Opiate Research Research Articles

Neuroimaging reveals distinct brain glucose metabolism patterns associated with morphine consumption in Lewis and Fischer 344 rat strains

Vulnerability to addiction may be given by the individual's risk of developing an addiction during their lifetime. A challenge in the neurobiology of drug addiction is understanding why some people become addicted to drugs. Here, we used positron emission tomography (PET) and statistical parametric mapping (SPM) to evaluate changes in brain glucose metabolism in response to chronic morphine self-administration (MSA) in two rat strains with different vulnerability to drug abuse, Lewis (LEW) and Fischer 344 (F344). Four groups of animals were trained to self-administer morphine or saline for 15 days. 2-deoxy-2-[18F]-fluoro-d-glucose (FDG)-PET studies were performed on the last day of MSA (acquisition phase) and after 15 days of withdrawal. PET data were analyzed using SPM12. LEW-animals self-administered more morphine injections per session than F344-animals. We found significant brain metabolic differences between LEW and F344 strains in the cortex, hypothalamus, brainstem, and cerebellum. In addition, the different brain metabolic patterns observed after the MSA study between these rat strains indicate differences in the efficiency of neural substrates to translate the drug effects, which could explain the differences in predisposition to morphine abuse between one individual and another. These findings have important implications for the use of these rat strains in translational morphine and opiate research.

The life of the heroin user: typical beginnings, trajectories and outcomes

Heroin is a worldwide scourge and a seemingly intractable one. The Life of the Heroin User: Typical Beginnings, Trajectories and Outcomes is the first book to apply a biographical approach to the lifecycle of the heroin user from birth until death. Chapters address each stage of the user's life, including childhood, routes to use, the development of dependence, problems arising from addiction, death and options for treatment and prevention. Drawing on over two decades of experience in the field of opiate research, Shane Darke examines major theoretical approaches to the development of opiate dependence and the efficacy of treatment options for opiate dependence. Key points are presented at the end of each chapter. The most detailed review available of what is likely to happen to the dependent heroin user, this is an important book for clinicians, researchers and students in the fields of drug and alcohol studies and public health.

Book Review: Drugs and Narcotics in History

and Narcotics in History, edited by Roy Porter and Mikulas Teich (Cambridge: Cambridge University Press, 1995), xii + 227 pp., $49.95 (cloth only). The past decade has witnessed global expansion of War on Drugs, rapid escalation of government antismoking campaigns in United States, and proliferation of prescription medications such as Prozac and Ritalin. The same period has also played spectator to unprecedented growth of historical literature on use and regulation of psychoactive substances.' The two developments are probably not unrelated. As opiate researcher Solomon Snyder pointed out in Brainstorming, his autobiographical account of politics of opiate research, scientists' research interests frequently follow trail of politicians' interests and allied government funding. It is hardly surprising, then, that historians, sociologists, and anthropologists should embrace an issue as fascinating and as hot as drug use. The topic is at once an integral part of modern civilization, an intimidating and seemingly intractable social problem, and an area in which historians and social scientists have potentialhowever illusory-to contribute to modern policy-making by revealing multiplicity of factors mediating society's response to drugs. This is spirit in which Roy Porter and Mikulas Teich assembled essays contained in and Narcotics in History. Unfortunately, not all essays shed light on either historical or contemporary dimensions of drug manufacture, use, and regulation, although some raise interesting issues-particularly those by Caroline Acker, Virginia Berridge, Andreas-Holger Maehle, Rudi Matthee, John Parascandola, and John Scarborough. The book's chief weakness is a singular lack of fit, presaged in introductory remarks of Porter and Teich. Here editors assert that studying history of drug use and examining contemporary drug situation are mutually illuminating, only to contradict themselves in next sentence, where they note that the present-day situation cannot be compared with one in past either quantitatively or qualitatively. This sort of discontinuity typifies and Narcotics. Because essays in and Narcotics vary greatly in scope and quality, it would be useful to have an introduction that links or juxtaposes papers and highlights common or contrasting themes and issues addressed. The two-and-a-halfpage introduction affords little in this way. Nor do editors offer a historiographic context in which to fit essays. In sum, pieces are left to stand on their own, as widely varying examples of field's expansion. The only unifying thread offered by editors is each essay's ability to raise questions about type of society which engenders specific ideas and policies about drug matters, how they come into being, are applied, and change in time (p. 2). This is not sufficient to tie together a group of essays ranging from Greek and Roman opium use (John Scarborough) to British and German pharmaceutical industries (S. W. F. Holloway and Erika Hickel), epidemiology of Native American drinking (Steve Kunitz and Jerrold Levy) and a personalized polemic against War on Drugs (Ann Dally). and Narcotics begins with John Scarborough's essay on opium poppy in Hellenistic and Roman times. Drawing heavily on Dioscorides' Materia Medica, Scarborough argues convincingly that Ancients developed sophisticated forms and uses of opium. He also addresses Marcus Aurelius' use of an opium-containing theriac and tonic, mediated through his physician, Galen. Historians have anachronistically labeled this an addiction. Instead, Scarborough urges that we not conflate consistent but varied use of relatively weak opium latex with consumption of poppy's more potent derivatives, morphine and heroin. In short, both content and context of drugs used are as important as use itself. …

