Understanding Opioid Actions, Pain and Analgesia: A Tribute to Dr. Gavril Pasternak.

This special issue is a tribute to our mentor, colleague and friend, Gavril W. Pasternak, MD, PhD. Homage to the breadth and depth of his work (~ 450 publications) over a 40 career in pharmacology and medicine cannot be captured fully in one special issue, but the 22 papers collected herein represent seven of the topics near and dear to Gav's heart, and the colleagues, friends and mentees who held him near to theirs. The seven themes include: (1) sites and mechanisms of opioid actions in vivo; (2) development of novel analgesic agents; (3) opioid tolerance, withdrawal and addiction: mechanisms and treatment; (4) opioid receptor splice variants; (5) novel research tools and approaches; (6) receptor signaling and crosstalk in vitro; and (7) mentorship. This introduction to the issue summarizes contributions and includes formal and personal remembrances of Gav that illustrate his personality, warmth, and dedication to making a difference in patient care and people's lives.

Endogenous opioids and feeding behavior: A decade of further progress (2004-2014). A Festschrift to Dr. Abba Kastin.

Functional elucidation of the endogenous opioid system temporally paralleled the creation and growth of the journal, Peptides, under the leadership of its founding editor, Dr. Abba Kastin. He was prescient in publishing annual and uninterrupted reviews on Endogenous Opiates and Behavior that served as a microcosm for the journal under his stewardship. This author published a 2004 review, "Endogenous opioids and feeding behavior: a thirty-year historical perspective", summarizing research in this field between 1974 and 2003. The present review "closes the circle" by reviewing the last 10 years (2004-2014) of research examining the role of endogenous opioids and feeding behavior. The review summarizes effects upon ingestive behavior following administration of opioid receptor agonists, in opioid receptor knockout animals, following administration of general opioid receptor antagonists, following administration of selective mu, delta, kappa and ORL-1 receptor antagonists, and evaluating opioid peptide and opioid receptor changes in different food intake models.

75 years of opioid research: the exciting but vain quest for the Holy Grail.

Over the 75-year lifetime of the British Pharmacological Society there has been an enormous expansion in our understanding of how opioid drugs act on the nervous system, with much of this effort aimed at developing powerful analgesic drugs devoid of the side effects associated with morphine--the Holy Grail of opioid research. At the molecular and cellular level multiple opioid receptors have been cloned and characterised, their potential for oligomerisation determined, a large family of endogenous opioid agonists has been discovered, multiple second messengers identified and our understanding of the adaptive changes to prolonged exposure to opioid drugs (tolerance and physical dependence) enhanced. In addition, we now have greater understanding of the processes by which opioids produce the euphoria that gives rise to the intense craving for these drugs in opioid addicts. In this article, we review the historical pathway of opioid research that has led to our current state of knowledge.

Endogenous opioids and feeding behavior: a 30-year historical perspective.

This invited review, based on the receipt of the Third Gayle A. Olson and Richard D. Olson Prize for the publication of the outstanding behavioral article published in the journal Peptides in 2002, examines the 30-year historical perspective of the role of the endogenous opioid system in feeding behavior. The review focuses on the advances that this field has made over the past 30 years as a result of the timely discoveries that were made concerning this important neuropeptide system, and how these discoveries were quickly applied to the analysis of feeding behavior and attendant homeostatic processes. The discoveries of the opioid receptors and opioid peptides, and the establishment of their relevance to feeding behavior were pivotal in studies performed in the 1970s. The 1980s were characterized by the establishment of opioid receptor subtype agonists and antagonists and their relevance to the modulation of feeding behavior as well as by the use of general opioid antagonists in demonstrating the wide array of ingestive situations and paradigms involving the endogenous opioid system. The more recent work from the 1990s to the present, utilizes the advantages created by the cloning of the opioid receptor genes, the development of knockout and knockdown techniques, the systematic utilization of a systems neuroscience approach, and establishment of the reciprocity of how manipulations of opioid peptides and receptors affect feeding behavior with how feeding states affect levels of opioid peptides and receptors. The role of G-protein effector systems in opioid-mediated feeding responses, which was the subject of the prize-winning article, is then reviewed.

Historical review: Opioid receptors.

A historical review of the early phases of molecular investigations of opioid receptors is presented. The 'modern' era of molecular studies of neurotransmitter and drug receptor research commenced in the 1970s with the identification of receptors using ligand binding techniques. These findings had several ramifications. Reversible ligand binding to opioid receptors using simple, sensitive and specific techniques provided a paradigm for the study of receptors for the principal neurotransmitters in the brain. The relatively high-throughput binding techniques employed facilitated drug development in the pharmaceutical industry. Differentiation of agonist and antagonist receptor interactions by Na(+) ions and other substances helped elucidate how ligand recognition at receptors is translated into second messenger alterations. Localizations of opioid receptors clarified many of the pharmacological actions of opiate drugs. Differential binding interactions of various drugs led to the identification of opioid receptor subtypes. Receptor influences in binding paradigms and smooth muscle pharmacology permitted the identification and isolation of endogenous opioid peptides.

