Research Seeks to Identify the Molecular Pathways Underlying Opioid-induced Hyperalgesia

A collaboration between the Sweedler and the Rodriguez-Zas labs at the University of Illinois at Urbana Champaign and the Pradhan lab at the University of Illinois at Chicago has identified genes that are involved in opioid-induced hyperalgesia, an abnormally increased sensitivity to pain.

Opioid-based therapies can be used to treat chronic pain that affects 30% to 40% of the population in the U.S. and Europe. These therapies aim at balancing pain management without causing an addiction risk.

Sandra L. Rodriguez-Zas and Jonathan V. Sweedler are co-authors on a recently published paper that investigates the pathways involved in opioid-induced hyperalgesia.
Sandra L. Rodriguez-Zas and Jonathan V. Sweedler are co-authors on a recently published paper that investigates the pathways involved in opioid-induced hyperalgesia.

Unfortunately, the chronic use of opioids can cause opioid-induced hyperalgesia, a condition where the patient receiving opioids for pain becomes more sensitive to certain kinds of pain. Increased opioid use and abuse has prompted the National Institute on Drug Abuse to fund projects that aim to understand the underlying chemical causes of pain.

“One of the treatments for migraines is to prescribe morphine, which is an opioid. The migraine symptoms are reduced, but the treatment can result in more headaches,” said Jonathan V. Sweedler, a professor of chemistry and faculty member at the Beckman Institute for Advanced Science and Technology.

“We were approached by Amynah Pradhan at the University of Illinois at Chicago, who is working on understanding different aspects of migraine and opioid-induced hyperalgesia using mice,” Sweedler said.

Using a mouse model, this multi-institutional team identified pathways that influence the sleep cycle and the immune system that are associated with the disorder.

“In our study, mice received morphine and we studied how morphine affected the levels of molecules in two central nervous system regions that are associated with drug abuse and the transmission of pain,” said Sandra L. Rodriguez-Zas, a professor of animal sciences at Illinois.

The researchers looked at the changes in gene transcripts, which are a set of instructions that tell the cell which proteins to make. They analyzed over 18,000 genes and found that more than 300 of them had changed in response to morphine and half changed differently between the regions studied.

“By looking at the networks that relate these genes, we can identify those genes that have a key role in the disorder and are promising targets for new therapies,” Rodriguez-Zas said. These studies have been carried out in male mice and the researchers are now looking to expand the same experiments in female mice to see if they also exhibit similar changes in gene expression.

“One of the observations on drug abuse that is not well understood is that people tend to take pain medications at certain times of the day but not others. Our studies suggest that there are certain aspects of the circadian rhythm involved,” Sweedler said.

“The novelty of our approach enabled us to detect these changes in the circadian rhythm pathway as well as the immune system,” Rodriguez-Zas said.

Results from the study, “Opioid-Induced Hyperalgesia is Associated with Dysregulation of Circadian Rhythm and Adaptive Immune Pathways in the Mouse Trigeminal Ganglia and Nucleus Accumbens,” were published in Molecular Neurobiology. The study was funded by the National Institute of Drug Abuse.


The paper is available online: DOI: https://doi.org/10.1007/s12035-019-01650-5