Reawakening anaesthesia research

European Journal of Anaesthesiology, 2009

General anaesthesia is administered each day to thousands of patients worldwide. Although more than 160 years have passed since the first successful public demonstration of anaesthesia, a detailed understanding of the anaesthetic mechanism of action of these drugs is still lacking. An important early observation was the Meyer-Overton correlation, which associated the potency of an anaesthetic with its lipid solubility. This work focuses attention on the lipid membrane as a likely location for anaesthetic action. With the advent of cellular electrophysiology and molecular biology techniques, tools to dissect the components of the lipid membrane have led, in recent years, to the widespread acceptance of proteins, namely receptors and ion channels, as more likely targets for the anaesthetic effect. Yet these accumulated data have not produced a comprehensive explanation for how these drugs produce CNS depression. In this review, we follow the story of anaesthesia mechanisms research from its historical roots to the intensely neurophysiologic inquiries regarding it today. We will also describe recent findings that identify specific neuroanatomical locations mediating the actions of some anaesthetic agents. Keywords anaesthetic mechanisms; anaesthetic targets; anaesthetics; ion channels; receptors Introduction`H ealthy discontent is a prelude to progress'-Mahatma Gandhi Over time humankind has employed an array of natural medicines and physical methods to alleviate pain and suffering. Ancient Indian and Chinese texts record the beneficial analgesic effects of cannabis and henbane. In Egypt around 3000 B.C., the opium poppy, hellebore, beer, and the legendary mandrake were used for similar purposes [1]. Other approaches to deal with surgical trauma and pain relied on physical methods such as cold, nerve compression, carotid artery occlusion or infliction of a cerebral concussion. The effectiveness of these historical agents is unknown but allude to an ever present need.

Anaesthesia and intensive care, 2009

The challenge to achieve a gestalt understanding of general anaesthesia is really dependent upon an understanding of the elusive concept of consciousness. Until very recently, anaesthesia has been understood to depend fundamentally on the lipid solubility of anaesthetic agents, unsurprisingly a misleading view which has followed from the greater simplicity of lipid chemistry compared with protein chemistry and, it is contended here, from a serious misunderstanding of the older experimental data. Nonetheless, because an over-simplistic view of lipids pertains in much pharmacological thinking about anaesthesia, this paper devotes some attention to potentially relevant aspects of lipid function and also to concepts of anaesthesia which are based on the properties of intracellular and extracellular water. It is argued that the more correct pharmacological explanation is likely to be action at hydrophobic sites of crucial functional molecules, most plausibly protein molecules: empirical ...

Naturwissenschaften, 2001

Almost a century ago, Meyer and Overton discovered a linear relationship between the potency of anaesthetic agents to induce general anaesthesia and their ability to accumulate in olive oil. Similar correlations between anaesthetic potency and lipid solubility were later reported from investigations on various experimental model systems. However, exceptions to the Meyer-Overton correlation exist in all these systems, indicating that lipid solubility is an important, but not the sole determinant of anaesthetic action. In the mammalian central nervous system, most general anaesthetics act at multiple molecular sites. It seems likely that not all of these effects are involved in anaesthesia. GABA A-and NMDAreceptor/ion channels have already been identified as relevant targets. However, further mechanisms, such as a blockade of Na + channels and an activation of K + channels, also come into play. A comparison of different anaesthetics seems to show that each compound has its own spectrum of molecular actions and thus shows specific, fingerprint-like effects on different levels of neuronal activity. This may explain why there is no known compound that specifically antagonises general anaesthesia. General anaesthesia is a multidimensional phenomenon. Unconsciousness, amnesia, analgesia, loss of sensory processing and the depression of spinal motor reflexes are important components. It was not realised until very recently that different molecular mechanisms might underlie these different components. These findings challenge traditional views, such as the assumption that one anaesthetic can be freely replaced by another. Changing concepts in anaesthesiology In 1846, ether anaesthesia was introduced in surgery by the dentist William W. Morton at the University Hospital in Boston. In the presence of a sceptical audience, he demonstrated how surgical interventions could be performed in the absence of consciousness, pain sensation and painful stimuli-induced movements. From that day, it took only a few years for this method to become standard all over the world (Table 1). Morton's technique enabled the rapid development of modern surgery and rates as one of the most-important discoveries in medical science. Nowadays, more than 17 million patients in the United States undergo general anaesthesia annually. In the nineteenth century, general anaesthesia was induced by nitrous oxide (laughing gas), ether or chloroform. In Fig. 1A, chemical structures of some currently used anaesthetics are shown. What is general anaesthesia? The Greek word αναισθησια can be translated by "insensitiveness".

