Worldwide, an estimated 12 to 21 million people abuse opioids — including prescription pain killers, morphine, and heroin — while in the U.S. alone, 1.9 million people are addicted to prescription pain relievers.  Although the seduction of opioids may be clear to some people, what remains unknown is the effect of these drugs on specific pathways in the brain. Now, research led by a scientist at the Icahn School of Medicine at Mount Sinai reveals that use of opiates alters the activity of a specific protein known as RGS9-2, which in turn impacts and alters the normal functioning of the brain's reward center. By identifying the specific brain pathways that promote pain relief, addiction, and tolerance, the researchers are hoping to develop less dangerous yet more effective analgesics.

How Opiates Create a Feeling of Pleasure

What exactly happens in your body when you take an opiate such as the painkiller oxycodone? Essentially, after swallowing the pill, the chemicals travel through your bloodstream all the way to your brain, where they link up and attach themselves to specialized proteins known as mu opioid receptors. Once this chemical connection occurs, it sends a signal to the ventral tegmental area in the midbrain, which is involved in cognition, motivation, and most importantly reward, and from there, the brain dumps a neurotransmitter, dopamine, into the nucleus accumbens. This entire biochemical process — this pathway through the brain's biochemical circuitry — and in particular the release of dopamine, which has been linked to every type of reward that has ever been studied, creates a feeling of pleasure, even euphoria. Indeed, this very same series of reactions occur whenever you eat or orgasm.

For some time, scientists have understood the big picture of what happens in the brain when a person takes an opiate. What scientists are trying to discover now is the biochemical progress that takes place at the smallest, molecular level.

For the current study, senior researcher Dr. Venetia Zachariou, associate professor in the Department of Pharmacology and Systems Therapeutics at the Icahn School of Medicine at Mount Sinai, designed an experiment using mice. She and her colleagues employed optogenetics, a new technique that allows scientists to activate specific neurons to determine the exact cell types of the brain reward center responsible for the reduced analgesic response. Past research conducted by Zachariou suggested RGS9-2, a signaling protein, may terminate the activity of opioid receptors in the brain, and this process may be linked to the development of tolerance — in short, this may be key to why some people become addicted to opioids and others do not. To better understand the role played by RGS9-2, then, Zachariou and her colleagues alternately blocked the protein and increased its expression in a mouse’s nucleus accumbens, one component of the brain's reward center.

What did the researchers discover? The actions of opioids altered dramatically with each manipulation of the RGS9-2. "In our earlier work, by inactivating RGS9-2, we saw a tenfold increase in sensitivity to the rewarding actions of morphine, severe morphine dependence, a better analgesic response, and delayed development of tolerance," Zachariou stated in a press release. "We were able to block addiction-related behaviors, but increasing the activity of the protein also lowered the pain relief response to morphine, and mice developed morphine tolerance much more quickly."

Zachariou explained that the brain's reward center has a strong impact on analgesic responses, and it is for this reason non-opioid medications need to be developed. By targeting the RGS9-2 protein, scientists might someday develop an alternative therapy that offers relief without addiction for patients who suffer chronic conditions that cause pain.

 

Source: Zachariou V, Lobo MK, Deisseroth K, et al.  Nucleus Accumbens Specific Interventions in RGS9-2 Activity Modulate Responses to Morphine. Neuropsychopharmacology. 2014.