Differential Roles of Opioid Receptors in Respiration, Respiratory Disease, and Opiate-induced Respiratory Depression

In summary, these findings indicate the importance of designing future experiments that delineate between opioid and nonopioid forms of respiratory disease and dysfunction, and the need to identify means of diagnosing them in order to achieve successful recovery. Apparently there is great diversity between animal species in terms of contributions of endogenous opioids to tonic control of ventilation, and future work should strive to identify which species is most appropriate as a model of human ventilatory control and disease. Certain opioid receptor types appear to be linked to independent respiratory functions. For instance, mu receptors in the brain stem produce strong inhibitory actions on respiratory parameters, including RR, VT, VE, and CO2 sensitivity. These effects have been observed in vivo and by electrophysiologic recordings in vitro. Delta receptors may also exert some inhibitory effect on respiration, especially in the NTS. In the CNS, the ventral surfaces of the medulla and pons, especially the NTS and NA, seem to be important sites for opioid-induced inhibition of respiration, whereas the spinal cord probably is not involved in opioid-mediated ventilatory depression. Kappa receptors appear to be devoid of respiratory depressant activity, whereas sigma receptors may stimulate some ventilatory parameters. Morphine and similar pure mu agonists, such as fentanyl and oxymorphine, probably produce their analgesic and respiratory depressant effects through stimulation of mu receptors. Mixed agonists/antagonists that have mu antagonist (or partial agonist) activity plus kappa agonist and/or sigma agonist activity show a ceiling effect for respiratory depression. Future tests need to determine which opioid receptor may be responsible for the ceiling effect. In addition, the effects of mu, delta, kappa, and sigma selective agonists on hypoxic drive should also be determined, as a drug that stimulates hypoxic sensitivity in the face of hypercapnic depression may produce less overall respiratory depression due to counteractive effects. In the future, clinically optimal opiates should have more specificity of action than those available now. This may be achieved by creating drugs selective for single receptors or by creating drugs with desirable combinations of receptor selectivities. The combinations of mixed agonists/antagonists with pure mu agonists currently in use today are promising, as they provide analgesia with reduced respiratory depression. In the early days of opiate research and development, combination drug regimens were thoroughly tested to determine the "ideal ratios" that would retain analgesic properties but not the other undesirable effects such as respiratory depression (196).(ABSTRACT TRUNCATED AT 400 WORDS)

Brainstorming: The Science and Politics of Opiate Research

In the galaxy of brain research, no star shines brighter than Solomon Snyder, a supernova to many. His memoir, Brainstorming , is a lambent account of successful research: a blend of political machinations, personnel legerdemain, astute observation, and competitiveness. From this ferment emanate departments of psychiatry, research papers, PhD theses, advances in medicine, and, eventually, Nobel laureates. The narrative begins in one of the many battles (the 1972 eruption) in the seemingly eternal war against drugs, a politically energized process dating back well before the Harrison Narcotic Act of 1914. In many respects it is an indictment of the process that subverts scientific/clinical endeavors to political gain. Money is not only the mother's milk of politics, it is the mother's milk of research, and politics is the mother that produces the milk. It is delivered in the form of grants and has resulted in a cottage industry known as grantsmanship,

Brainstorming: the science and politics of opiate research

Describes the scientific research that led to a better understanding of how drugs affect the brain and looks at the future of drug research.

