Action Of General Anesthetics Research Articles

General anesthetic action profile on the human prefrontal cortex cells through comprehensive single-cell RNA-seq analysis.

The cellular and molecular actions of general anesthetics to induce anesthesia state and also cellular signaling changes for subsequent potential "long term" effects remain largely elusive. General anesthetics were reported to act on voltage-gated ion channels and ligand-gated ion channels. Here we used single-cell RNA-sequencing complemented with whole-cell patch clamp and calcium transient techniques to examine the gene transcriptome and ion channels profiling of sevoflurane and propofol, both commonly used clinically, on the human fetal prefrontal cortex (PFC) mixed cell cultures. Both propofol and sevoflurane at clinically relevant dose/concentration promoted "microgliosis" but only sevoflurane decreased microglia transcriptional similarity. Propofol and sevoflurane each extensively but transiently (<2h) altered transcriptome profiling across microglia, excitatory neurons, interneurons, astrocytes and oligodendrocyte progenitor cells. Utilizing scRNA-seq as a robust and high-through put tool, our work may provide a comprehensive blueprint for future mechanistic studies of general anesthetics in clinically relevant settings.

Components of General Anesthesia: History of the Concept Transformation.

The concept that the state of general anesthesia consists of a number of components representing the distinct and desired central effects of general anesthetics was formulated when it was common to believe that all components of anesthesia have a lipid-centered mechanism of action. The transformation of this concept was associated with changes in our understanding of the mechanisms underlying general anesthetic action. First came the shift from a lipid- to a protein-centered mechanism of action, which opened the way to various molecular targets associated with general anesthesia. Then, it was found that different components of anesthesia may have completely different underlying mechanisms, such as blockade of movement in response to noxious stimulation by isoflurane centers at the spinal cord level, not at the brain, as is the case with other components. The chain of discoveries associated with newfound differences between components of anesthesia accompanied general progress toward a more comprehensive understanding of the mechanism of action of general anesthetics, including anesthetic binding sites, details of receptors and ion channels involved in neurotransmission, and the critical role of neuronal networks. There are several important consequences of our improved understanding. First, a single measurement of anesthetic depth (eg, minimum alveolar concentration index [MAC index]) might not be appropriate for the different component of anesthesia. Second, because the mechanism of action of the components varies, synergy for 1 component does not exclude an additive effect or even antagonism for another component.

Claustrum modulates behavioral sensitivity and EEG activity of propofol anesthesia.

The claustrum has long been regarded as a vital center for conscious control. Electrical stimulation or damage to the claustrum can result in decreased awareness or loss of consciousness, suggesting that the claustrum may be a target for the action of general anesthetics. This study aimed to determine the role of the claustrum in propofol anesthesia. We first applied a fiber photometry calcium signal recording system to record the claustral neuronal activity during the entire process of propofol anesthesia. Chemogenetic activation of claustral neurones was then performed to verify their role in anesthesia. Finally, muscimol (GABAa receptor agonist) and gabazine (GABAa receptor antagonist) were microinjected into the claustrum to determine whether their GABAa receptors were involved in modulating propofol anesthesia. EEG and behavioral indicators, such as anesthetic sensitivity and efficacy, were recorded and analyzed. An evident anesthesia-related change in claustrum neuronal activity was suppressed during propofol-induced unconsciousness and restored following recovery from anesthesia. Chemogenetic activation of claustrum neuronsresults in attenuated propofol sensitivity, a shorter anesthesia duration, and an EEG shift toward wakefulness. Manipulation of GABAa receptors in the claustrum showed bidirectional control of propofol sensitivity, as activation decreases anesthesia efficiency while inactivation augments it. Additionally, inhibiting claustrum GABAa receptors increases cortical EEG slow waves. Claustrum neurones and their GABAa receptors are implicated in the modulation of propofol anesthesia in both behavioral and EEG assessments. Our findings create scope to reveal the brain targets of anesthetic action further and add to the existing evidence on the consciousness-modulating role of the claustrum.

A hypothesis concerning distinct schemes of olfactory activation evoked by perceived versus nonperceived input

SignificanceThe authors propose that odors are consciously perceived or not, depending on whether the olfactory cortex succeeds in activating the endopiriform nucleus-a structure that, in turn, is capable of activating multiple downstream brain areas. The authors further propose that the cellular mechanisms of endopiriform nucleus activation are an attenuated form of cellular events that occur during epileptic seizure initiation. If correct, the authors' hypothesis could help explain the mechanisms of action of certain general anesthetics.

