Health sciences researchers at UArizona are seeking to improve opioid treatment while reducing its side effects

University of Arizona health sciences researchers are taking their foot off the brakes in their quest to improve opioid treatment while reducing its side effects.

Led by John Streicher, PhD, associate professor in the department of pharmacology at the Medical College of Arizona-Tucson and a member of the Comprehensive Center for Pain and Addiction of Arizona Health Sciences, the researchers expanded on their previous research that focused on one specific protein — heat shock protein 90 — and its role in receptor activation. Opioids and pain relief. Their previous investigations found that inhibition of Hsp90 in signaling pathways in the spinal cord has an important role in enhancing efficacy and reducing side effects of opioid treatment.

Dr. Streicher’s research team has shown that Hsp90 can prevent pathways in the spinal cord from producing the natural pain-relieving responses that they are designed to do in the body. To get around this, they have been studying drugs that can block Hsp90 activation in animal models. Their work showed that the use of these inhibitors opens the way and provides another avenue for improved pain relief.

Once we had established the important role this protein plays in the spinal cord, we wanted to explore how it regulates pain. We’ve delved deeper into the mechanisms that make this a valid drug target so that we can translate it more accurately to the clinic.”

Dr. John Streicher, Ph.D., Associate Professor, Department of Pharmacology, Arizona Medical College-Tucson

The new research has been published in Signal science, provides insights into one of the constitutive mechanisms underpinning the role of Hsp90 in alleviating pain. The study focused on monophosphate-activated protein kinase. AMPK is a pain-related protein that is a target of several drugs, including Metformin, an anti-diabetic drug.

Previous research has identified a relationship between AMPK and pain to suggest that activation of the protein reduces pain. However, Dr. Streicher’s research has found a new connection when it comes to pain modulation with opioid therapy: AMPK can act to block or reduce pain relief by opioids.

said Dr. Streicher, who co-wrote the manuscript with Katherine Gabriel, MD, from the College of Medicine-Tucson. “Our paper goes into detail on what AMPK does, the neurons in which it is expressed and in general what causes it to decrease pain relief. This provides a mechanistic basis for our translational work to develop drugs as true clinical treatment options.”

Dr. Streicher’s team found that one effect of using Hsp90 inhibitors was that the drugs also helped overcome the opioid-induced negative feedback loop regulated by AMPK. In this context, AMPK acts as a brake system to shut down the pain relief pathway and prevent the potential benefits of opioids. However, Hsp90 inhibitors can disrupt this feedback loop, opening the door to increased efficacy and a lower dose of opioids.

“I think of this negative feedback loop as one foot on the accelerator and the other foot on the brake. If you put your foot a little bit heavier on the gas, things get activated. And if you put one foot on the brake a little bit harder, now you’re slowing down that activation,” he said. Dr. Streicher.

“In terms of opioids for pain relief, AMPK is the foot on the brakes. When we inhibit Hsp90, we take our foot off that brake and that allows us to enhance effectiveness Opioids.”

The results are further evidence that Hsp90 inhibitors can give clinicians the opportunity to implement a dose reduction strategy for patients. Fewer opioids can be prescribed, but patients will get the same levels of pain relief while experiencing fewer side effects.

When an opioid such as morphine enters the body, it binds to a protein target called the mu-opioid receptor (MOR) and triggers a series of effects known as the signaling cascade. While signaling molecules work downstream, some cause positive effects, such as pain relief. Others produce negative side effects, such as: respiratory depression that can cause death; reward that may lead to addiction; and tolerance, which can increase the amount of medication needed to provide the same amount of pain relief.

In his lab, Dr. Streicher continues to research how Hsp90 works in the spinal cord to amplify the analgesic effects of opioids, including studying a previously unknown signaling circuit in the spinal cord discovered during an earlier study. Working with the College of Medicine – Quantitative Proteomics Laboratory in Tucson, Dr. Streicher and his team have identified more than 200 proteins that may provide additional insight into how MOR signaling is regulated in the spinal cord.

The new findings could have additional translational effects for patients who use AMPK drugs, such as Metformin, for conditions such as diabetic neuropathy.

“This is speculative, but perhaps one reason it’s so difficult to treat these patients with opioids is because other drugs that target AMPK interfere with what opioids aim to do,” Dr. Streicher said.

The prospects for developing an Hsp90-inhibiting clinical drug are promising, as many cancer researchers are studying Hsp90 inhibitors and showing strong proof-of-concept in vitro. However, FDA approval is likely years away.

“The goal of our research is to understand how opioids and pain work and to develop the ability to make a drug that will improve opioid treatment. This is another step in the path that brings us closer to making that a reality,” Dr. Streicher said.