The opioid system controls pain, reward and addictive behaviors. Opioids exert their pharmacological actions through three opioid receptors, mu, delta and kappa 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.
AdvertisementTo 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.
The direct comparison of mice lacking each of the three opioid-receptor genes reveals that mu- and delta-opioid receptors act oppositely in regulating emotional reactivity. This highlights a novel aspect of mu- and delta-receptor interactions, which contrasts with the former commonly accepted idea that activation of mu- and delta-receptors produces similar biological effects (Traynor & Elliot, 1993).
The opioid system consists of three G protein-coupled receptors, mu-, delta-, and kappa, which are stimulated by a family of endogenous opioid peptides.
mu-opioid receptors are a key molecular switch triggering brain reward systems and potentially initiating addictive behaviors. The lack of mu-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 mu-opioid receptors in diseases characterized by deficits in attachment behavior, such as autism or reactive attachment disorder. The data also highlight mice lacking mu-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 mu-receptor knockout mice. Blocking the mu-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 mu-receptor function should greatly help to further our knowledge of the general mechanisms that underlie addiction.
Opiate addicts, who mainly abuse the mu-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, delta-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.
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