An estimated 20 percent of adults in the US experience chronic pain.1 To help patients manage their condition, clinicians have employed one main type of pain-relieving drug: opioids. With their capacity to reduce debilitating pain, opioids also come with serious side effects, including hyperalgesia and respiratory depression. The highly addictive properties of opioids have led to widespread misuse and dependency, fueling a devastating opioid crisis that has affected countless individuals and communities worldwide.
While some researchers have focused on developing new strategies and treatments for pain relief, others have sought to improve existing treatments.
Researchers at the University of Arizona boosted the pain-relieving properties of the opioid morphine by inhibiting an isoform of Heat shock protein 90 (Hsp90).2 The approach also reduced tolerance to morphine without increasing unwanted side effects. The findings, published in Scientific Reports, revealed a novel target that scientists could explore to improve the efficacy and safety profile of opioids for pain management.
“This is a really fascinating separation of the pharmacology [of morphine],” said Mark Hutchinson, biological pharmacologist at the University of Adelaide who was not involved with the study.
For nearly a decade, pharmacologist John Streicher and his team at the University of Arizona have studied opioid signaling in the brain with the goal of improving opioid drugs. They previously found that the protein Hsp90, which is most often studied for its role in heat-related protein degradation, regulated opioid signaling.3 However, it was unknown whether the protein contributed to morphine’s pain-relieving effects.
To test this, the researchers injected the Hsp90 inhibitor KU-32 into the spinal cord of mice prior to morphine treatment and then exposed the animals to the tail-flick test, an established pain model in mice. When mice’s tails are placed on a hot surface, they flick them away; a longer delay before flicking indicates a lower level of pain. Mice treated with both KU-32 and morphine showed a delayed tail flick response relative to mice that received only morphine, suggesting that Hsp90 blockade, in combination with the opioid, improved pain tolerance.
Streicher and his team also tested the drug combination in a chronic pain model in mice. Three weeks after injection of an HIV protein, which induces peripheral neuropathy, the team treated the mice with KU-32 plus morphine and found that it increased pain relief more than morphine alone.
Across these models, Hsp90 inhibition enhanced morphine’s pain relief effects by around two- to three-fold but not its side effects. Mice given the combination treatment did not experience a worsening in constipation or respiratory depression—two of the main side effects of opioid use in humans—beyond what was seen with morphine alone. Additionally, they found that KU-32 did not alter reward learning compared to morphine alone, suggesting that it did not increase the addictive properties of morphine.
“If you can tweak the [proteins] right, you can get more of the good without getting more of the bad,” said Hutchinson.
Although the combination treatment enhanced pain relief when administered to the spinal cord, Streicher and his colleagues previously found that inhibition of Hsp90 in the brain blocked these effects, suggesting that Hsp90’s effects were region-specific.4 In another study, they showed how different Hsp90 isoforms activated different pathways in the brain and spinal cord.5 In the present study, they systemically delivered inhibitors of different Hsp90 isoforms and found that targeting Hsp90β, which is mainly expressed in the spinal cord, recapitulated the enhanced pain relief provided by morphine and KU-32.
“That's a really powerful tool to say it's not all Hsp90, it's actually a subset,” said Hutchinson. “That opens up some really specific follow-up studies to look at defined mechanisms as to how this system is actually achieving these benefits for opioid use within future pharmacological development.”
Before they can test whether the findings will translate to humans in clinical trials, Streicher said that they need to improve the design and delivery of Hsp90 inhibitors and better understand the mechanism by which blocking Hsp90 leads to pain relief.
“The side effects should be reduced, but that remains to be fully shown. We tried to be diverse in the side effects and the pain models tested, but we hardly got everything,” said Streicher. “There's a lot more than that in the human experience.”
But the findings suggest that isoform-specific drugs may be crucial for patients needing long-term treatment for chronic pain, said Streicher. However, some of these isoform-specific drugs themselves have side effects, so finding the right one is a main goal of the team. “You could just hit the one molecular variant that gives you the benefit that you want, and not the other molecular variant that drives the side effects like retinal degeneration,” he added.
- Rikard SM, et al. Chronic pain among adults—United States, 2019–2021. MMWR Morb Mortal Wkly Rep. 2023;72(15):379-385.
- Duron DI, et al. Inhibiting spinal cord-specific hsp90 isoforms reveals a novel strategy to improve the therapeutic index of opioid treatment. Sci Rep. 2024;14(1):14715.
- Streicher JM. The role of heat shock protein 90 in regulating pain, opioid signaling, and opioid antinociception. Vitam Horm. 2019;111:91-103.
- Stine C, et al. Heat shock protein 90 inhibitors block the antinociceptive effects of opioids in mouse chemotherapy-induced neuropathy and cancer bone pain models. Pain. 2020;161(8):1798-1807.
- Bejarano P, et al. Identification of the Hsp90 isoforms and co-chaperones that repress opioid anti-nociception in the spinal cord. The FASEB Journal. 2020;34(S1):1-1.