Direct visualization of general anesthetic propofol on neurons by stimulated Raman scattering microscopy

SummaryThe consensus for the precise mechanism of action of general anesthetics is through allosteric interactions with GABA receptors in neurons. However, it has been speculated that these anesthetics may also interact with the plasma membrane on some level. Owing to the small size of anesthetics, direct visualization of these interactions is difficult to achieve. We demonstrate the ability to directly visualize a deuterated analog of propofol in living cells using stimulated Raman scattering (SRS) microscopy. Our findings support the theory that propofol is highly concentrated and interacts primarily through non-specific binding to the plasma membrane of neurons. Additionally, we show that SRS microscopy can be used to monitor the dynamics of propofol binding using real-time, live-cell imaging. The strategy used to visualize propofol can be applied to other small molecule drugs that have been previously invisible to traditional imaging techniques

Identifying c-fos Expression as a Strategy to Investigate the Actions of General Anesthetics on the Central Nervous System.

Although general anesthetics have been used in the clinic for more than 170 years, the ways in which they induce amnesia, unconsciousness, analgesia, and immobility remain elusive. Modulations of various neural nuclei and circuits are involved in the actions of general anesthetics. The expression of the immediate-early gene c-fos and its nuclear product, c-fos protein, can be induced by neuronal depolarization; therefore, c-fos staining is commonly used to identify the activated neurons during sleep and/or wakefulness, as well as in various physiological conditions in the central nervous system. Identifying c-fos expression is also a direct and convenient method to explore the effects of general anesthetics on the activity of neural nuclei and circuits. Using c-fos staining, general anesthetics have been found to interact with sleep- and wakefulness-promoting systems throughout the brain, which may explain their ability to induce unconsciousness and emergence from general anesthesia. This review summarizes the actions of general anesthetics on neural nuclei and circuits based on a c-fos expression.

Bioelectric activity monitoring of the hippocampal complex: action of inhalation anesthetics as a functional sample

Monitoring of the bioelectric activity of the hippocampal complex is performed according to the indications of patients with pharmacoresistant mesial temporal lobe epilepsy, who are indicated for surgical removal of the epileptic focus. The work was aimed at comparing the dynamics of the amplitude-frequency parameters of the bioelectrical activity of the hippocampal complex under the action of general anesthetics by comparing the parameters recorded before surgery and intraoperatively. The study included 8 patients with mesial temporal lobe epilepsy who, within the framework of pre-surgical planning, underwent invasive monitoring of the bioelectrical activity of the cortex and hippocampal com- plex, and then underwent surgical resection of the epileptic focus under general anesthesia with sevoflurane. Registration of 12 hippocampal tracks was carried out in dynamics: during extraoperative and intraoperative neurophysiological monitoring. In the state of calm wakefulness, the pattern of bioelectric activity of the hippocampal complex without structural changes was formed mainly by the activity of the alpha and theta frequency ranges. Under general anesthesia with sevoflurane, a slow-wave delta-range activity was recorded on the intraoperative ES- ubCoG. When the hippocampal complex was involved in the epileptic system, its activity in the state of passive wakefulness was represented by the slow-wave frequency range. Under the conditions of inhalation anesthesia with sevoflurane, the proportion of delta activity significantly decreased, and a state of dysrhythmia was observed without a clear dominance of activity in any range.