Opiates for the people

Brainstorming: The Science and Politics of Opiate Research. By Solomon H. Snyder. Harvard University Press: 1989. Pp. 208. $22.50. To be published in Britain next month, £17.95.

The nonimpact of opiate research on opiate abuse.

The nonimpact of opiate research on opiate abuse.

Cardiovascular effects of endogenous opiate systems.

Opiates are among the oldest pharmacological substances known to man; their analgesic, euphoric, and addictive effects have been traditional focal points for opiate research. Without doubt, the cardiovascular effects of opiates have also been apparent to the user or abuser of opiate substances for several centuries. Persons seeking analgesic, euphoric, or antidiarrheal actions from opiate alkaloids have probably noted dizziness upon sudden st,anding due to the orthostatic hypotension these substances produce. His­ torically, however, scientific study on the cardiovascular responses to ad­ ministered opiates has lagged behind other areas of opiate research. This is understandable as, relative to doses required for their analgesic actions in humans, the cardiovascular effects of opiates are less noticeable and, indeed, undesirable. Early studies established that cardiovascular responses to morphine var­ ied among species; both autonomic and histamine-releasing properties con­ tributed to their hypotensive and bradycardic actions (1-5). Generally speaking, morphine was shown to produce prominent effects upon brain­ stem and hypothalamic centers that resulted in increased parasympathetic and decreased sympathetic tone (3-6). These effects upon autonomic out­ flow caused a depression of both heart rate and blood pressure. A resurgence of interest in opiate-cardiovascular interactions followed the discovery of endogenous opiate systems (for review see 7). A family of opioid peptides were found to be located at sites suggesting an autonomic action (8); also, opiate receptors were shown to be densely distributed in the brainstem and hypothalamus in close proximity to cardiovascular centers as well as endogenous opiate pathways (9, to). These anatomical findings

Some thoughts about opiopeptins, peptides with opiate-like activity

When the announcement was made late in 1975, that two closely related pentapeptides (enkephalins) with opiate-like activity had been isolated from porcine brain, there was much excitement. For the biologists not particularly interested in opiates, the finding meant that there were new fields to plow because the novel substances in all probability must be associated with unknown neurons with important physiologic functions. To the pharma- cologists, however, especially those who had been engaged in opiate research, this was tremendously uplifting. I recall saying to myself: Even without any facts, it was not too difficult for me to rationalize and formulate a plausible hypothesis involving the newly discovered peptides to explain heroin addiction. Persons finding it difficult to cope with the stresses of today's competitive society must have a deficiency of enkephalin. Instinctively, they crave heroin to remedy this aberration, and taking the replacement drug, gain instantaneous relief. However, this alleviation can only be temporary because repeated administration of the narcotic turns off the synthesis of the native opioid ligand and this results in further depletion of an already reduced supply. A compensatory mechanism must then develop to certain biochemical processes ordinarily inhibited by enkephalin. As they become increasingly suppressed by repeated high doses of the exogenous substitute a counter-adaptive response results in the inhibited sites developing suprasensitivity, and when the heroin is discontinued, the suprasensitive processes became manifest by an overshoot rebound or the withdrawal syndrome. Thus, now that the endogenous ligand is known it should not be too difficult to determine its physiologic role and sort out the processes it regulates. This knowledge should pave the way to explain acute opiate effects as well as tolerance and physical dependence. Seven years later I am somewhat less ebullient but still full of hope and optimism. Since the isolation of the enkephalins several more peptides with greater potency have been identified and the literature on peptides with

Recent developments in opiate and opioid peptide research and their relation to tolerance and dependence