Molecular imaging of the brain: a historical perspective.

The rapid expansion of modern molecular imaging methods since the time of their initial conception in the 1970s has given rise to numerous discoveries of molecular mechanisms that underlie brain function in health and disease. Uses in clinical diagnosis and therapy monitoring are still evolving. Future clinical trials, in which molecular imaging is imbedded and correlated with clinical outcomes, will be critical to advancing new uses for patient management. Receptor occupancy studies are already well integrated into many drug development studies and clinical trials; such studies will provide a basis for new studies that will further advance clinical uses of brain molecular imaging.

From outer to inner space: traveling along a scientific career from astrochemistry to drug research.

This professional history describes my journey as a research scientist after my early training and experiences in the pre- and early post-World War II United States. My graduate training concentrated on a problem in astrochemistry: phenomena on comets. As my career developed, I felt confident enough in myself as an experimentalist to enter, and make contributions to, several different fields: structural biochemistry (via nuclear magnetic resonance spectroscopy), molecular immunology, pharmacology, neurochemistry, and cell biology. One emphasis is on the nature and quality of my scientific training that permitted me to do cross-disciplinary work. A second emphasis is on the technical and intellectual developments in late twentieth-century science and how, along with the changes in American society as it passed through three major wars, they influenced my life and thought.

[Opioid receptors in the era of molecular biology: they account for more than 6,000 years of empirical pharmacology]. / Receptores opioides a la luz de la biología molecular: explican mas de 6.000 años de farmacología empírica.

The medicinal use of opium and of morphine in different cultures and ancient civilizations is described. Research within the past 40 years have demonstrated the existence of brain opiate receptors. Morphine and related opioid analgetic interact at these sites in the nervous system to produce the characteristic pharmacological effects of these drugs. The opiate receptors have structural homologies with a variety of other cell membrane receptors; they activate second messenger-based chemical transduction systems in the cell membrane and are endowed with several regulation mechanisms. These opiate receptors are presumably activated under specific physiological conditions by endogenous ligands (opiopeptins). It is currently thought that morphine mimicks the opiopeptins by interacting with these receptors either at different molecular subsites or with a different mode of action.

Receptores opioides a la luz de la biología molecular: explican mas de 6.000 años de farmacología empírica / Opioid receptors in the era of molecular biology: explain more than 6.000 years of empiric pharmacology

The medicinal use of opium and of morphine in different cultures and ancient civilizations is described. Research within the past 40 years have demonstrated the existence of brain opiate receptors. Morphine and related opioid analgetic interact at these sites in the nervous system to produce the characteristic pharmacological effects of these drugs. The opiate receptors have structural homologies with a variety of other cell membrane recpetors; they activate second messenger-based chemical transduction systems in the cell embrane and are endowed with several regulation mechanisms. These opiate receptors are presumably activated under specific physiological conditions by endogenous ligands (opiopeptins). It is currently thought thar morphine mimicks the opiopeptins by interacting with these receptors either at different molecular subsites or with a different mode of action

Opiate receptors--the historical breakthrough in drug research.

Morphine (Fig. 1) remains the most powerful analgesic but its therapeutic value is compromised by its strong reinforcing properties, making it highly addictive. This has stimulated the quest to find an analgesic lacking dependence-producing properties. So far no such drug has been discovered. However, this search has helped to disclose the large range of endogenous opioid peptides and the various receptors on which they act. This diversity and opportunity for interaction between exogenous drug and endogenous peptide, makes opiate dependence, tolerance and withdrawal complicated phenomena that are not fully understood at the molecular and cellular levels. The occurrence of opiate receptors in 'reward' pathways also makes them possible targets for the treatment of other addictions, adding a further dimension to the picture.

Subunit structure and purification of opioid receptors.

Considerable evidence indicates the existence of multiple types of opioid receptors. The three major types have been named mu, delta and kappa. The earlier evidence was based on pharmacological as well as membrane binding experiments. This paper will emphasize more recent studies using solubilized opioid binding sites. Several laboratories, including our own, have succeeded in separating kappa receptors from other types. A similar separation of mu from delta receptors has not yet been achieved. By crosslinking experiments with 125I- human beta-endorphin we have been able to provide strong evidence for differences in molecular size between the major binding components of mu (65K) and delta (53K) receptors. It is not yet established whether the difference resides in the protein or carbohydrate portion of these glycoproteins. These results suggest that the three major types of opioid receptors represent distinct molecular entities. An active opioid binding protein solubilized from bovine striatal membranes has been purified to apparent homogeneity. The major purification steps involve affinity chromatography and lectin chromatography on immobilized wheat germ agglutinin. The purified material gave a single band of molecular weight 65K Da on SDS-PAGE. Its specific activity for opioid binding was ca. 13,000 pmol/mg protein and its properties are those of a component of the mu receptor.