Membrane-Mediated Activity of Local Anesthetics

The activity of local anesthetics (LAs) has been attributed to the inhibition of ion channels, causing anesthesia. However, there is a growing body of research showing that LAs act on a wide range of receptors and channel proteins far beyond simple analgesia. The current concept of ligand recognition may no longer explain the multitude of protein targets influenced by LAs. We hypothesize that LAs can cause anesthesia without directly binding to the receptor proteins just by changing the physical properties of the lipid bilayer surrounding these proteins and ion channels based on LAs' amphiphilicity. It is possible that LAs act in one of the following ways: They 1) dissolve raft-like membrane microdomains, 2) impede nerve impulse propagation by lowering the lipid phase transition temperature, or 3) modulate the lateral pressure profile of the lipid bilayer. This could also explain the numerous additional effects of LAs besides anesthesia. Furthermore, the concepts of membrane-mediated activity and binding to ion channels do not have to exclude each other. If we were to consider LA as the middle part of a continuum between unspecific membrane-mediated activity on one end and highly specific ligand binding on the other end, we could describe LA as the link between the unspecific action of general anesthetics and toxins with their highly specific receptor binding. This comprehensive membrane-mediated model offers a fresh perspective to clinical and pharmaceutical research and therapeutic applications of local anesthetics. SIGNIFICANCE STATEMENT: Local anesthetics, according to the World Health Organization, belong to the most important drugs available to mankind. Their rediscovery as therapeutics and not only anesthetics marks a milestone in global pain therapy. The membrane-mediated mechanism of action proposed in this review can explain their puzzling variety of target proteins and their thus far inexplicable therapeutic effects. The new concept presented here places LAs on a continuum of structures and molecular mechanisms in between small general anesthetics and the more complex molecular toxins.

Alex Proekt, M.D., Ph.D., Recipient of the 2021 James E. Cottrell, M.D., Presidential Scholar Award

Alex Proekt, M.D., Ph.D., Recipient of the 2021 James E. Cottrell, M.D., Presidential Scholar Award

The potential role of stress and sex steroids in heritable effects of sevoflurane†.

Most surgical procedures require general anesthesia, which is a reversible deep sedation state lacking all perception. The induction of this state is possible because of complex molecular and neuronal network actions of general anesthetics (GAs) and other pharmacological agents. Laboratory and clinical studies indicate that the effects of GAs may not be completely reversible upon anesthesia withdrawal. The long-term neurocognitive effects of GAs, especially when administered at the extremes of ages, are an increasingly recognized health concern and the subject of extensive laboratory and clinical research. Initial studies in rodents suggest that the adverse effects of GAs, whose actions involve enhancement of GABA type A receptor activity (GABAergic GAs), can also extend to future unexposed offspring. Importantly, experimental findings show that GABAergic GAs may induce heritable effects when administered from the early postnatal period to at least young adulthood, covering nearly all age groups that may have children after exposure to anesthesia. More studies are needed to understand when and how the clinical use of GAs in a large and growing population of patients can result in lower resilience to diseases in the even larger population of their unexposed offspring. This minireview is focused on the authors' published results and data in the literature supporting the notion that GABAergic GAs, in particular sevoflurane, may upregulate systemic levels of stress and sex steroids and alter expressions of genes that are essential for the functioning of these steroid systems. The authors hypothesize that stress and sex steroids are involved in the mediation of sex-specific heritable effects of sevoflurane.

The influence of the chosen method of anesthesia on the severity of postoperative cognitive dysfunction in patients with ophthalmic surgery

Reduction of cognitive functions in the postoperative period is gaining importance in the context of the insurance medicine introduction. Operational stress and anaesthetization are factors which increase the risk of deepening and developing postoperative cognitive dysfunction. The function of short-term memory, attention function, and the speed of psychomotor cognitive reactions are the most vulnerable to the action of general anesthetics. The influence of various methods of anesthesia on cognitive functions in ophthalmic surgery patients after end-to-end keratoplasty has been studied in this research work. Dexmedetomidine was used (the selective agonist of α-adrenoreceptors) as one of the components of multimodal anaesthetization. The sedative effect of this drug is explained by inhibition of neural activity in the blue spot of the brain stem. Dexmedetomidine is known to be used for sedation of patients. It allowed possibility to reduce the amount of fentanyl which was necessary for intra-and post-operative anaesthetization. Our research was conducted on the basis of ME "DRCOH". 78 patients at the age of 18 to 60 years were examined after end-to-end keratoplasty. Non-inclusion criteria: presence of concomitant pathology, neurological diseases, use of psychotropic substances and alcohol 6 months before the study. The study was conducted using neuropsychological testing: the Mini Mental State Examination (MMSE),the Frontal Assessment Battery (FAB), and Luria’s test. Testing was performed before the operation, in 6, 24 hours, 7 and 21 days. Patients were randomized into two groups. The first group – group k (n1=45) included patients who were provided with anaesthetic management according to the following scheme:premedication — ondansetron 4 mg, dexamethasone 4 mg, ketorolac 30 mg intravenously, sibazone 10 mg, fentanyl 0.1 mg intramuscularly 40 minutes before intervention. Induction of propofol – 2-2.5 mg/kg fractionally to achieve clinical symptoms of anaesthetization, fentanyl – 0.005% 0.1 mg tracheal intubation after relaxation on the background of atracuriumbenzylate – 0.3-0.6 mg/kg. Maintaining of anaesthetization: oxygen-sevoflurane mixture FiO250-55%, sevoflurane 1,4-1,8 vol.% on exhalation (1-1. 5 WT.) with the flow of no more than 1 l/min. BIS indicators were kept at the level of 30-40, during the surgery, the bolus injection of 0.1 mg of fentanyl was used in the event of hemodynamic reactions. Anaesthetic support was performed using the infusion of dexmedetomidin for 40 minutes, ondansetron 4 mg, dexamethasone 4 mg, ketorolac 30 mg intravenously in the second group d (n2=33). Induction, relaxation and maintenance of anaesthetization were performed as in the previous group. Intra-operative monitoring of patients in both groups included: non-invasive measurement of blood pressure (BP), heart rate (HR), pulse oximetry, determination of blood gases (oxygen, carbon dioxide and inhaled anesthetic on inhalation and exhalation). Control of the depth of anaesthetization was performed on the basis of BIS and ANI - monitoring. The use of dexmedetomidinu as the component of a multi-modal method of anaesthetizational al lowed obtaining less pronounced POCD, due to the reduction in the number of used drugs. Further use of the combination of highly selective agonists of α2-adrenoreceptors with regional anaesthetization in ophthalmic surgery is the promising method.

