Research in the opioid field continues apace, with ongoing developments in our understanding of the underlying biology through to the clinical consequences of modulating opioid receptors. The sheer volume of research being carried out in this field precludes a thorough bench-to-bedside review and has necessitated a somewhat focused approach within this volume, in particular the use and potential uses of ligands that activate one, or more, of the receptors. Contributions to Research and Development of Opioid-Related Ligands include chapters describing current research into the main clinical uses of opioids, analgesia and opioid abuse treatment, as well as what the editors consider to be key areas of pre-clinical development. Not surprisingly the identification of a fourth opioid-like receptor, the NOP receptor, has provided the stimulus for many studies with the aim of determining the potential therapeutic value of modulating the activity of this receptor. A number of chapters within this volume reflect the current interest in this new member of the family.
The 16 chapters of Research and Development of Opioid-Related Ligands are arranged into 5 themes, starting with the clinical studies of pain and opioid abuse treatment and followed by chapters on new ligand development, novel assays and concepts, classical opioid pharmacology and NOP receptor pharmacology. An emphasis is placed on translational science and how our increased knowledge may lead to new medicines. The development and use of ligands selective for one receptor or another continues to be of substantial interest, and indeed, the availability of such ligands has allowed the pharmacology of the NOP receptor to be studied in detail from soon after its discovery. Interestingly, ligands induce distinct receptor conformations and produce different signaling cascades, indicating that ligand-directed signaling or biased agonism may have important therapeutic implications. In addition we have now reached a point where selectively promiscuous ligands (ligands that bind to more than one receptor but with defined efficacy at each) can be designed. The rationale for, and progress in, targeting such ligands is made in a number of the chapters.
Preface .............................................................................................................................. xi
Commentaries
1. Commentary on the Current Status of Clinically Used Analgesics ..................... 3
Thomas M. Dodds
2. Commentary on the Current State of Opioid-Related Research ......................... 5
John W. Lewis
Clinical Studies of Pain and Opioids
3. The Clinical Importance of Conditioning Pain Modulation: A Review and
Clinical Implications ................................................................................................ 9
Mellar P. Davis
4. Treatment of Pain and Opioid Abuse ................................................................... 39
Shanthi Mogali and Sandra D. Comer
5. Treatment of Opioid Dependence ......................................................................... 61
Andrew J. Saxon
6. Buprenorphine in the Treatment of Neuropathic Pain ..................................... 103
Guy H. Hans
Development of New Ligands
7. Buprenorphine and Related Orvinols ................................................................ 127
Stephen M. Husbands
8. Structure-Activity Relationships of Nociceptin Receptor (NOP) Ligands
and the Design of Bifunctional NOP/Mu Opioid Receptor-Targeted
Ligands .................................................................................................................. 145
Nurulain T. Zaveri, Dennis Yasuda, Blair V. Journigan, Pankaj R. Daga,
Faming Jiang, and Cris Olsen
Novel Assays and Concepts
9. Mu, Delta and Kappa Opioid Agonist Effects In Novel Assays of
Pain-Depressed Behavior .................................................................................... 163
S. Stevens Negus and Ahmad A. Altarifi
10. Functionally Biased Agonism of Mu and Kappa Opioid Receptors ............... 177
Donald J. Kyle
Pharmacology of Classical Opioid Receptors
11. Peripherally Restricted Opioid Analgesics ........................................................ 201
Patrick J. Little
12. The Delta Opioid Receptor .................................................................................. 223
A. M. Symons-Liguori and T. W. Vanderah
13. Kappa Opioids: Problems and Opportunities in Analgesia ............................ 245
Eduardo R. Butelman and Mary Jeanne Kreek
14. Mixed Mu/Kappa Opioid Agonists ..................................................................... 257
Jean M. Bidlack and Brian I. Knapp
Pharmacology of NOP Receptors
15. Medicinal Chemistry, Pharmacology, and Biological Actions of Peptide
Ligands Selective for the Nociceptin/Orphanin FQ Receptor ......................... 275
Girolamo Calo' and Remo Guerrini
16. A Review of the NOP (ORL-1)-Nociceptin/Orphanin FQ System Covering
Receptor Structure, Distribution, Role in Analgesia and Reward and
Interactions with Other Receptors ..................................................................... 327
Garth T. Whiteside and Donald J. Kyle
17. Pharmacology of Mixed NOP/Mu Ligands ....................................................... 369
Lawrence Toll, Taline V. Khroyan, Willma E. Polgar, Stephen M. Husbands, and
Nurulain T. Zaveri
18. Pharmacological Investigation of NOP-Related Ligands as Analgesics
without Abuse Liability ....................................................................................... 393
Devki Sukhtankar and Mei-Chuan Ko
Editors' Biographies .................................................................................................... 417
Indexes
Author Index ................................................................................................................ 421
Subject Index