In 1680, the English physician Thomas Sydenham wrote, Among the remedies which it has pleased Almightly God to give man to relieve his suffering, none is so universal and so efficacious as opium. Over the intervening centuries, the admiration of the medical community for the pain relieving effects of opium and its derivatives has been tempered by an increasing awareness of their toxicity and addictiveness. This, together with the lack of any other known class of drugs that exert the powerful analgesic action of opiates, has stimulated an intensive search for synthetic opiates with the desirable properties of morphine, but without the undesirable sideeffects. More recently, natural morphine-like substances have been found in the brain. These substances promise to open new avenues to an understanding of precisely where in the body opiates act, how they do so and why they are addictive. The general aim of this conference is to discuss drug-related problems and drug dependence. The basic scientist approaches this important field of study by attempting to understand precisely how these drugs affect the organism, and, in the case of opiates, how they interact with the central nervous system (CNS). My intention isto describe some recent advances in opiate research, including some of our own work, and to give an overview of how these affect the problems of dependence. Drugs, hormones and neurotransmitters all produce their effects at very low concentration. It is usually assumed they act at specific receptor sites located on the external surface of cells in the target organs. The notion that some tissues might possess such receptors for opiates is supported by the facts that (1) opiate agonists have similar chemical structure, (2) they are stereospecific in that only the laevo isomers are active, and (3) opiate antagonists can be formed by very slight molecular modifications of agonists. For these reasons, pharmacologists assumed that specific opiate receptors must exist in the brain and possibly in other tissues. In the early 1970s, receptors for opiates were identifed by binding radioactively labelled opiates to fragments of membrane from homogenized brain cells. Not only was this binding shown to be stereospecific, but perhaps more importantly, the affinity or tightness with which a range of agonists bound to the receptor closely paralleled their pharmacological activity. With these techniques it was soon demonstrated that the distribution and density of the opiate receptor in different regions of the CNS corresponded to those regions and pathways believed associated with the sensory and emotional aspects of pain. What are these receptors for opiates doing there? The findings suggested the presence of a natural morphine-like substance in the brain, possibly a neurotransmiffer, that acts at these receptors. The speculafion ended when, in 1975, a remarkable discovery was made w two pentapeptides were isolated from the brain which behaved like opiates in a number of pharmacological tests using peripheral tissues, such as the mouse vas deferens and guinea pig ileum. These actions were stereospecific and were antagonized by naloxone, indicating an action on the opiate receptor. 12 These pentapeptides, with the amino acid sequences of TYR-GLY-GLY-PHE-MET and TYR-GLY-GLY-PHE-LEU, were given the names Methionine- and Leucine-Enkephalin respectively. This sequence was soon recognized by some chemists to be present within the pituitary homone betalipotropin. The enkephalin sequence occurs at positions 61-65 in the 91 amino acid beta-lipotropin molecule, and the C-terminal fragment (amino acids 61-91) was found to be a potent opiate peptide. The term endorphins has been applied to the family of larger peptides, the prototype beta-Upotropin 61-91 being called beta-endorphine (for review, see Snyder,

Opiate receptors and endogenous opiates: Panorama of opiate research

1. In the last ten years basic research on the mechanism of action of opiates has led to the clearcut demonstration of the existence of opiate receptors — — possibly several slightly different kinds — — in the nervous system. 2. A number of endogenous ligands also called endorphins or enkephalins for these receptors have been discovered that proved to be peptides with opiate-like pharmacological activity and were shown to be localized in strategic neuronal pathways in the brain, spinal cord and pituitary gland. 3. Clinical researchers are beginning to explore the possible role of these opiate-like peptides in a variety of clinical situations such as: pain and analgesia, tolerance and dependence, reinforcement mechanisms, memory processes and learning, and mental illness such as schizophrenia. 4. The discovery of biologically active opioid and other peptides coexisting with more traditional neurotransmitters in the same neurons may lead to a reevaluation of our fundamental notions of how the brain operates. This is viewed as a major advancement not only to our understanding of the theoretical basis of drug actions but also as a first step towards the development of new, practically useful methods for treating the clinical problems associated with drug abuse.

Tolerance to the Mydriatic effects of morphine in mice.

When injected to mice, opiates produce mydriasis. Animals treated chronically with morphine, developed tolerance to the mydriatic effects of morphine. The degree and consistency of the response make the pupil a valuable tool in opiate research.

