Researchers at UT Health San Antonio are leading a groundbreaking effort to understand exactly how chronic pain develops in the body, with the goal of creating the first targeted, non-opioid treatment that actually resolves pain rather than temporarily suppressing it. A five-year, $9 million National Institutes of Health study that began in 2022 recently received approval to continue into its next phase, allowing a consortium of five institutions across the country to accelerate their work mapping the biological mechanisms behind chronic pain, particularly temporomandibular joint (TMJ) disorders and facial pain. Why Understanding Pain at the Cellular Level Matters? Chronic pain is one of the most common health conditions worldwide, with back pain being the most frequently reported type, followed closely by head and face pain linked to TMJ disorder. While not immediately life-threatening like cancer or infectious disease, chronic pain can dramatically diminish quality of life and functional lifespan. Epidemiological studies suggest that chronic pain may shorten lifespan by as much as 10 years due to reduced physical activity and overall health decline. The key insight driving this research is that pain doesn't simply happen in the brain; it must first be generated by sensory neurons in the affected tissue. "Although pain is ultimately processed in the brain, it must first be generated by sensory neurons," explained Armen N. Akopian, PhD, professor in the Department of Endodontics at UT Health San Antonio's School of Dentistry and the lead researcher on the project. "Just as vision requires eyes to initiate visual processing, pain requires functioning sensory neurons. Without understanding what happens at this initial and focal point, we cannot design effective treatments". This fundamental understanding has shaped the research strategy. Rather than developing drugs that simply mask pain signals, the team is working to identify the specific biological mechanisms that cause pain to transition from acute to chronic, with the ultimate goal of preventing or actively resolving that transition. How Are Researchers Mapping Pain in the Body? During this phase of the project, the UT San Antonio team is pursuing several interconnected research approaches to create detailed biological maps of how pain originates and spreads: - Neuronal Identification: Identifying and characterizing trigeminal neurons that innervate facial muscle and temporomandibular joint tissues, cataloging differences across male, female, and older mice with and without TMJ disorder to understand how pain mechanisms vary by sex and age. - Nerve Mapping: Creating detailed maps of afferent neurites, which are projections from a neuron's cell body, that innervate facial muscle and TMJ tissue, defining their location, plasticity, and phenotype in mice and non-human primates to understand where and how pain originates. - Human Tissue Analysis: Examining and cataloging nerve and cellular plasticity in tissues from patients with myalgia and TMJ disorders to translate findings from animal models into human biology and validate mechanisms in actual patient tissue. - Gene Expression Profiling: Using transcriptomic profiling to analyze which genes are turned on or off in pain-generating neurons, revealing that trigeminal neurons are far more specialized than previously thought, with neurons innervating facial skin being distinctly different from those innervating muscles, joints, the tongue, or the dura mater involved in headache. The team is approximately 80 percent complete with a comprehensive map of neurons that innervate key facial muscles involved in chewing and speech, as well as the temporomandibular joint itself. Each neuron type is distinct in both gene expression and functional properties, representing a major advance in understanding the biology of facial pain. What Happens When Pain Becomes Chronic? At the core of this research effort is a focus on neuronal excitability. Pain begins when sensory neurons become sensitized and hyperexcitable, a process shaped by interactions between neurons and non-neuronal cells in muscles and joints. After sensitization occurs, stimuli that were once harmless may become painful, a phenomenon known as allodynia. Painful stimuli may also become disproportionately severe, a condition called hyperalgesia. Akopian's team examines pain at multiple levels, including patient-reported experience, neuronal firing patterns, gene expression changes that control excitability, and signaling from non-neuronal cells in affected tissue. Together, this data helps identify biologically meaningful targets for chronic pain treatment. Clinically, even modest reductions in pain can be transformative. On a standard 10-point pain scale, a 25 percent reduction can shift pain from an 8 to a 6, making it bearable, or from a 5 to a 3, rendering it barely perceptible. "Facial joint and muscle pain can interfere with eating and speaking. Chronic pain can be devastating over time," said Armen N. Akopian, PhD. Armen N. Akopian, PhD, Professor in the Department of Endodontics at UT Health San Antonio School of Dentistry How Could This Research Change Pain Treatment? The detailed mapping and mechanistic understanding of TMJ pain provides a framework for discovering novel, non-opioid pain therapies. Most existing pain medications temporarily suppress symptoms but do not prevent pain from becoming chronic. Some, such as opioids, can lead to tolerance and dependence, requiring escalating doses and carrying a risk of addiction. The research consortium is also contributing transcriptomic and clinical data to National Institutes of Health repositories, including patient questionnaires and molecular datasets. These centralized, harmonized datasets are essential for high-quality meta-analyses and help eliminate bottlenecks created by incompatible datasets from different studies. This secure, standardized approach accelerates discovery while protecting patient privacy and data integrity. "Our goal is fundamentally different," Akopian stated. "We want to pinpoint that transition from acute to chronic pain. When chronic pain is already present, we want to actively resolve it. This requires targeting the biological mechanisms that sustain chronic pain, not just masking symptoms. A drug that truly prevents or resolves chronic pain would be revolutionary". For UT San Antonio, this grant renewal elevates the institution's national visibility in pain research and validates the Center for Pain Therapeutics and Addiction Research that has been built there. If the opportunity is used well, it can lead to breakthroughs that reshape the field and firmly establish the institution as a leader in pain research.
