In the U.S., opioids such as morphine or fentanyl have two faces. The friendly face provides pain relief for millions of people, while the grim one fuels an opioid overdose and abuse crisis that will claim nearly 70,000 lives by 2020.
Scientists who study opioids and pain, like myself, have been trying to find a way to separate the two faces of opioids that seem inseparable. Researchers are working to develop drugs that can deliver pain relief while minimising side effects such as addiction and overdose.
What is the action of opioids?
The system of your body consists of a group of neurotransmitters that your brain produces naturally. These neurotransmitters enable communication between your neurons and activate receptors. These neurotransmitters are small, protein-like molecules such as endorphins and These molecules control a wide range of body functions, such as pain, pleasure, and memory. They also affect the movement of your digestive tract.
The opioid neurotransmitters are found in many places in your body. These include pain centres in the spinal cord and brain, as well as reward and pleasure centres in your brain and neurons throughout your gut. Normal opioid neurotransmitters release in small amounts in these specific locations so that your body can regulate itself in a balanced manner.
Targeting opioid signal transduction
It is when you use opioid drugs like morphine and fentanyl in high doses over a prolonged period of time that the problem arises. These drugs can travel through your bloodstream and activate all the opioid receptors in your body. The pain centres of your brain and spinal cord will provide pain relief. You’ll get a high from the drugs when they hit your brain’s pleasure and reward centres. This could lead you to become addicted if you use them repeatedly. You may experience constipation when the drug hits you in your stomach, as well as other opioid-related side effects.
How can scientists create opioids that don’t have side effects?
My research team and I have taken the approach of understanding how cells react when they receive a message from an opioid transmitter. This process is called opioid signal transduction by neuroscientists. Each neuron has a similar communication network to that of neurotransmitters in your brain. This network connects receptors and proteins within each neuron. These connections trigger specific effects, such as pain relief. After a natural or synthetic opioid neurotransmitter activates an opioid receptor, it activates the proteins in the cell to carry out its effects.
Scientists are only just beginning to understand how opioid signal transduction works. One thing is certain: not every protein involved in the process performs the same function. Some proteins are important for pain relief, while others are important for side effects such as respiratory depression or the decrease in respiration rate that causes overdoses to be fatal.
What if we targeted the “good” signal, like pain relief, and avoided the “bad” signal, which leads to addiction and even death? Researchers are approaching this idea in a variety of ways. In 2020, the U.S. Food and Drug Administration will approve oliceridine as the first opioid painkiller based on this idea. It is a drug with fewer respiratory side effects.
But relying solely on one drug can have its downsides. This drug may not be effective for everyone or for every type of pain. Other side effects may also appear later. There are many options available to help all patients.
My research team is targeting heat shock protein 90, or Hsp90. This protein has multiple functions within each cell. Hsp90 is a popular target in cancer research. Researchers have been developing Hsp90 inhibitors as treatments for various cancer types.
Hsp90 plays a role in opioid signal transduction. Blocking the Hsp90 protein in the brain prevented opioid pain relief. Blocking the Hsp90 protein in the spinal cord led to increased opioid pain relief. Recently published research revealed more information on how inhibiting Hsp90 results in increased pain relief within the spinal cord.
Our research shows that manipulating opioid signalling via Hsp90 is a way to improve opioids. Combining an Hsp90 inhibitor that targets the spine cord with an opioid could increase the pain relief provided by the opioid while reducing its side effects. You can reduce the amount of opioid you take and your addiction risk by taking less. We are developing new Hsp90 inhibitors to help achieve this goal.
There are many ways to develop an improved opioid drug that does not have the side effects associated with current drugs such as morphine or fentanyl. The opioid Janus has two faces: friendly and grim. Separating them could provide the pain relief that we need without addiction or overdose.
