Tucson Standard

Researchers at the University of Arizona Health Sciences have identified a novel approach to enhance the safety of opioids by increasing their pain-relieving properties while reducing unwanted side effects through spinal inhibition of a Heat shock protein 90 (Hsp90) isoform.

Opioids, though considered the gold standard for chronic pain treatment, are associated with significant negative side effects, including constipation, addiction potential, and respiratory depression. A study published in Scientific Reports suggests a new method to treat acute and chronic pain by decreasing the required opioid dosage for effective pain relief and lowering addiction risks.

"We have been investigating the role of Heat shock protein 90 in regulating opioid signaling in the spinal cord for some time," said John Streicher, member of the Comprehensive Center for Pain & Addiction at U of A Health Sciences and professor in the College of Medicine – Tucson's Department of Pharmacology. "This study provides proof of principle that Hsp90 isoform inhibitors are effective at improving opioid pain relief and reducing side effects. This is the critical link that makes our work translationally relevant, giving us a clear path forward to develop a new drug that could benefit millions of people who live with chronic pain."

Heat shock protein 90 is primarily studied within cancer research as it aids other proteins' functions, including those promoting tumor growth. Streicher's research focuses on its role in opioid receptor activation and pain relief.

Streicher's prior studies revealed that Hsp90 acts differently on opioid receptors in the brain versus the spinal cord. Inhibiting Hsp90 in the brain negated morphine's analgesic properties; however, inhibiting it in the spinal cord enhanced morphine’s pain-relieving effects.

In mouse models using nonselective Hsp90 inhibitors, researchers observed up to a fourfold increase in morphine’s potency while also reducing tolerance—a condition where increased medication is needed over time for similar effectiveness.

Nonselective Hsp90 inhibitors were previously linked to serious side effects such as macular degeneration. Streicher aimed to target specific isoforms among Hsp90’s four variants individually to mitigate these issues.

"Isoforms are different versions of the same thing," Streicher explained. "They have similar but not identical roles." By targeting each isoform selectively, researchers isolated those active in the spinal cord from Hsp90-alpha—the variant active in the brain—associated with retinal degeneration.

Using selective inhibitors provided by collaborator Brian Blagg from Notre Dame University, researchers administered these inhibitors systemically via IV injection into mice. The results showed increased pain relief and reduced side effects without severe adverse outcomes associated with nonselective inhibitors.

The findings indicate that selective Hsp90 inhibitors could support dose-reduction plans alongside physician-prescribed opioids for chronic pain management. The aim is lower opioid prescriptions with maintained efficacy and fewer side effects.

"What I'm envisioning is you'd be given a pill that is a combination therapy of an opioid with one of these isoform inhibitors," Streicher said. "The addition of that Hsp90 inhibitor would make the opioid better – it would increase the effectiveness of the pain relief and decrease the side effects."

Streicher’s team continues to optimize selective Hsp90 inhibitors into stable oral drugs.

"Dr. Streicher's research is an excellent example of innovative translational science needed to transform health care for pain and addiction," stated Regents Professor Todd Vanderah, director of Comprehensive Center for Pain & Addiction and head of Pharmacology Department. "This study marks an important step toward developing novel evidence-based therapies providing better treatment options with fewer disruptive side effects."

The research team included co-first authors David Duron; Parthasaradhireddy Tanguturi; Christopher Campbell; Kerry Chou; co-authors Paul Bejarano; Katherin Gabriel; Jessica Bowden; Sanket Mishra; Christopher Brackett; Brian Blagg from Notre Dame University’s Chemistry Department; Deborah Barlow and Karen Houseknecht from University New England’s Biomedical Sciences Department.

Funding was provided partly by National Institute on Drug Abuse under Award No. R01DA052340 and Arizona Biomedical Research Commission under Award No. ADHS18-198875.

A version originally appeared on UofA Health Sciences website.