How does the opioid system control pain, reward and addictive behavior?

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.

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 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).

mu-opioid-receptor

The finding that morphine’s analgesic and addictive properties are abolished in mice lacking the mu-opioid receptor has unambiguously demonstrated that mu-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 mu-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 mu-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 mu-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

delta-opioid-receptor

Analysis showed an unexpected alteration of emotional reactivity in the delta-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 delta-agonists in the treatment of mood disorders.