The effects of the general anesthetic sevoflurane on neurotransmission: an experimental and computational study

The brain functions can be reversibly modulated by the action of general anesthetics. Despite a wide number of pharmacological studies, an extensive analysis of the cellular determinants of anesthesia at the microcircuits level is still missing. Here, by combining patch-clamp recordings and mathematical modeling, we examined the impact of sevoflurane, a general anesthetic widely employed in the clinical practice, on neuronal communication. The cerebellar microcircuit was used as a benchmark to analyze the action mechanisms of sevoflurane while a biologically realistic mathematical model was employed to explore at fine grain the molecular targets of anesthetic analyzing its impact on neuronal activity. The sevoflurane altered neurotransmission by strongly increasing GABAergic inhibition while decreasing glutamatergic NMDA activity. These changes caused a notable reduction of spike discharge in cerebellar granule cells (GrCs) following repetitive activation by excitatory mossy fibers (mfs). Unexpectedly, sevoflurane altered GrCs intrinsic excitability promoting action potential generation. Computational modelling revealed that this effect was triggered by an acceleration of persistent sodium current kinetics and by an increase in voltage dependent potassium current conductance. The overall effect was a reduced variability of GrCs responses elicited by mfs supporting the idea that sevoflurane shapes neuronal communication without silencing neural circuits.

Intraoperative multi-pulse transcranial electric stimulation: the effect of general anesthetics impact on the excitability of the pyramidal tract

The results of intraoperative neurophysiological monitoring during neurosurgical treatment of pathological processes in the central nervous system are analyzed. The mechanisms of action of general anesthetics on the excitability of the pyramidal system during anesthesia with propofol and sevoflurane have been clarified. It has been established that anesthetics with different mechanisms differ in their effect on excitability and conductivity in the system motor neuron of the cortex pathways alpha-motor neuron. Inhalation anesthetic sevoflurane causes a slowdown in the conduction of a nerve impulse and a violation of the mechanisms of convergence of excitation on the alpha-motor neuron of the spinal cord. In this regard, during general anesthesia with sevoflurane, in order to achieve the effectiveness of transcranial electrical stimulation, the number of stimuli in the package should be increased first with a relatively high stimulation current. Under general anesthesia with propofol, the processes of convergence of excitation are not inhibited, therefore, effective electrical stimulation is achieved by increasing the stimulation current with a stable number of stimuli. With an increase in doses of general anesthetic to a level at which periodic patterns are recorded on the electroencephalogram, a deep inhibition of the excitability and conductivity of the pyramidal system occurs. Under these conditions, effective performance of transcranial electrical stimulation is achieved with submaximal values of the current strength and the number of stimuli.

