Research in mice shows molecular mechanism underlying Oxycodone addiction

RGS9-2, a key signaling protein in the brain known to play a critical role in the development of addiction-related behaviors, acts as a positive modulator of oxycodone reward in both pain-free and chronic pain states, according to a study conducted at the Icahn School of Medicine at Mount Sinai and published in the journal Neuropsychopharmacology. The mechanisms of oxycodone action uncovered through this study will help scientists and physicians develop strategies and tools to dissociate the analgesic (pain relief) actions of opioids from the addiction-related effects.

Pixabay images

Using mouse models of acute and chronic pain, Mount Sinai researchers found that RGS9-2, the intracellular protein that controls the function of opioid receptors in the brain reward center, promotes addiction to oxycodone in pain-free, acute, and chronic pain states. Mice that lacked the gene responsible for encoding RGS9-2 (RGS9KO mice) showed less propensity to develop addiction-related behaviors. Furthermore, the loss of RGS9-2 function does not affect the acute analgesic effects of oxycodone. The research team also found that RSG9-2 plays a protective role towards the development of oxycodone tolerance, as RGS9KO mice became tolerant to the analgesic effects of the drug earlier than those that had the gene. Researchers found that the same mechanisms control sensitivity to oxycodone addiction in pain-free as well as chronic pain states.

Oxycodone is a painkiller that is widely prescribed for acute and chronic pain conditions and is also among the most abused opioids. Oxycodone acts on the same brain receptors as morphine and heroin, the mu opioid receptors, which are present in many areas of the brain that mediate pain relief but are also expressed in the brain network associated with addiction. While there has been an extensive investigation into the mechanisms underlying the analgesia, dependence, and addiction potential of morphine, the mechanism by which oxycodone exerts its actions remained unknown.

“Although oxycodone produces similar analgesic and behavioral effects to those observed with morphine, our study demonstrates that the intracellular actions of morphine and oxycodone are distinct,” says Venetia Zachariou, Ph.D., Associate Professor in the Fishberg Department of Neuroscience and The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai. “Our work reveals that intracellular factors that prevent the actions of morphine may actually promote the actions of oxycodone. This information is particularly important for pain management strategies, as a common course is to have patients oscillate between oxycodone and morphine to achieve pain relief.”

This study provides new information on pathways involved in behavioral responses to oxycodone in pain-free and neuropathic pain states, which will help researchers and clinicians to determine the risks and benefits of oxycodone prescription for the treatment of pain. This knowledge may lead to the development of more efficacious and less addictive compounds for pain management.

Citation: Sevasti Gaspari, Valeria Cogliani, Lefteris Manouras, Ethan M Anderson, Vasiliki Mitsi, Kleopatra Avrampou, Fiona B Carr and Venetia Zachariou. “RGS9-2 Modulates Responses to Oxycodone in Pain-Free and Chronic Pain States.” Neuropsychopharmacology 2017.
DOI: 10.1038/npp.2017.4
Research funding: National Institute of Neurological Disorders and Stroke
Adapted from press release by The Mount Sinai Hospital.

Researchers develop in vitro model of brain for research

Harvard University researchers have developed a multiregional brain-on-a-chip that models the connectivity between three distinct regions of the brain. The in vitro model was used to extensively characterize the differences between neurons from different regions of the brain and to mimic the system’s connectivity.  The research was published in the Journal of Neurophysiology.

Image of the in vitro model showing three distinct regions of the brain connected by axons.
Credit: Disease Biophysics Group/Harvard University

“The brain is so much more than individual neurons,” said Ben Maoz, co-first author of the paper and postdoctoral fellow in the Disease Biophysics Group in the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS). “It’s about the different types of cells and the connectivity between different regions of the brain. When modeling the brain, you need to be able to recapitulate that connectivity because there are many different diseases that attack those connections.”

Researchers from the Disease Biophysics Group at SEAS and the Wyss Institute modeled three regions of the brain most affected by schizophrenia the amygdala, hippocampus and prefrontal cortex. They began by characterizing the cell composition, protein expression, metabolism, and electrical activity of neurons from each region in vitro.

“It’s no surprise that neurons in distinct regions of the brain are different but it is surprising just how different they are,” said Stephanie Dauth, co-first author of the paper and former postdoctoral fellow in the Disease Biophysics Group. “We found that the cell-type ratio, the metabolism, the protein expression and the electrical activity all differ between regions in vitro. This shows that it does make a difference which brain region’s neurons you’re working with.”

Next, the team looked at how these neurons change when they’re communicating with one another. To do that, they cultured cells from each region independently and then let the cells establish connections via guided pathways embedded in the chip.

The researchers then measured cell composition and electrical activity again and found that the cells dramatically changed when they were in contact with neurons from different regions.

“When the cells are communicating with other regions, the cellular composition of the culture changes, the electrophysiology changes, all these inherent properties of the neurons change,” said Maoz. “This shows how important it is to implement different brain regions into in vitro models, especially when studying how neurological diseases impact connected regions of the brain.”

To demonstrate the chip’s efficacy in modeling disease, the team doped different regions of the brain with the drug Phencyclidine hydrochloride commonly known as PCP which simulates schizophrenia. The brain-on-a-chip allowed the researchers for the first time to look at both the drug’s impact on the individual regions as well as its downstream effect on the interconnected regions in vitro.

The brain-on-a-chip could be useful for studying any number of neurological and psychiatric diseases, including drug addiction, post-traumatic stress disorder, and traumatic brain injury.

“To date, the Connectome project has not recognized all of the networks in the brain,” said Parker. “In our studies, we are showing that the extracellular matrix network is an important part of distinguishing different brain regions and that, subsequently, physiological and pathophysiological processes in these brain regions are unique. This advance will not only enable the development of therapeutics, but fundamental insights as to how we think, feel, and survive.”

Citation: Dauth, Stephanie, Ben M. Maoz, Sean P. Sheehy, Matthew A. Hemphill, Tara Murty, Mary Kate Macedonia, Angie M. Greer, Bogdan Budnik, and Kevin Kit Parker. “Neurons derived from different brain regions are inherently different in vitro: A novel multiregional brain-on-a-chip.” Journal of Neurophysiology (2016): jn-00575.
DOI: 10.1152/jn.00575.2016
Research funding: Defense Advanced Research Projects Agency.
Adapted from press release by Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS).