The opioid system controls pain, reward and addictive behaviors. Opioids exert their pharmacological actions through three opioid receptors, µ, d and ? whose genes have been cloned (Oprm, Oprd1 and Oprk1, respectively). Opioid receptors in the brain are activated by a family of endogenous peptides like enkephalins, dynorphins and endorphin, which are released by neurons. Opioid receptors can also be activated exogenously by alkaloid opiates, the prototype of which is morphine, which remains the most valuable painkiller in contemporary medicine.
By acting at opioid receptors, opiates such as morphine or heroin (a close chemically synthesized derivative) are extremely potent pain-killers, but are also highly addictive drugs.
To understand how molecules act in the brain and control behavior one can manipulate genes encoding these molecules in complex organisms, such as the mouse, and explore the consequences of these targeted genetic manipulations on animal responses in vivo.
Today, genetically modified mouse models represent a state-of-the art approach towards understanding brain function.
The direct comparison of mice lacking each of the three opioid-receptor genes reveals that µ- and d-opioid receptors act oppositely in regulating emotional reactivity. This highlights a novel aspect of µ- and d-receptor interactions, which contrasts with the former commonly accepted idea that activation of µ- and d-receptors produces similar biological effects (Traynor & Elliot, 1993).µ-opioid-receptor
Endogenous opioid binding to µ-receptors is furthermore hypothesized to mediate natural rewards and has been proposed to be the basis of infant attachment behavior (Moles 2004).Mice lacking the µ-receptor gene show
The most recent findings are the direct visualization of an opioid receptor in the mouse brain. The combination of fluorescent genetically encoded proteins (green fluorescent protein GFP from the jellyfish (Aequora victoria) with mouse engineering provides a fascinating means to study dynamic biological processes in mammals. Fluorescent genetically encoded proteins are unique high-contrast, noninvasive molecular markers for live imaging in complex organisms and provide the exploration of the receptor localization and function in vivo.
Scherrer et al. have knocked enhanced green fluorescent protein (EGFP) into the opioid d receptor gene and produced mice expressing a functional DOR-EGFP C-terminal fusion in place of the native DOR. After manipulation of the mouse genome mutant animals express a fluorescent functional version of the d-receptor in place of the native receptor (knock-in mouse) (Scherrer et al. 2006). This is the first example of a G protein coupled receptor directly visible in vivo.
G protein-coupled receptors (GPCRs) are the largest family of membrane receptors and are therapeutically essential, representing targets for 50% of marketed drugs (Scherrer et al., 2006). µ-, d- and ?-opioid-receptors are GPCRs of the nervous system.
The DOR-EGFP mouse provides a unique approach to explore receptor localization and function in vivo. GPCR represent the largest and most versatile family of membrane receptors, and each member has a specific cellular life cycle. The EGFP-knocking approach could be extended to other GPCRs, particulary in the case of orphan receptors for which in vivo pharmacology is still in its infancy (Scherrer et al., 2006).
Altogether there have been(i) identified genes encoding receptors from a complex neuromodulatory system,
for the first time a genetic manipulation was pioneered to achieve functional imaging of opioid receptors in vivo.
•The opioid system consists of three G protein-coupled receptors, µ-, d-, and ?, which are stimulated by a family of endogenous opioid peptides.
•µ-opioid receptors are a key molecular switch triggering brain reward systems and potentially initiating addictive behaviors. The lack of µ-receptors abolishes the analgesic effect of morphine, as well as place-preference activity and physical dependence. This receptor therefore mediates therapeutic (analgesia) and adverse (addiction) activities of morphine, suggesting that further development of morphine-like compounds may necessarily lead to addictive analgesics.
•Studies of mutant mice also suggest a role for µ-opioid receptors in diseases characterized by deficits in attachment behavior, such as autism or reactive attachment disorder. The data also highlight mice lacking µ-opioid receptors as a useful animal model to evaluate the consequences of deficits in the affiliative system during development and adulthood.