The General Anesthetic Isoflurane Bilaterally Modulates Neuronal Excitability

SummaryVolatile anesthetics induce hyperactivity during induction while producing anesthesia at higher concentrations. They also bidirectionally modulate many neuronal functions. However, the neuronal mechanism is unclear. The effects of isoflurane on sodium channel currents were analyzed in acute mouse brain slices, including sodium leak (NALCN) currents and voltage-gated sodium channels (Nav) currents. Isoflurane at sub-anesthetic concentrations increased the spontaneous firing rate of CA3 pyramidal neurons, whereas anesthetic concentrations of isoflurane decreased the firing rate. Isoflurane at sub-anesthetic concentrations enhanced NALCN conductance but minimally inhibited Nav currents. Isoflurane at anesthetic concentrations depressed Nav currents and action potential amplitudes. Isoflurane at sub-anesthetic concentrations depolarized resting membrane potential (RMP) of neurons, whereas hyperpolarized the RMP at anesthetic concentrations. Isoflurane at low concentrations induced hyperactivity in vivo, which was diminished in NALCN knockdown mice. In conclusion, enhancement of NALCN by isoflurane contributes to its bidirectional modulation of neuronal excitability and the hyperactivity during induction.

Anaesthesia with diethyl ether impairs jasmonate signalling in the carnivorous plant Venus flytrap (Dionaea muscipula).

General anaesthetics are compounds that induce loss of responsiveness to environmental stimuli in animals and humans. The primary site of action of general anaesthetics is the nervous system, where anaesthetics inhibit neuronal transmission. Although plants do not have neurons, they generate electrical signals in response to biotic and abiotic stresses. Here, we investigated the effect of the general volatile anaesthetic diethyl ether on the ability to sense potential prey or herbivore attacks in the carnivorous plant Venus flytrap (Dionaea muscipula). We monitored trap movement, electrical signalling, phytohormone accumulation and gene expression in response to the mechanical stimulation of trigger hairs and wounding under diethyl ether treatment. Diethyl ether completely inhibited the generation of action potentials and trap closing reactions, which were easily and rapidly restored when the anaesthetic was removed. Diethyl ether also inhibited the later response: jasmonic acid (JA) accumulation and expression of JA-responsive genes (cysteine protease dionain and type I chitinase). However, external application of JA bypassed the inhibited action potentials and restored gene expression under diethyl ether anaesthesia, indicating that downstream reactions from JA are not inhibited. The Venus flytrap cannot sense prey or a herbivore attack under diethyl ether treatment caused by inhibited action potentials, and the JA signalling pathway as a consequence.

Atomistic Simulations of Membrane Ion Channel Conduction, Gating, and Modulation.

Membrane ion channels are the fundamental electrical components in the nervous system. Recent developments in X-ray crystallography and cryo-EM microscopy have revealed what these proteins look like in atomic detail but do not tell us how they function. Molecular dynamics simulations have progressed to the point that we can now simulate realistic molecular assemblies to produce quantitative calculations of the thermodynamic and kinetic quantities that control function. In this review, we summarize the state of atomistic simulation methods for ion channels to understand their conduction, activation, and drug modulation mechanisms. We are at a crossroads in atomistic simulation, where long time scale observation can provide unbiased exploration of mechanisms, supplemented by biased free energy methodologies. We illustrate the use of these approaches to describe ion conduction and selectivity in voltage-gated sodium and acid-sensing ion channels. Studies of channel gating present a significant challenge, as activation occurs on longer time scales. Enhanced sampling approaches can ensure convergence on minimum free energy pathways for activation, as illustrated here for pentameric ligand-gated ion channels that are principal to nervous system function and the actions of general anesthetics. We also examine recent studies of local anesthetic and antiepileptic drug binding to a sodium channel, revealing sites and pathways that may offer new targets for drug development. Modern simulations thus offer a range of molecular-level insights into ion channel function and modulation as a learning platform for mechanistic discovery and drug development.

