I remember the moment I became conscious after my teenage tonsillectomy. There were two things in quick succession: I became aware of the darkness behind my eyelids, and then I felt a pain like fire in my throat. It was my first surgery, and for the pain, my first brush with the opioid drug Percocet. Ever since then my journey with pain—particularly chronic pain—has been a complicated one.
The Centers for Disease Control and Prevention (CDC) defines chronic pain as pain that lasts for at least three months, or, if it’s connected to an injury, pain that continues after the tissue is healed. According to the CDC, chronic pain is common: a 2012 National Health Interview Study reported that over 11 percent of U.S. adults live with daily pain.
In my twenties, doctors diagnosed my body’s unusual aches and sensitivity, as well as the lingering islands of pain on my low back, chest, and scalp (like permanent invisible bruises), as fibromyalgia. I learned that the scalding pain in my lower abdomen is a “textbook case” of Interstitial Cystitis. And as I approached my thirties, I landed in the ER multiple times for excruciating muscle spasms which felt like someone was holding a blowtorch to my back. I ended up working from bed for months at a time.
Doctors grew frustrated when I refused opioids; contrary to certain people’s experience, opioids don’t make me feel good. Even though they made the pain recede, I couldn’t bear the side effects of disorientation, dizziness, icy sweats, ringing ears, and paralyzing nausea.
“Well, what do you want me to do?” one attending physician asked, rolling his eyes.
I wanted the doctors to treat my pain without opioids, and if I’m a patient patient, I might get my wish, thanks to a new series of studies from scientists at New York University, the University of Texas at Dallas, and Philly’s own Thomas Jefferson University.
“I think there have been relatively few mechanisms that might regulate pain that have been discovered in the last few years…so it’s exciting,” says Dr. Matthew Dalva of the new research, which was first published in July 2017 in the online journal PLOS Biology.
Dalva is a professor and Vice Chair in the Department of Neuroscience in the Vickie and Jack Farber Institute for Neuroscience at the Sidney Kimmel Medical College at Jefferson University.
He says he and his colleagues in New York and Texas did not set out to discover a possible new target for the treatment of chronic pain, but experiments on a process happening outside spinal cord nerve cells could point that way.
Chronic pain sufferers are anxious for a new take on chronic pain. Not much is known about why chronic pain persists (like migraines, fibromyalgia, back pain, or neuropathic pain, which is pain from damaged nerves), but it does have major economic, clinical, psychological, and social consequences. The CDC also notes that some people, including members of racial or ethnic minority groups, women, and elderly people, are at particular risk for having their pain dismissed or inadequately treated.
Right now, options for non-opioid treatment of chronic pain are somewhat limited. There are over-the-counter drugs like acetaminophen (Tylenol), which may help temporarily scramble the processing of a natural hormone connected to the sensation of pain. Non-steroidal anti-inflammatory drugs (NSAIDs, like Advil or aspirin) control pain by reducing inflammation. Each of these can be effective, but they also have long-term side effects if they’re over-used, like liver damage (acetaminophen) or gastrointestinal problems (NSAIDs).
Opioids like Percocet, Vicodin and many others, traditionally used for cancer patients, have within the last two decades increasingly been prescribed for patients with chronic pain (like my Interstitial Cystitis or back pain). The CDC estimates that 20 percent of people who go to the doctor for non-cancer pain receive a prescription for an opioid medication.
Opioids work by imitating a pain-killing substance that exists in our own bodies. The drugs activate natural receptors on our nerve cells and reduce our perception of pain, among other effects. But our increasing understanding of the complicated potential road to addiction, overdose, or death associated with opioids is sounding an alarm about their widespread use, which is tough to balance against the fact that many people genuinely need them.
As a recent article in Penn Medicine Magazine points out, drug overdoses are now the top cause of death for adults under 50 in the U.S. (almost 150 deaths every day), and most of those involve opioids. The issue is critical in Philadelphia. Last spring, the Philadelphia Department of Public Health reported that in 2016, more than 900 city residents died of drug overdoses (a significant rise over the previous year), and more than 80 percent of those involved opioids. Additionally, there were more than 6,400 Philadelphia emergency room visits for overdose-related complaints (a number that has risen by more than 50 percent over the last ten years).
This makes Dalva’s research—and the future possibility of treating pain without opioids—compelling. The key may be something called phosphorylation.
