9 things to know about opioids, pain relief and Heat shock protein 90

The opioid epidemic has been brewing, growing and changing since 1990, when the increased prescribing of opioids led to more people than ever being exposed to the pain-relieving yet potentially deadly drugs. The Centers for Disease Control and Prevention notes three distinct waves of increases in opioid overdose deaths driven by prescription opioids, heroin and now synthetic opioids such as fentanyl.

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At the University of Arizona Health Sciences, researchers, including John Streicher, PhD, a member of the U of A Health Sciences Comprehensive Center for Pain & Addiction and professor of pharmacology at the U of A College of Medicine – Tucson, sat down with the U of A Health Sciences Office of Communications to talk about his research into Heat shock protein 90 and his goal of making opioids safer.

Q: Your research focuses on making opioids safer. Why is that important?

Streicher: There are more than 100 million people in some form of chronic pain. Through the ongoing opioid crisis, we’ve learned a lot more about the people who need help and what a massive problem chronic pain and opioids are. Every time I publish something new on pain, I get messages from desperate people who are seeking some sort of hope to manage their crippling chronic pain. The medical system cannot help them. My work is driven by the desire to help ease the suffering of these people, to help give them their lives back. My ultimate goal is to develop a highly effective pain drug that won’t drive addiction and other side effects that can degrade the quality of life of suffering patients.

Q: What is the primary focus of your research?

Streicher: My basic lab program is very interested in opioids and pain, specifically how drugs like morphine act on opioid receptors that produce effects in your brain like pain relief. Morphine has an effect in your body because of this receptor. There’s a link between the receptor activation by morphine and the effect in the brain called signal transduction. Our program overall is looking at the signaling links between receptor activation and the downstream effect of pain relief, as well as side effects such as addiction.

Q: So in effect, you could change the way opioids affect the brain?

Streicher: Yes, by modifying the signaling cascade. Some signals promote the things that are good about opioids, like pain relief, and some signals promote the things that are bad – side effects such as addiction, respiratory depression and so on. In my lab, we’ve tried to figure out what these signaling molecules are – which ones are good, which ones are bad – and then try to use that for drug discovery to find new drugs that will be pain relieving without the side effects.

Q: Are you homing in on any specific signaling molecules?

Streicher: One of the proteins in the middle that we’ve been studying for a number of years is called Heat shock protein 90, or Hsp90. Hsp90 does a lot of things, but one of the things it does is controls how that receptor talks to the downstream changes in your brain, like pain. I started researching Hsp90 many years ago at the University of New England, where we studied what it was doing in the brain. When I moved to the University of Arizona, I had a doctoral student, David Duron, who wanted to see what Hsp90 was doing in the spinal cord, because we know that different signals can have different effects in different parts of your central nervous system. David was the first author on a paper, published in 2020, that really changed the direction of my lab’s Hsp90 research.

Q: What was the pivotal finding from that study?

Streicher: When you inhibit Hsp90 in the brain, it seems to repress the pain-relieving effects of morphine, so you still have pain. By inhibiting Hsp90 within the spinal cord, we saw the complete opposite effect – we actually made pain relief stronger. The finding that Hsp90 inhibition within the spinal cord enhances antinociception, or pain relief, due to morphine really drove this research more toward translational applications of Hsp90 inhibitors. We have been digging further into the mechanisms that make this a druggable target so that we can more precisely translate it to the clinic.

Q: How do you envision this be used in the clinic? 

Streicher: It could allow us to pursue what is called a dose reduction strategy, where you can take less opioid drug, so your side effects should be lower, but pain relief will be the same because the pain relief is more effective. Take less drug, achieve the same pain relief, lower side effects. That’s a strategy we are pursuing now with our ongoing research to translate the results of these findings to potential clinical use down the road.

Q: You mentioned HSP90 does a lot of different things. Have HSP90 inhibitors been researched for uses other than pain?

Streicher: Hsp90 inhibitors have been studied for a long time as a treatment for cancer. There are a lot of inhibitors that have been tested over the years, but all of them have bad side effects such as liver toxicity and retinal degeneration. No one wants to take a medicine that is going to make you go blind. But it is important to note that all of those first-generation Hsp90 inhibitors were nonselective, meaning they target the entire protein. So how do we get around the side effect problem of a nonselective inhibitor? Our solution is to target the individual isoforms of Hsp90, of which there are four. Each isoform is a slightly different version of Hsp90 that works independently with similar but not identical roles.

Q: Have you made any progress toward that goal?

Streicher: Yes. We published a paper in July 2024 about a study where we used selective inhibitors to target each isoform. We were able to identify and isolate the isoforms that are active in the spinal cord from Hsp90-alpha, the one that is active in the brain. Hsp90-alpha is the isoform that has been linked to the serious side effect of retinal degeneration. We also found that you can give these isoform-selective inhibitors by a translatable route and get the benefits – pain relief goes up and side effects go down, and presumably we’re going to avoid some of those nasty side effects of the nonselective Hsp90 inhibitors.

Q: What’s next?

Streicher: The Hsp90 isoforms are all a little bit different from each other, and that is what lets us make a chemical that will only inhibit some and not the others. This is proof of principle that we can use these inhibitors to make opioids safer. Our ongoing work is to optimize the drug and make it something that could be taken by mouth instead of by injection. The next step beyond that would be to take it to the Food and Drug Administration for toxicity testing and approval, after which it could go into clinical trials. I’m envisioning doctors prescribing a combination therapy of an opioid that includes an Hsp90 isoform inhibitor. The goal of our research is to develop a drug that’s going to improve opioid therapy, and we are getting closer to making that a reality.