Molecular Bases of Anesthesia PDF

Preface

The concept of this monograph began with the search for a comprehensive, focused source of information on anesthetic mechanisms. Here, we have gathered a number of contributions from researchers with diverse points of view, and have sought to cover the most important areas of current interest concerning anesthetic mechanisms. The focus of this monograph is squarely on neuroreceptors, with deliberate emphasis on ion channels. This reflects the area of greatest current interest. Lipid interactions with general anesthetics have not been covered separately, but information relevant to this topic is covered in the introductory chapter. This bias is fully consistent with a rapidly accumulating body of evidence, including the recent identification of targets for anesthetics on protein ion channels.

The field of anesthetic mechanisms is far different from what it was a decade or two ago. The unique pharmacology and low potencies of general anesthetics complicated the search for appropriate targets, and our meager understanding of the basic foundations of consciousness led to myriad anesthetic theories. Likewise, basic conceptual issues, such as whether lipids or proteins were the primary targets of anesthetics, resulted in little common ground between these two groups of researchers. The seminal observation that the effects of anesthetics on lipids were very modest and mimicked by other conditions (such as small changes in temperature) caused many researchers to focus on proteins as targets of anesthetic action. At the same time, the basic physiology and structure of receptors and ion channels were elucidated. For example, insight into benzodiazepine actions at the GABA A receptors led to studies with barbiturates, alcohols, and volatile anesthetics at this family of ligandgated ion channels. Simultaneously, studies were being conducted with anesthetics at other potential loci of action.

The use of molecular biological techniques has also been applied to this study of anesthetic mechanisms. As can be seen from many of the contributions to this monograph, recombinant receptors have been very useful in elucidating anesthetic actions. Several researchers have used mutagenesis techniques to identify crucial segments of receptors involved in anesthetic action. Putative loci for volatile anesthetics and alcohols, as well as intravenous anesthetics have been described. These are exciting findings providing a framework to evaluate theories of anesthesia and allowing a better understanding of anesthetic actions at the molecular level. Substitution of various amino acids at crucial loci on a receptor provide an opportunity to determine the size of potential binding sites. Moreover, the use of transgenic animals may provide the opportunity to determine if the in vitro effects of anesthetics cause in vivo changes in anesthetic effects. Such experiments, if successful, may provide a method for determining the pharmacological relevance of experimental observations and resolving discrepancies between opposing theories of anesthesia. Many of the opposing concepts relating to anesthetic mechanisms are not fully resolved. It is our hope that this volume will provide the information and framework for readers to review and evaluate these issues. In addition, we trust that this book will be a useful reference for those with an interest in anesthesiology, and will stimulate further study.