Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

How does the Opioid System Control Pain, Reward and Addictive Behaviors?

15.10.2007
Brigitte Kieffer, Ph.D, Institut de Génétique et de Biologie Moléculaire et Cellulaire Illkirch, France presents exciting new methods that now allow to understand how molecules act in the brain and control behaviour.

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
The finding that morphine’s analgesic and addictive properties are abolished in mice lacking the µ-opioid receptor has unambiguously demonstrated that µ-receptors mediate both the therapeutic and the adverse activities of this compound (Matthes 1996). Importantly, a series of studies has shown that the reinforcing properties of alcohol, cannabinoids, and nicotine — each of which acts at a different receptor — are also strongly diminished in these mutant mice. The genetic approach therefore highlights µ-receptors as convergent molecular switches, which mediate reinforcement following direct (morphine) or indirect activation (non-opioid drugs of abuse; see Contet 2004).

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
• a loss of morphine-induced analgesia, reward, and dependence
• increased sensitivity to painful stimuli
• reduced reward to non-opioid drugs of abuse and
• altered emotional responses
d-opioid-receptor
Analysis showed an unexpected alteration of emotional reactivity in the d-receptor knockout mice (Filliol et al 2000). The mutant mice demonstrated increased levels of anxiety, and a depressive-like behavior – these findings have important implications on the field of opioid research und uncover the therapeutic potential for d-agonists in the treatment of mood disorders.

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,
(ii) developed gene targeting approaches to elucidate the function of these genes in the mammalian brain;
It was found that µ-receptors control reward, while d-receptors regulate emotional responses and

for the first time a genetic manipulation was pioneered to achieve functional imaging of opioid receptors in vivo.

Conclusion

•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.

References

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
Further information:
http://www.ecnp.eu

More articles from Health and Medicine:

nachricht Study suggests possible new target for treating and preventing Alzheimer's
02.12.2016 | Oregon Health & Science University

nachricht The first analysis of Ewing's sarcoma methyloma opens doors to new treatments
01.12.2016 | IDIBELL-Bellvitge Biomedical Research Institute

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

Im Focus: Molecules change shape when wet

Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water

In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

IHP presents the fastest silicon-based transistor in the world

05.12.2016 | Power and Electrical Engineering

InLight study: insights into chemical processes using light

05.12.2016 | Materials Sciences

High-precision magnetic field sensing

05.12.2016 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>