no wayn estimate 20% of adults In the United States, we experience chronic pain.1 To help patients manage their condition, clinicians have used opioids, a major type of painkiller. Opioids, with their ability to reduce debilitating pain, also come with serious side effects, including hyperalgesia and respiratory depression. The highly addictive nature of opioids has led to widespread misuse and dependence, sparking a devastating opioid crisis affecting countless individuals and communities around the world.
Some researchers have focused on developing new strategies and treatments for pain relief, while others have sought to improve existing treatments.
University of Arizona researchers Enhanced pain relief properties. Inhibits an isoform of heat shock protein 90 (Hsp90), producing the opioid morphine.2 This approach also reduced tolerance to morphine without increasing unwanted side effects. The results of the study were published as follows: scientific reportThey reveal new targets that scientists can explore to improve the efficacy and safety profile of opioids for pain management.
“This is a really interesting separation of pharmacology. [of morphine],” said Mark Hutchinsonis a biological pharmacologist at the University of Adelaide who was not involved in the study.
Pharmacologist for almost 10 years John Streicher His team at the University of Arizona studied opioid signaling in the brain with the goal of improving opioid medications. They previously showed that the most frequently studied protein, Hsp90, for its role in heat-related protein degradation. Regulated opioid signaling.3 However, it is not known whether this protein contributes to the pain-relieving effects of morphine.
To test this, the researchers injected the Hsp90 inhibitor KU-32 into the spinal cords of mice before morphine treatment and then exposed the animals to the tail-flick test, an established model of pain in mice. If you place a mouse’s tail on a hot surface, it will flick its tail. The longer the delay before blinking, the lower the pain level. Rats administered both KU-32 and morphine showed a delayed tail flick response compared to rats administered morphine alone, suggesting that Hsp90 blockade in combination with opioids improved pain tolerance.
Streicher and his team also tested the drug combination in a chronic pain model in mice. Three weeks after being injected with the HIV protein that causes peripheral neuropathy, the team found that giving mice a combination of KU-32 and morphine resulted in greater pain relief than morphine alone.
Across these models, Hsp90 inhibition improved the pain-relieving effect of morphine approximately two- to three-fold, but not its side effects. Mice receiving the combination treatment did not experience worsening of constipation or respiratory depression, two major side effects of opioid use in humans, beyond those seen with morphine alone. Additionally, KU-32 did not alter reward learning compared to morphine alone, suggesting that it did not increase the addictive nature of morphine.
“If you could adjust [proteins] you’re right. You can get more of the good without getting more of the bad,” Hutchinson said.
Although the combination treatment improved pain relief when administered to the spinal cord, Streicher and his colleagues previously found inhibition of Hsp90. in the brain Blocking these effects suggests that the effects of Hsp90 are region-specific.4 Another study showed how different Hsp90 isoforms are activated. different pathways in the brain and spinal cord.5 In this study, they systematically delivered inhibitors of different Hsp90 isoforms and summarized that targeting Hsp90β, which is expressed primarily in the spinal cord, provides enhanced pain relief provided by morphine and KU-32.
“This is a very powerful tool to be able to say that not all Hsp90s are Hsp90s, but actually a subset,” Hutchinson said. “This initiates very specific follow-up studies to investigate the defined mechanisms of how this system actually achieves these benefits for opioid use in future pharmacological developments.”
Before testing whether the findings will translate to humans in clinical trials, Streicher said there is a need to improve the design and delivery of Hsp90 inhibitors and better understand the mechanisms by which blocking Hsp90 leads to pain relief.
“Side effects should be reduced but still need to be fully identified. We tried a variety of side effects and tested pain models, but we didn’t get close to everything,” Streicher said. “There is more to the human experience than that.”
But the findings suggest that isoform-specific drugs may be important for patients who need long-term treatment for chronic pain, Streicher said. However, some of these isoform-specific drugs have their own side effects, so finding a suitable drug is the team’s main goal. “You just need to select one molecular variant that provides the desired benefit rather than another molecular variant that causes side effects such as retinal degeneration,” he added.
