How do these opiates even work?

        Despite the fact that humans have been abusing opiates for centuries, the mechanism for how these opiates work in our brains to give us the pleasure of reward is still in its primitive stages. As Dr. Steidl pointed out in his talk, however, it seems that the dopamine system is important. According to his research findings, opiates, such as morphine, activate the dopamine system via disinhibition, a process of inhibiting GABA neurons in the ventral tegmental area (VTA) that were inhibiting dopamine release in local neurons and the nucleus accumbens (NAc). But is this the only way that morphine activates the reward system? Could there be inputs from the other parts of the brain that also help activate the dopamine reward system? In order to answer this question, Dr. Steidl and his team looked at morphine-induced locomotion (since dopamine has shown to induce locomotion) between M5-knockout mice and control mice. The M5-muscarinic receptor is found exclusively on dopamine neurons in the VTA and recieves cholinergic input from the pedunculopontine tegmental nuclei (PPTg). They found that these M5-knockout mice showed reduced morphine-induced locomotion. This allowed Dr. Steidl to summarize that in addition to the disinhibition of the GABA neurons, this cholinergic pathway is also important in morphine-induced activation of the dopamine system.
       There are numerous other studies that look at the mechanism of the opiate-induced activation of the dopamine system. The study by Hnasko et. al. looks at the bigger picture and looks at morphine reward in dopamine-deficient mice. What if someone took away all the dopamine in a mice brain. How would the mice react compared to normal mice and would morphine have an effect on it. They found that these dopamine-deficient mice were severely hypoactive, hypophagic, and required daily administration of L-dopa to prevent starvation. This shows us exactly how important dopamine is to our daily behavior. Without it, the simplest pleasures and even essentials of life don't seem important. After this administration of L-dopa, these mice were administered morphine and the researchers looked at a number of things. They first looked at morphine-induced locomotion via the open field paradigm (total locomotion in a big box is recorded) and found that these dopamine-deficient mice were very lethargic and showed almost no change in locomotion when compared to basal activity. Next, they looked at pain sensitivity via the tail flick test (light beam focused on mice tail and reaction time measured) and found that the dopamine-deficient mice flicked their tails a lot faster than the normal mice. This led them to believe that dopamine may play a role in suppressing pain. Finally, they looked at reward-seeking behavior via the conditioned place preference test (mice exposed to two rooms and given morphine in one and saline in other; then tested to see which they prefer). They found that these dopamine-deficient mice were able to develop a preference for the morphine-condition room, indicating that dopamine isn't essential for reward-seeking behavior in mice. There has to be a new pathway and the cholinergic pathway that Dr. Steidl found may play a part in it.
        Other research have shown that there is a difference in how morphine's rewarding effects activate the dopamine system that depends on whether the mice are morphine-deprived (drug withdrawal) and drug naive. This study by Nader and van der Kooy looked mice who had been grown a dependence on morphine and were experience withdrawal and mice who had never been exposed to morphine. By giving these mice either a dopamine antagonist or lesions on the PPTg, these researchers found that in deprived mice, morphine's rewarding effect is dopamine-mediated (only deprived mice failed to develop conditioned place preference for morphine environment when given dopamine antagonists) while in naive mice, morphine's rewarding effect is PPTg-mediated (only naive mice failed to develop conditioned place preference for morphine environment when given PPTg lesions). This further provides evidence of a cholinergic pathway originating in the PPTg that is involved in morphine's rewarding that Dr. Steidl proposes.
        In conclusion, this is just a simple preview of the research involved with how researchers think morphine, and similar opiates, affect the mice brain. Due to the fact that Dr. Steidl research is fairly new and still has found something so novel, it is necessary to look at this further. By blocking these pathways, it may be possible to help drug addicts recovering from opiates, since they are highly addicting. However, this would be futile if we weren't aware of all the pathways that morphine acts through. If we try to block only the ones we know, we will be wasting time and money because the morphine will still have its affect through different pathways as shown by these studies.


Steidl et. Yeomans: http://jpet.aspetjournals.org/content/328/1/263.full.pdf+html

Hnasko et al: https://courses.washington.edu/psy222/extracredit/extracredit/Morphine%20reward%20in%20dopamine-deficient%20mice.pdf

Nader et van der Kooy: http://www.jneurosci.org/content/17/1/383.full.pdf+html