Opioid drugs like morphine and fentanyl are like the two-faced Roman god Janus: the kind face offers pain relief to millions of sufferers, while the grim visage drives a crisis of opioid abuse and overdose that has claimed nearly 70,000 lives across the United States United only in 2020 .
Scientists like me who study pain and opioids have been looking for a way to separate these two seemingly inseparable faces of opioids. Researchers are trying to design drugs that provide effective pain relief without the risk of side effects, including addiction and overdose.
One possible path to achieving this lies in understanding the molecular pathways that opioids use to work their effects in your body.
How do opioids work?
The opioid system in your body is a set of neurotransmitters that your brain naturally produces that enable communication between neurons and activate protein receptors. These neurotransmitters include small protein-like molecules such as enkephalins and endorphins.
These molecules regulate a huge number of functions in your body, including pain, pleasure, memory, movement of your digestive system, and more.
Opioid neurotransmitters activate receptors found in many places in the body, including the pain centers in the spinal cord and brain, the reward and pleasure centers in the brain, and throughout the neurons in the gut.
Normally, opioid neurotransmitters are only released in small amounts at these exact locations, so your body can use this system in a balanced way to regulate itself.
The problem arises when taking an opioid drug such as morphine or fentanyl, especially in high doses for a long time. These drugs travel through your bloodstream and can activate all of the opioid receptors in your body.
You will get pain relief through the pain centers in the spinal cord and brain. But you’ll also get a euphoric high when those drugs hit the reward and pleasure centers of your brain, and this could lead to addiction with repeated use.
When the drug affects your intestines, you may develop constipation, along with other common opioid side effects.
Target opioid signal transduction
How can scientists design opioid drugs that don’t cause side effects?
One approach my research team and I take is to understand how cells respond when they receive the message from an opioid neurotransmitter. Neuroscientists call this process opioid receptor signal transduction.
Just as neurotransmitters are a communication network within the brain, each neuron also has a communication network that connects receptors to proteins within the neuron.
When these connections are made, they trigger specific effects such as pain relief.
So, after a natural opioid neurotransmitter or synthetic opioid drug activates an opioid receptor, it activates proteins within the cell that carry out the effects of the neurotransmitter or drug.
Opioid signaling is complex, and scientists are just beginning to understand how it works. However, one thing is clear: not all proteins involved in this process do the same thing.
Some are more important for pain relief, while others are more important for side effects such as respiratory depression or decreased respiratory rate that makes overdoses fatal.
So what if we target the good signs like pain relief and avoid the bad signs that lead to addiction and death? Researchers are approaching this idea in different ways.
Indeed, in 2020 the US Food and Drug Administration approved the first opioid drug based on this idea, oliceridine, as a pain reliever with fewer respiratory side effects.
However, relying on just one drug has drawbacks. That medication may not work well for all people or all types of pain.
It may also have other side effects that only show up later. Many options are needed to treat all patients in need.
My research team is targeting a protein called Heat shock protein 90, or Hsp90, which has many functions inside every cell.
Hsp90 has been a hot target in the cancer field for years, with researchers developing Hsp90 inhibitors as a treatment for many types of cancer.
We found that Hsp90 is also very important in the regulation of opioid signal transduction. Blocking Hsp90 in the brain blocked opioid pain relief. However, blockade of Hsp90 in the spinal cord increased opioid pain relief.
Our recently published work has uncovered further details on exactly how Hsp90 inhibition leads to increased pain relief in the spinal cord.
Our work shows that manipulating opioid signaling through Hsp90 offers a forward path to improving opioid medications.
Taking an Hsp90 inhibitor that affects the spinal cord along with an opioid drug could improve the pain relief provided by the opioid while reducing its side effects.
With better pain relief, you can take fewer opioids and reduce your risk of addiction. We are currently developing a new generation of Hsp90 inhibitors that could help achieve this.
There could be many paths to developing an improved opioid drug without the burdensome side effects of current drugs such as morphine and fentanyl. Separating the kind and brooding faces of the opioid Janus could help provide much-needed pain relief without addiction and overdose.
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