenocortical suppression than etomidate. ⋯ The other strategy seeks to reduce the duration of adrenocortical suppression after etomidate administration by modifying the drug's structure to render it susceptible to rapid metabolism by esterases. In this chapter, we describe the methods used to evaluate the hypnotic and adrenocortical inhibitory potencies of two lead compounds designed using the aforementioned strategies. Our purpose is to provide a case study for the development of novel analogs of existing drugs with reduced side effects.