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 A promising target for kidney fibrosis
21.04.2017 | Brigham and Women's Hospital

nachricht Stem cell transplants: activating signal paths may protect from graft-versus-host disease
20.04.2017 | Technische Universität München

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: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

Im Focus: Quantum-physical Model System

Computer-assisted methods aid Heidelberg physicists in reproducing experiment with ultracold atoms

Two researchers at Heidelberg University have developed a model system that enables a better understanding of the processes in a quantum-physical experiment...

Im Focus: Glacier bacteria’s contribution to carbon cycling

Glaciers might seem rather inhospitable environments. However, they are home to a diverse and vibrant microbial community. It’s becoming increasingly clear that they play a bigger role in the carbon cycle than previously thought.

A new study, now published in the journal Nature Geoscience, shows how microbial communities in melting glaciers contribute to the Earth’s carbon cycle, a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

New quantum liquid crystals may play role in future of computers

21.04.2017 | Physics and Astronomy

A promising target for kidney fibrosis

21.04.2017 | Health and Medicine

Light rays from a supernova bent by the curvature of space-time around a galaxy

21.04.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>