In her lab at the University of Oxford, Annina Schmid explores the cellular and molecular changes associated with neuropathic pain.
Image credit:© JOHN CAIRNS, Nicholas Irving, Modified by Erin Lemieux
A physiotherapist by training, Annina Schmid never thought she would pursue a research path that was not fully clinical. During her graduate studies, she connected with neurophysiologist Elspeth McLachlan, who introduced her to mechanistic research approaches that could unravel the biology of chronic pain.
Early work in rat models suggested neuroinflammation might explain why patients with mild nerve compression reported pain beyond the injured site. Building on this, Schmid examined carpal tunnel syndrome (CTS), analyzing patient skin biopsies and identifying morphological changes extending far from the compression site.
Using CTS to Map Chronic Neuropathic Pain
Schmid and her team leverage CTS as a model to study neuropathic pain’s cellular and molecular roots. This condition is ideal for research due to its prevalence, localized nature, minimal comorbidities, and effectiveness of surgical treatment. These factors enable comparisons between injured and healthy nerves in the same patient and allow pre/post-surgery analysis.
Schmid’s team uses human induced pluripotent stem cell-derived sensory neurons in lab dishes or microfluidic systems to study chronic pain mechanisms.
Pao-Sheng (Paul) Chang, Schmid’s laboratory
By tracking patients before and six months after surgery, the team observed improved pain, numbness, and tingling, alongside better hand function despite incomplete nerve regeneration. Skin biopsies revealed gene expression patterns linked to nerve recovery, including upregulation of ADCYAP1, which encodes PACAP. This molecule, acting as both a neuromodulator and neurotrophic factor, enhances neuronal growth and survival. In vitro tests showed PACAP exposure stimulated neuronal outgrowth, suggesting potential therapeutic targets for nerve regeneration.
The researchers also analyzed blood samples from CTS patients to identify systemic biomarkers. Pre-surgery samples showed elevated pro-inflammatory cytokines, while recovery demonstrated pro-resolution markers like IL-9, associated with pain reduction. “It was unexpected to find such signatures in mild nerve injuries,” Schmid noted.
Expanding Insights Beyond CTS
Using Morton’s neuroma biopsies—tissue from a similar entrapment neuropathy—the team found demyelination and immune cell infiltration, particularly pain-associated macrophages. Current studies explore whether these cells directly increase neuronal excitability or act via signaling molecules. Schmid’s team is extending these findings to other conditions, including motor vehicle accident injuries and whiplash, identifying shared neuroinflammatory and nerve density changes.
For Schmid, integrating clinical and translational research creates a “full-circle” approach. She credits her openness to opportunities in basic science for this journey, which now spans clinical trials to molecular studies in vitro. “Recognizing these opportunities, even when daunting, has been invaluable,” she reflects.