Pain is a universal experience, but how it’s felt and for how long can vary dramatically from person to person. For some, a surgery or herniated disc is a temporary agony that fades with time. For others, pain can become a chronic, debilitating condition, lingering long after an injury has healed. Scientists are working to understand this complex phenomenon, and new research suggests why some individuals experience pain differently.
Our experience of pain relies on a complex network of nerves known as the pain neuroaxis. This system involves both peripheral nerves (those outside the brain and spinal cord) and central neurons (those in the brain, brainstem, and spinal cord). When you feel pain, these neurons fire, sending signals along this pathway to your spinal cord and brain. Many regions of your brain then interpret these signals as pain.
“Acute pain is beneficial to protecting our bodies, but chronic pain often serves no purpose and outlives its initial purpose and represents a dysfunction,” noted Steve Davidson, PhD, associate director of NYU’s Pain Research Center, New York City.
Scientists are still learning why normal acute pain sometimes transforms into abnormal chronic pain. New research published in Science Advances challenges a long-held belief: it’s not always more neuronal stimulation that causes pain. Instead, the balance between activation and repression in specific neurons is crucial for a normal pain experience.
A Surprising ‘Volume Control’ for Pain
This new research focuses on specific neurons called projection neurons found in part of the brainstem called the medullary dorsal horn. These neurons are crucial relay stations, sending pain messages to other parts of the brain, like the parabrachial nucleus, which is involved in processing emotions and motivation alongside pain.
To study pain, researchers used mice. For acute pain, they exposed mice to bright ultraviolet light, similar to how a bright light can cause discomfort in your eye at the optometrist. For chronic pain, a loose stitch was tied around the trigeminal nerve below the eye, mimicking a migraine-like pain.
Interestingly, during the peak of acute pain, these pain-relay projection neurons became less excitable, explained Alexander Binshtok, PhD, professor in pain research at the Hebrew University of Jerusalem, Jerusalem, Israel, and an author of the study. It’s as if their “volume control” was turned down, causing them to fire fewer signals to the brain even though the pain stimulus was strong. As the mice’s behavior indicated they were no longer experiencing pain, the excitability of these neurons returned to normal.
After 20 years in the pain field, Binshtok reflected on the long-standing paradigm that pain is linked to increased nerve activity. “What was surprising is that when we have inflammatory pain, some of the neurons actually decrease the activity in a way to control the level of pain,” he said.
Using electrophysiology and computer modeling, the researchers traced the mechanism behind this “volume control” to an increase in the neuron’s potassium A-current (IA). This current acts as a brake on the neuron’s activity — when IA increases, it makes it harder for the neuron to fire.
This suggests a built-in protective mechanism that helps regulate the intensity of acute pain and prevents the system from being overwhelmed. As Binshtok explained, “If suddenly these mechanisms are not working, every input from the periphery will be amplified.”
The Shift to Chronic Pain
The picture changes dramatically when pain becomes chronic. In the mice experiencing long-term pain, researchers observed no such increase in the IA. Instead, these same medullary dorsal horn neurons showed increased excitability and firing. It’s as if the protective “brake” is missing or not working effectively.
This suggests a critical difference in how our bodies handle acute vs chronic pain. In acute pain, there appears to be a natural system that helps tune down the pain signals. But if this system isn’t functioning properly, or if this tuning mechanism is absent, it could contribute to pain becoming a persistent problem.
Davidson summarized the finding that there is a mechanism to reduce activity during acute pain but not in chronic pain with an analogy: “It’s like automatic braking when you are driving too fast in the city — but this mechanism is disabled on the highway, during chronic pain.”
Binshtok noted that while it seemed surprising for a neuron to decrease its activity when bombarded with input at first, “apparently this is not a surprising phenomenon when we look at other systems like the hippocampus or cortex, this adaptation is pretty common.”
And this is the first time, Binshtok said, that the same neurons were shown to respond differently in acute vs chronic pain.
Looking Ahead
The ultimate goal in pain research, noted Patrick Sheets, PhD, associate professor of pharmacology and toxicology at the Stark Neurosciences Research Institute at Indiana University School of Medicine, Indianapolis, is to develop “some sort of small molecule that then would eliminate aspects of pain that we don’t want while preserving the ability of the person to function normally without being overwhelmed by something like addiction or lethargy.”
And ultimately, it may be that pain treatment will need a personalized approach. Sheets noted that certain drugs may end up working depending “primarily on what type of pain you have, and that can be challenging — understanding what sort of pain people are going through, diagnosing it, and then understanding what’s happening at the cellular and circuit level so that you can hopefully intervene.”
However, whether this IA-driven mechanism could provide relief for chronic pain sufferers is still a long way from being realized. For one thing, the study did not identify the specific potassium channel responsible for changes in IA current, Sheets noted.
Davidson also pointed out that, “ideally, the IA effect would be reversed or blocked experimentally to block the behavioral effect.” Without that, he noted, we don’t know whether the increased IA current is the true cause of the change in pain behavior.
Additionally, the study focused on male mice — in female mice, they did not observe the same sensitivity to ultraviolet light. Sheets noted that he has also observed sex-linked differences in his own mouse studies. (There is evidence that men and women experience pain differently as well.)
And Binshtok noted that even if they find the IA target that could potentially regulate chronic pain in mice, they would still need to confirm the mechanism in humans.
There’s still a lot left to learn. However, Davidson said, “Certainly looking into the IA current now looks like a promising avenue for exploration.”
