A groundbreaking study by scientists at the National Institutes of Health (NIH) has unveiled the underlying biological mechanisms that cause normally harmless sensations like heat and touch to become painful in the presence of inflammation. The findings, published by researchers from the National Center for Complementary and Integrative Health (NCCIH) and the National Institute of Dental and Craniofacial Research (NIDCR), may open the door to more precise treatments for chronic and inflammatory pain.
Decoding the Language of Sensation
The study focuses on somatosensory neurons—the nerve cells in the skin responsible for detecting touch, heat, pressure, and pain. By employing advanced imaging techniques and molecular analysis, researchers were able to observe how these neurons respond to various stimuli, and more importantly, how these responses are altered by inflammation.
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“To develop better treatments for pain, it’s critical that we deepen our understanding of the biology behind how sensory signals are received, transmitted, and ultimately perceived by the brain,” said Dr. Alex Chesler, senior investigator at NIH and co-author of the study. “Over the past few years, we developed a platform for watching sensation in action, revealing new details about the cells and molecules required and, in this study, how inflammation triggers pain.”
The researchers discovered that gentle stimuli such as warmth and light touch activate different sets of receptor cells. However, when a stimulus becomes noxious—strong enough to potentially cause harm—these neural roles begin to overlap, helping to explain how the body detects and distinguishes between benign and damaging experiences.
Inflammation’s Role in Pain Perception
Although inflammation’s link to pain has long been recognized, the molecular and cellular changes that occur during inflammation have remained unclear. To investigate this, the researchers injected prostaglandin E2—a known inflammation-inducing molecule—into the skin of mice.
The injection caused nociceptors, or pain-sensing neurons, to become hypersensitive to heat for extended periods. This finding provides a clearer understanding of how inflammation sustains heat-related pain, revealing that inflammation can enhance the brain’s perception of pain by keeping pain pathways constantly active.
“This explains how inflammation drives ongoing pain and why heat becomes more painful,” said Dr. Nick Ryba, senior investigator and study co-author. “However, what was unexpected was that touch detection remained unchanged.”
The Mystery Behind Tactile Allodynia
Interestingly, while the perception of heat changed dramatically with inflammation, the basic sensory pathways for touch remained unaltered. This helped explain tactile allodynia, a condition where light touch becomes painful during inflammation.
According to the study, this touch-related pain isn’t due to changes in the touch pathways themselves. Instead, it results from the inflammatory activation of nociceptors that are “layered” on top of normal touch signals. The researchers found that an ion channel called PIEZO2, previously identified as essential for touch sensation, also plays a key role in tactile allodynia.
“This was a major step in linking inflammatory pain to molecular activity in the skin’s nerve cells,” said Dr. Ryba.
Implications for Human Pain Treatment
While the study was conducted in mice, Dr. Chesler noted that the neural pathways and mechanisms observed in the research closely mirror those in humans, reinforcing the study’s significance.
“By learning more about how touch and heat are signaled in the body, we’re identifying new clues for treating pain,” Chesler said. “Our study shows how different types of pain may benefit from different types of treatments. In short, by identifying exactly which cells and molecules ‘turn up the volume’ of different types of pain, we may be able to identify the ‘switches’ that can turn the volume down.”
This refined understanding of pain pathways offers promising insights for the development of personalized, targeted pain therapies. For instance, conditions such as neuropathic pain, fibromyalgia, and inflammatory diseases may be more effectively managed by modulating specific receptors or ion channels involved in the body’s pain response.
Collaborative Research with Long-Term Goals
The study represents the latest milestone in a long-standing collaboration between Dr. Chesler’s Sensory Cells and Circuits Lab and Dr. Ryba’s Taste and Smell Section, both based at NIH.
Their joint work is centered on understanding how sensory stimuli are processed by the nervous system and how this processing affects behavior. In this case, the researchers combined live-cell imaging, gene expression profiling, and behavioral analysis to map the body’s pain response at unprecedented detail.
The team hopes their research can serve as a foundation for drug development targeting specific types of pain, especially those associated with chronic inflammation. Moreover, the findings may be relevant not just to dermatological pain but also to internal inflammatory disorders, including gastrointestinal and musculoskeletal conditions.
About the NIH and NCCIH
The National Center for Complementary and Integrative Health (NCCIH) leads scientific research on complementary and integrative health approaches. Its mission is to rigorously evaluate alternative treatments and determine how they can contribute to health and wellness when integrated with conventional medical care.
For more information about this study or related NCCIH research initiatives, visit www.nccih.nih.gov.
Key Takeaways:
- NIH researchers have identified how inflammation alters sensory neuron responses, leading to heightened pain sensitivity.
- Heat and touch are processed by distinct neural pathways, but inflammation causes overlap in pain signaling.
- Findings highlight new targets for treating inflammatory and chronic pain without affecting normal touch perception.
- The study, conducted in mice, offers strong translational relevance for human pain treatment and precision medicine approaches.
As Dr. Chesler emphasized, “Understanding these differences brings us closer to achieving relief for millions suffering from chronic pain.”