Inhibitory actions of general anesthetics on hippocampal CA1 neurons modified by activation of amygdala circuitry are demonstrated on the novel amygdala-hippocampal slice preparation

In order to examine effects of general anesthetics on hippocampal synaptic transmission in the absence and presence of amygdala circuitry activation, we have developed a unique amygdala-hippocampal slice preparation in which projections between amygdala and hippocampal CA1 are conserved. Stimulating electrodes were placed in radiatum stratum (Rad) to stimulate CA1, and in amygdala-hippocampal area (AH) to simulate amygdala inputs to hippocampus. Two sets of extracellular recording microelectrodes were positioned in cell bodies and dendrites of CA1 to record population spikes (PSs) and excitatory post-synaptic potentials (EPSPs), respectively. Intravenous anesthetics did not elicit consistent effects on PS and EPSP following a test stimulus on Rad. A pre-pulse of AH in addition to a test-pulse on Rad produced significant reduction of PS amplitude without a change in EPSP. Pre-treatment with tetanus-pulse on AH reversed the anesthetic-induced reduction of PS. The results suggest that inhibitory actions of general anesthetics in CA1 can be modified by activation of amygdala, suggesting that preoperative anxiety and fear could modify anesthetic actions. The modification was more prominent in the presence of intravenous anesthetics than with volatile agents.

Propofol Inhibits Cerebellar Parallel Fiber-Purkinje Cell Synaptic Transmission via Activation of Presynaptic GABAB Receptors in vitro in Mice.

Propofol is a widely used intravenous sedative-hypnotic agent, which causes rapid and reliable loss of consciousness via activation of γ -aminobutyric acid A (GABAA) receptors. We previously found that propofol inhibited cerebellar Purkinje cells (PC) activity via both GABAA and glycine receptors in vivo in mice. We here examined the effect of propofol on the cerebellar parallel fiber (PF)-PC synaptic transmission in mouse cerebellar slices by whole-cell recording technique and pharmacological methods. We found that following blockade of GABAA and glycine receptors activity, propofol reversely decreased the amplitude of PF-PC excitatory postsynaptic currents (PF-PC EPSCs), and significantly increased paired-pulse ratio (PPR). The propofol-induced decrease in amplitude of PF-PC EPSCs was concentration-dependent. The half-inhibitory concentration (IC50) of propofol for inhibiting PF-PC EPSCs was 4.7 μM. Notably, the propofol-induced changes in amplitude and PPR of PF-PC EPSCs were abolished by GABAB receptor antagonist, saclofen (10 μM), but not blocked by N-methyl-D-aspartate receptor (NMDA) receptor antagonist, D-APV (50 μM). Application of the GABAB receptor agonist baclofen induced a decrease in amplitude and an increase in PPR of PF-PC EPSCs, as well masked the propofol-induced changes in PF-PC EPSCs. Moreover, the propofol-induced changes in amplitude and PPR of PF-PC EPSCs were abolished by a specific protein kinase A (PKA) inhibitor, KT5720. These results indicate that application of propofol facilitates presynaptic GABAB receptors, resulting in a depression of PF-PC synaptic transmission via PKA signaling pathway in mouse cerebellar cortex. The results suggest that the interaction with GABAB receptors may contribute to the general anesthetic action of propofol.

Application of new techniques in mechanistic study of general anesthesia

Background The mechanisms underlying the actions of general anesthetics are poorly understood. The application of breakthrough techniques in neuroscience research could advance our understanding of general anesthesia. Objective To review the application of research techniques to study the mechanisms underlying the actions of general anesthetics. Content Studies using conventional neuroscience research techniques revealed that general anesthetics may cause deep anesthesia by targeting at least three parts, thalamocortical pathway, classical sleep-wake circuitry, and cortical fragmentation circuits. The combination of viral vector-assisted retrograde and anterograde neuronal tracing and transgenic Cre-mouse lines allows tracing neural pathways involving particular neuron types. Application of optogenetics, chemogenetics, in vivo calcium imaging, and microdialysis and neuroimaging techniques would overcome the obstacles unconquerable to conventional techniques and fulfill in vivo real-time neuroimaging, neurochemical and behavioral monitoring, and neuromodulations as well. Trend More investigations incorporate the multidisciplinary techniques to systemically study the potential targets of general anesthetics, and evaluate the involvement of the targets in various aspects of anesthesia. These studies could pave the avenue to eventually solve the mystery of general anesthesia. Key words: Anesthetics, general; Mechanism; New techniques

Cover Feature: On the Action of General Anesthetics on Cellular Function: Barbiturate Alters the Exocytosis of Catecholamines in a Model Cell System (ChemPhysChem 10/2018)

Cover Feature: On the Action of General Anesthetics on Cellular Function: Barbiturate Alters the Exocytosis of Catecholamines in a Model Cell System (ChemPhysChem 10/2018)