Neurochemical Mechanisms of Opiates and Endorphins

This volume comprises 21 articles that present a fairly complete survey of current opiate research. As such, it is a primary resource for scientists working with opiates and opiate peptides. However, the research it presents is also of considerable exemplary value to other neurobiologists and to neuropharmacologists. Unfortunately, in a scientific area where the tempo of discovery is extremely rapid, it is difficult for an edition of this sort to remain current for long. Moreover, due to the youth of this field, many of the biochemical details of the synthesis of the opiate peptides and their precursor forms are sketchy, and the theories of the activities and the actions of the peptides remain tentative. It would be premature to take the title of the volume too seriously in terms of providing a final integrated view of the mechanism of opiates and endorphins. This should not be interpreted as a criticism

Book Reviews

Book reviewed in this articleSmoking: A social interactional theory of cigarette smoking and quitting. By Robert R. Clark. Clinical Toxicology. Volume 18. Proceedings of the European Society of Toxicology. Edited by W. A. M. Duncan and B. J. Leonard. Workers Who Drink. By Carl J. Schramm, Wallace Mandell and Janet Archer. The Working Addict. By David Caplovitz. Drug Detoxification: A Comprehensive Examination. By Joyce Lowinson and John Langrod. Methadone Detoxification: Personality Correlates and Therapeutic Implications. By John Langrod, Joyce Lowinson and Lois Alksne. Phencyclidine Abuse: An Appraisal. Edited by Robert C. Petersen and Richard C. Stillman. Drugs, Crime and Politics. Edited by Arnold S. Trebach. Ten‐ to Fourteen‐year‐olds and Alcohol: A developmental study in the Central Region of Scotland. By P. P. Aitken. Edinburgh. Developments in Opiate Research. Edited by Albert Herz. The Treatment of Alcoholics. Critical Concerns in the Field of Drug Abuse. Edited by A. Schecter, H. Alksne and E. Kaufman. Handbook of Psychopharmacology. Volume 12: Drugs of Abuse. Edited by Leslie L. Iversen, Susan D. Iversen and Solomon H. Snyder. Alcohol: What do you know? Teaching about Alcohol and Drinking.

Developments in Opiate Research. Albert Herz

Previous articleNext article No AccessNew Biological BooksDevelopments in Opiate Research. Albert Herz Eric J. SimonEric J. Simon Search for more articles by this author PDFPDF PLUS Add to favoritesDownload CitationTrack CitationsPermissionsReprints Share onFacebookTwitterLinkedInRedditEmail SectionsMoreDetailsFiguresReferencesCited by The Quarterly Review of Biology Volume 54, Number 2Jun., 1979 Published in association with Stony Brook University Article DOIhttps://doi.org/10.1086/411265 Copyright 1979 The Stony Brook Foundation, Inc.PDF download Crossref reports no articles citing this article.

Clinical relevance of opiate receptor and opioid peptide research

Clinical relevance of opiate receptor and opioid peptide research

The Opiate Receptors

The extract of the opium poppy is among the oldest materials used for medicinal purposes, and the study of the major alkaloid in this extract, morphine. is one of the oldest areas of biological research. Our lack of understanding on the molecular level of how morphine and its analogues produce their effects may be in large part related to the fact that they exert most of their actions on the central nervous system. the most complex organ in animals and man. The opiates produce a large variety of pharmacological responses, the most important of which are analgesia. euphoria, and addiction. The latter includes the development of tolerance and physiological and psychological dependence. The discovery of opiate receptors in the central nervous system of animals and man and the resulting discovery of endogenous opiate-like ligands for these receptors (discussed in this issue by L. Terenius and introduced briefly in this review) have given rise to considerable activity and excite­ ment in the field of opiate research. In this review we attempt to cover. within the limitations of space, the most significant advances in our knowledge of opiate receptors since their discovery.

Recent developments in opiate research and their implications for psychiatry.

Considerable progress in opiate research has been made during the last few years regarding the identification and localization of opiate receptors in vitro and in vivo, the analysis of drug-receptor interactions and the characterization of an endogenous ligand of the opiate receptor. There is little evidence that effects induced by chronic exposure to opiates - development of tolerance and dependence -are due to changes in opiate receptor mechanisms; it is supposed that the adaptive changes occur mainly in the chain of events triggered by the drug-receptor interaction. Such changes may be directly or indirectly related to the metabolism of neurotransmitters and/or cyclic nucleotides. The obvious links between physical and psychic equivalents of opiate dependence are discussed. Present data points to the significance of brain stem and limbic structures in both these processes, monoamines probably playing an important role. Relations between psychic manifestations of opiate addiction and mental disorders are pointed out.