Current Anaesthesia & Critical Care, 2000

The mystery behind the possibility of inducing sleep, coma or an anaesthetic state with drugs, stimulated scientists in the 19 th century, and even earlier, to postulate hypotheses about the working mechanisms of these agents. Substantial progress was made at the beginning of the 20 th century when the correlation between lipid solubility of a drug and its anaesthetic potency was shown. This correlation gave rise to many theories based on the disturbance of the lipid bilayer by anaesthetics. This all changed in the 1980s when it became clear that proteins were also affected. The refinement of electrophysiological techniques allowed the properties of different proteins at a cellular level to be studied and directed research towards finding the receptor that could explain the clinically observed phenomena. In the 1990s it gradually became clear that the interaction between anaesthetic agents and proteins was a complex one, and that no protein could be pinpointed as the essential target. At the beginning of the millennium, we face a challenge to integrate this knowledge into the network of subcellular, cellular and regional interactions that form the brain. The progress of this project will very much depend, as in the past, on the development of basic research in other fields.

Anaesthesia, 1981

This review aims to give a balanced view of the various mechanisms which have beenproposed to explain the phenomenon ofgeneral anaesthesia on both a molecular and whole animal level. An attempt is made to interrelate these and produce one cohesive model.

Journal of neuroanaesthesiology and critical care, 2023

Gamma-aminobutyric acid (GABA), a nonpeptide amino acid transmitter, is a major component of modern neuropharmacology and one of the most crucial target sites for general anesthetics and therapeutic drugs. GABA type A receptors (GABA A Rs) are the most abundant inhibitory neurotransmitter receptors in the central nervous system. They are part of the rapid-acting, ligand-gated ion channel (LGIC) receptor category, a pentameric Cys-loop superfamily member that mediates inhibitory neurotransmission in the mature brain. GABA A Rs mainly consist of two α subunits, two β subunits, and one additional subunit from either γ or d arranged around a central chloride (Cl -) selective channel. Multiple GABA A R subunit subtypes and splice variants have been identified. Each variant of GABA A R exhibits distinct biophysical and pharmacologic properties. Several compounds allosterically modulate the GABA A R positively or negatively. The widely used positive GABA A R modulators include benzodiazepines (anxiolytic and anticonvulsant), general anesthetics (volatile agents like isoflurane, and intravenous agents like barbiturates, etomidate, and propofol), long-chain alcohols, some anticonvulsants, and neuroactive steroids. The binding sites for each drug are distinctly different. The anesthetic drugs enhance receptor-mediated synaptic transmission and thus interrupt the thalamocortical transmission, which controls the sleep-wake patterns. Abnormality in the GABA A R function has been implicated in several neurological conditions, such as sleep disorders, seizures, depression, cognitive function, neurological recovery after injury, and neuroplasticity. Understanding the GABA A R lays the foundation for the development of highly specific drugs in the treatment of neurological disorders and general anesthesia.

Annually, millions of surgeries are carried out worldwide under general anesthesia. Patients undergoing elective or emergency procedures may have important comorbidities affecting significant functions such as cardiovascular, neurologic, and metabolic. Physicochemical and pharmacological properties differ between anesthetic drugs. Different molecular reactions within the human body are triggered by surgery and anesthesia. Cellular protective mechanisms against any kind of insult may be either enhanced or attenuated under general anesthesia. An extensive literature supporting neurotoxic effects of anesthetic drugs has been published in animal models including nonhuman primates, whereas human data are limited. Surgery and anesthesia exposure may be related to a higher incidence of neurological dysfunction mostly in extreme age patients (children and older patients). Postoperative cognitive dysfunction, delirium, and progression of previously diagnosed neurodegenerative disorders are some of the unsatisfactory clinical outcomes. Apoptosis has been described as a common mechanism triggered by intracellular reactions after anesthesia exposure. Nevertheless, some anesthetics may inhibit these pathways limiting cellular injury. Some anesthetics are associated with a protective effect as a result of enzymatic modulation and activation of antiapoptotic proteins.

2020

According to the definition of the International Association for the Study of Pain (IASP), pain is defined as: "Unpleasant subjective feeling and emotional experience associated with current or potential tissue damage of a particular localisation", which, as such, poses a challenge for epidemiological research to determine its frequency and prevalence. We have all heard the motto that surgery has experienced its unprecedented development on the wings of anaesthesia. This is most certainly the case, since it is precisely the pain that prevents any invasive procedure on the human body, hence the very elimination of pain has opened up the way for the application and development of surgery. For this reason, the skill and now the science of anaesthesia are epochal civilizational achievements, which is why it is worth remembering the attempts and successes of its application. The very beginning of mankind cannot be imagined without the humans facing some sort of pain. As long ag...

Anaesthesia and intensive care, 1975

The disciplines of anaesthesia and clinical pharmacology are related in as much as both have a mutual interest in the safe and conservative use of drugs in man. Anaesthetists have effectively been practising rational therapeutics for many years and they have much to offer academic departments of clinical pharmacology in terms of teaching and research programmes. Similarly, the clinical pharmacologist can usefully contribute to anaesthetic training and research programmes in relation to aspects such as education, precise analytical methods, data-handling and clinical trial techniques. The inter-relationship of the two disciplines can be of mutual advantage and has the potential to provide a stronger basis for sound therapeutic practice.