Chronic pain is one of the most common health conditions worldwide. Back pain is the most commonly reported type, followed by head and face pain associated with the jaw joint, in the form of temporomandibular joint disorder (TMJ).
Although not life-threatening like cancer or infectious disease, chronic pain can dramatically reduce quality of life and functional lifespan. As mobility declines, people may face limited career options and increasing difficulty in performing basic daily activities. Epidemiological studies indicate that chronic pain can shorten life expectancy by up to 10 years due to reduced physical activity and general deterioration of health.
“Pain in the joints and facial muscles can affect eating and speech. Chronic pain can be devastating over time,” said Armen N. Akopian, PhD, who is leading the charge for the project arm as a professor in the Department of Endodontics in the School of Dentistry at UT Health San Antonio, the academic health center of the University of Texas at San Antonio (UT San Antonio).
A renewed investment in TMJ pain research
A five-year study by the National Institutes of Health’s National Institute of Neurological Disorders and Stroke, which began in 2022, recently received approval at three years, allowing researchers to continue their work examining the biological mechanisms of TMJ disorders. The UT San Antonio project is part of a national consortium of five institutions conducting complementary studies across the country.
The ultimate goal is to create a starting point for the development of the first targeted, non-opioid treatment for chronic pain associated with muscle and joint dysfunction.
NIH’s continued investment provides an opportunity for UT San Antonio to expand both its scientific impact and institutional visibility in pain research.
For UT San Antonio, this grant raises our national profile and validates the Center for Pain Treatment and Addiction Research we have established. If we use this opportunity well, it can lead to discoveries that reshape the field and firmly establish our institution as a leader in pain research.”
Armen N. Akopian, PhD, Professor, Department of Endodontics, School of Dentistry, UT Health San Antonio
Mapping the biology of facial pain
During this phase of the project, the UT San Antonio team aims to identify and characterize the trigeminal neurons that innervate facial muscles and TMJ tissues, accounting for differences between male, female and aged mice with and without TMJ disorder. The researchers will also create detailed maps of afferent neurites—projections from the cell body of a neuron—that innervate facial muscles and TMJ tissue, determining their location, plasticity, and phenotype in mice and nonhuman primates. These maps will help scientists understand where and how pain originates and how it travels to other parts of the body.
The work is being extended to human studies, with the team examining and quantifying nerve and cell plasticity in tissues from patients with myalgia and TMJ disorders.
At the core of this effort is a focus on neuronal excitability. Pain begins when sensory neurons become sensitized and hyperexcitable – a process modulated by interactions between neurons and non-neuronal cells in muscles and joints.
“Although pain is ultimately processed in the brain, it must first be generated by sensory neurons,” Hakopian said. “Just as vision requires the eyes to initiate visual processing, pain requires functional sensory neurons. Without understanding what happens at this initial and focal point, we cannot design effective treatments.”
From awareness to chronic pain
After sensitization, stimuli that were once harmless can become painful, a phenomenon known as allodynia. Painful stimuli can also become disproportionately severe, a condition called hyperalgesia.
Akopian’s team examines pain at multiple levels – including patient-reported experience, neuronal firing patterns, changes in gene expression that control excitability, and signaling by non-neuronal cells in the affected tissue. Together, these data help identify biologically relevant targets for the treatment of chronic pain.
Clinically, even modest reductions in pain can be transformative. On a standard 10-point pain scale, a 25% reduction can shift pain from an 8 to a 6, making it bearable, or from a 5 to a 3, making it barely noticeable.
“Our goal is to link these pain experiences with measurable changes in neuronal firing patterns and gene expression,” Hakopian said.
Transcriptomics reveals unexpected specificity
One of the most powerful tools to guide the study is transcriptional profiling. Since 2015, Akopian and his team have completed dozens of studies analyzing neurons from the trigeminal and dorsal root ganglia.
“Our work – and that of a parallel NIH consortium known as Precision U19 – revealed that trigeminal neurons are much more specialized than previously thought,” Akopian said. “The neurons innervating the skin of the face are not the same as those innervating the muscles, joints, tongue or dura mater, which is involved in the headache.”
The team is now about 80% complete with a comprehensive map of neurons innervating the main facial muscles involved in chewing and speaking, as well as the temporomandibular joint itself. Each type of neuron is distinct in both gene expression and functional properties. Once complete, the map will represent a significant advance in understanding the biology of facial pain.
Create shared data resources
In addition to experimental findings, the consortium will contribute transcriptional and clinical data to NIH repositories. These include patient questionnaires and molecular datasets.
“These pooled, harmonized datasets are essential for high-quality meta-analyses,” Akopian said. “NIH wants to eliminate the bottleneck created by incompatible data sets by ensuring that data are validated and accessible to qualified researchers.”
This secure, standardized approach speeds discovery while protecting the privacy and integrity of patient data.
Towards non-opioid solutions for chronic pain
Detailed mapping and mechanistic understanding of TMJ pain provides a framework for the discovery of new, non-opioid pain treatments. The long-term goal is to develop treatments specifically designed for chronic pain – not just acute pain.
Most existing pain medications temporarily suppress symptoms but do not prevent the pain from becoming chronic. Some, such as opioids, can lead to tolerance and dependence, requiring escalating doses and carrying a risk of addiction.
“Our goal is fundamentally different,” Hakopian said. “We want to trace this transition from acute to chronic pain. When chronic pain already exists, we want to actively resolve it. This requires targeting the biological mechanisms that support chronic pain, not just masking the symptoms. A drug that actually prevents or resolves chronic pain would be revolutionary.”