Phosphorylation is common process that changes the shape and function of proteins. To most of us, Dalva says, protein might mean egg whites for breakfast, but he explains, “When biologists say ‘protein,’ they actually mean things like little machines in your body.” Your DNA has the basic assembly of your various proteins covered, but if the shape or job of a particular protein needs adjusting, it happens through phosphorylation. This is triggered by an enzyme called a kinase.
Typically researchers have targeted only phosphorylation inside of cells, but Dalva and the team studied it outside of the nerve cells (neurons) in the spinal cord—something we haven’t done much of, because we don’t know the function phosphorylation has out there.
Our neurons actually look a bit like plants with their roots and branches reaching out to each other. The chemicals that signal all the sensations in our body jump in tiny electrical pulses across the spaces, called synapses, between the neurons’ brambly tips.
Different proteins in neurons that sense pain help serve as receptors for the substances that jump between the cells, and sometimes, those proteins collaborate. One protein, EphB2, lives embedded in the outer layer of spinal cord neurons, though part of it pokes outside of the cell. As the new study demonstrates, EphB2 becomes phosphorylated from the outside when it’s activated by a second protein in the neighborhood, ephrin-B (probably working with the help of a kinase that hasn’t introduced itself to us properly yet).
That phosphorylation, happening in a particular piece of EphB2, affects a third nearby protein also working as a receptor on the neuron: glutamate receptor N-methyl-D-aspartate (NMDAR to its friends). Researchers found that the phosphorylation of EphB2 drew a greater number of NMDARs into the synapse, as well as changing how the NMDARs worked, so that they let a greater number of ions flow into the cell. When these proteins team up because of that extracellular (outside the cell) phosphorylation, it results in increased pain signals.
“We’re exploring something that we know is important, because it happens at the synapse, but then because we discovered how it worked, we can start asking other questions,” Dalva says. “Now that we know the interaction [between EphB2 and NMDAR], we can ask whether it’s really important for pain.”
Dalva appreciates the many funders for this research, including the National Institute on Drug Abuse, the National Institute of Mental Health, and others.
The discoveries involved a scrupulous series of experiments, first on cultured nerve cells, Dalva explains: “One of the neat things scientists can do is take neurons from an animal brain and grown them on a dish,” and the cells do some of the things they’d normally do in life, like make new synapses (yes, TINY ZOMBIE BRAINS).
In the dish, researchers proved that the phosphorylation of EphB2 was indeed affecting NMDARs, and that this was happening outside of the cell. They could even use a substance called K252b to block the phosphorylation from happening, and prevent the two proteins from teaming up.
They were able to move onto experiments in mice, by injecting some of the subjects with a special virus that mutated their neurons’ EphB2 protein to act as if it was already phosphorylated, rather than waiting for ephrin-B to work on it naturally. The researchers found that all of the mice (natural EphB2 or not) displayed increased sensitivity once their EphB2 and NMDAR proteins teamed up. But the really crucial discovery came when doses of K252b lowered pain sensitivity only for the mice with the natural, unmutated protein, proving that the increased pain was related to the extracellular phosphorylation event. (For a more detailed picture, read this piece by University of Pennsylvania doctoral fellow Nathan Fried.)
The experiments also proved that blocking this phosphorylation could reduce pain after it had been present for a few months, which, as Dalva puts it, shows we can combat “aberrant neural plasticity.” That is to say, even when neurons have been changed over time in a way that increases pain, we might be able to reverse the change, which could be big news for chronic pain patients.
Dalva carefully notes that we’re not close to testing any drugs yet—K252b is not eligible as a human treatment; scientists simply used it as a tool to test their suspicions about the importance of this extracellular phosphorylation.
Now that more is understood about this mechanism, “It makes us optimistic that we could target this with a more sophisticated approach,” Dalva says of the next steps. “This is a very new and unconventional idea, so we need to know a lot about it before we go forward.”
We still need to figure out exactly why and how this phosphorylation process starts, but studying the kinases involved could be the next step, Dalva explains. And fortunately, kinases are “very druggable.” It could mean a revolution in how we treat chronic pain, targeting a process outside of the cells involved.
“The really strange thing about what we do is that we’re really peering into the darkness, and we can’t see what’s there.” But the experiments are like flashlight beams that let scientists make more and more accurate guesses about what is in the nearby darkness.
As for me, I’m taking ibuprofen, doing physical therapy, and watching the medical news out of Philly.