•The rewarding properties of both opioid, as well as non-opioid drugs of abuse (cannabinoids, ethanol and nicotine, natural reinforcers) are abolished in the µ-receptor knockout mice. Blocking the µ-receptor may build a valuable approach for the treatment for drug abuse.
•Beyond the rewarding aspect of drug consumption, pharmacological studies have also suggested a role for this receptor in the maintenance of drug use, as well as craving and relapse. As a consequence, expanding our understanding of µ-receptor function should greatly help to further our knowledge of the general mechanisms that underlie addiction.
•Opiate addicts, who mainly abuse the µ-opioid agonist heroin, present a high incidence of depressive disorders that seem to contribute to the maintenance of the addictive state. Also, the treatment of chronic pain states frequently includes antidepressant therapy. Therefore, in addition to their potential analgesic activity, d-agonists may be useful in improving emotional states and, more generally, may be considered in the future as an alternative therapy to alleviate affective disorders.
Traynor JR, Elliott J. delta-Opioid receptor subtypes and cross-talk with mu-receptors. Trends Pharmacol Sci 1993;14(3):84-6
Matthes HW, Maldonado R, Simonin F, Valverde O, Slowe S, Kitchen I, Befort K, Dierich A, Le Meur M, Dolle P, Tzavara E, Hanoune J, Roques BP, Kiefer BL. Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene. Nature 1996;383(6603):819-23
Filliol D, Ghozland S, Chluba J, Martin M, Matthes HW, Simonin F, Befort K, Gaveriaux-Ruff C, Dierich A, LeMeur M, Valverde O, Maldonado R, Kiefer BL. Mice deficient for delta- and mu-opioid receptors exhibit opposing alterations of emotional responses. Nat Genet 2000;25(2):195-200
Moles A, Kiefer BL, D'Amato FR. Deficit in attachment behavior in mice lacking the mu-opioid receptor gene. Science 2004;304(5679):1983-6
Scherrer G, Tryoen-Toth P, Filliol D, Matifas A, Laustriat D, Cao YQ, Basbaum AI, Dierich A, Vonesh JL, Gaveriaux-Ruff C, Kiefer BL. Knockin mice expressing fluorescent delta-opioid receptors uncover G protein-coupled receptor dynamics in vivo. Proc Natl Acad Sci USA 2006;103(25):9691-6
Contet CS, Kieffer BL and Befort K. Mu opioid receptor: a gateway to drug addiction. Curr Op Neurobiol 2004;14:1-9
Maria Vrijmoed-de Vries | alfa
'Living bandages': NUST MISIS scientists develop biocompatible anti-burn nanofibers
16.02.2018 | National University of Science and Technology MISIS
New process allows tailor-made malaria research
16.02.2018 | Eberhard Karls Universität Tübingen
Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale
Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...
For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.
But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...
Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.
The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...
Theoretical physicists propose to use negative interference to control heat flow in quantum devices. Study published in Physical Review Letters
Quantum computer parts are sensitive and need to be cooled to very low temperatures. Their tiny size makes them particularly susceptible to a temperature...
Let’s say the armrest is broken in your vintage car. As things stand, you would need a lot of luck and persistence to find the right spare part. But in the world of Industrie 4.0 and production with batch sizes of one, you can simply scan the armrest and print it out. This is made possible by the first ever 3D scanner capable of working autonomously and in real time. The autonomous scanning system will be on display at the Hannover Messe Preview on February 6 and at the Hannover Messe proper from April 23 to 27, 2018 (Hall 6, Booth A30).
Part of the charm of vintage cars is that they stopped making them long ago, so it is special when you do see one out on the roads. If something breaks or...
15.02.2018 | Event News
13.02.2018 | Event News
12.02.2018 | Event News
16.02.2018 | Information Technology
16.02.2018 | Health and Medicine
16.02.2018 | Physics and Astronomy