Publications
APS Bulletin • Volume 14, Number 5, 2004
Resource Reviews
John D. Loeser, MD, Department Editor
The Delta Receptor
Reviewed by Gregory W. Terman, MD PhD
Kwen-Jen Chang, Frank Porreca, and James H. Woods, Eds. New York, Marcel Dekker, Inc., 2004. Hard cover, 512 pages. ISBN 0824740319. $165.
This book consists of chapters by a “who’s who” of delta receptor pharmacologists. In the preface, the editors claim to be targeting both an academic and a pharmaceutical industry audience and they have succeeded. Whether the book will be of interest to a larger audience (e.g., clinicians) is a question with an answer that depends on one’s faith in both the preclinical pharmacology presented and the ingenuity of drug companies in overcoming problems with delta opiates in vivo.
The book is divided into three parts. Part 1, “The Delta Receptor,” traces the story of the biochemical characterization of the delta receptor by its enkephalin binding in the mouse vas deferens (chapter by Kwen-Jen Chang) to its cloning by both Evans and Kiefer (both of whom submit chapters) and its identification in the human (Yamamura). Several additional chapters (Law; Traynor; Loh) detail the molecular pharmacology of this G-protein coupled receptor.
Part 2 is “Delta Ligands.” The development of pharmacological tools has facilitated study of this receptor. Agonists, antagonists, inverse agonists, and mixed opiate-receptor agonists are all discussed by authors who were involved in their development (e.g. , McNutt; Portoghese; Mosberg; Negri; Yamamura; Schiller; K-J Chang). All these chapters involve stories of a search for pharmacologically stable compounds with sufficient lipid solubility to easily pass the gut/blood and/or blood/brain barriers and thus have potential clinical utility.
Part 3 is “Pharmacology and Physiology.” The hunt for new, potentially useful pharmaceutics was prompted by the results of interesting preclinical studies of the physiology and behavioral pharmacology of delta opiate systems. Delta opiates have been implicated in modulating such wide-ranging phenomena as depression (Woods) immune function (Gomez-Flores), gastrointestinal peristalsis and mucosal repair (Brown), cardioprotection (Gross), opiate craving (Negus) and analgesia (Porreca and colleagues; Narita and Suzuki; Heinricher and Fields).
The chapter on interactions between mu and delta receptors (Rothman) is of particular importance when thinking about much of the data in this book and perhaps the future of delta opiate receptor research. Three different opiate receptors (mu, delta, and kappa receptors) have been cloned to date. There have been no convincing cloning studies thus far demonstrating the existence of additional opiate receptor subtypes, despite the many pharmacology studies supporting such receptor subtypes over the years. The idea that delta and mu receptors (and perhaps delta and kappa receptors) are expressed together in the membrane to form heteromultimeric receptors gives a fascinating mechanism for explaining various subtype binding characteristics despite the use of only three major opiate receptor building blocks. The analgesic effects of Biphalin (Lipkowski et al.) with its dual agonist effects at delta and mu receptors is a good example of using heteromultimers to pharmacological advantage.
Sadly, there have been few clinically relevant success stories in delta receptor mediated analgesia. Indeed, I could find nothing in this book (or a quick Medline search) about any clinical experience with delta opiates. Even in the preclinical studies, the stories of delta analgesics are site specific and complex as the chapters in this book detail. Moreover, the epileptogenic effects of some delta agonists (Chang) have scared away many drug companies—despite the success of benzodiazepines in treating this side effect, its rapid tolerance, and the apparent absence of respiratory depression and physical dependence side effects that might make delta drugs preferable to mu drugs in pain therapy.
I found this book to be a reminder of some fascinating (often still unexplained) research findings and a primer on drug development of pharmacological tools initially without the benefit of in vitro expression systems and narrative from authors, some of whom have been involved in this story for more than 25 years.
Dr. Terman is Associate Professor of Anesthesiology at the University of Washington.
Reviewer content represents the opinion of the reviewer, not APS.
Please direct your suggestions for future Resource Reviews to John D. Loeser, MD, Department Editor, at jdloeser@u.washington.edu