Julie Blendy, professor of pharmacology at University of Pennsylvania’s Perelman School of Medicine, presented her research on the molecular and genetic mechanisms behind opioid use disorders in the annual Frank G. Standaert Lectureship in Pharmacology at Georgetown University Medical Center on Jan. 12. 

Blendy utilizes a mouse model to investigate the functional effect of a single nucleotide substitution in the gene OPRM1, which codes for the mu opioid receptor. This receptor binds opioids and is distributed throughout the brain and spinal cord. The original nucleotide, or building block of DNA, is an adenine, corresponding to the A allele, but in some individuals, this adenine is substituted by a guanine, which corresponds to the G allele. 

By inducing this substitution in mice, Blendy’s lab was able to show that possession of the G allele was associated with lower mu opioid receptor levels. However, Blendy wanted to understand what the behavioral implications of this “loss-of-function” G allele were. According to Blendy, prior research has shown that this allele affects pain tolerance.

“Human studies have actually shown that individuals with the G allele will have actually elevated pain responses. It’s also associated with a decreased pain threshold, and individuals with the G allele require significantly more opiates or morphine to attain that analgesic effect,” Blendy said. 

Blendy’s research found that G/G mice — mice that are homozygous for the G allele — did in fact have a lower pain threshold and did not undergo locomotor sensitization, which is an increase in movement upon drug exposure. Additionally, the effects of this genotype varied by sex; the G/G males exhibited higher drug-seeking behavior and preference for the rewarding stimulus of the drug, while the females did not.

Since these initial experiments focused on the acute phase of substance abuse induced by short-term exposure to the drug, Blendy wanted to apply the mouse model to understanding the chronic opioid-dependent phase, which is linked to changes in brain plasticity.

“Brain plasticity can be shown at the level of individual neurons, specifically dendritic spines, for example, which can impact how cells communicate with each other, which ultimately can impact how the whole connectivity of the brain is working,” Blendy said. 

Blendy’s connectivity studies showed that males with the G/G genotype had less neuronal activity in most brain regions post-morphine exposure, an effect not seen in the G/G females. The female G/G mice also had high clustering among brain regions, meaning that many brain regions seem to be functionally connected to each other. These findings provide insight into how much energy is required to transition from the acute state to the opioid dependent state, according to Blendy. 

“In general, G/G females require a large amount of energy to convert from an acute to a dependent state and have a less stable network in this dependent state. Actually challenging to determine if this means they are more protected or more vulnerable to opioid use disorders,” Blendy wrote to The Hoya. 

Dr. Rebekah Evans, an assistant professor in the department of neuroscience at Georgetown University who also studies brain connectivity, attended the talk and wondered how the mu opioid receptor mutation impacts another brain region called the striatum, which is involved in developing habits and addiction.

“The striatum has clusters of mu-opioid-receptor-positive neurons called striosomes that are important for compulsive and repetitive behaviors and I am very curious as to whether the mu-opioid-receptor mutation Dr. Blendy has identified alters the function and circuit connections of these striosomes,” Evans said. 

Blendy acknowledged that the initial findings are not inclusive of other victims of the opioid crisis, specifically newborns. Therefore, she said she decided to use her mouse model to study the impact of morphine on pups in utero and in days immediately following birth. She found that pups with the G/G genotype did not experience failure to thrive or miss any developmental milestones, a finding that could have important clinical applications. 

“Clinically, sometimes babies are sent home and then develop withdrawal. And then it’s more expensive to bring them back to the hospital to treat them,” Blendy said. “And so genotyping might perhaps give a clue as to whether or not those are key things to look for or not.”

The next steps for Blendy’s research include the co-treatment of the mice with other commonly used drugs, such as benzodiazepines, which are used to treat anxiety. Ultimately, Blendy said she hopes these studies will help inform medication development to help mitigate the opioid epidemic.

Evans said that future research into substance abuse disorders should also account for other external factors.

“Understanding how genetic differences interact with environmental differences will be incredibly important for developing preventative interventions to reduce opioid addiction and relapse,” Evans said.