Exploring Adenosine A3 as a Novel Target for Trigeminal Neuropathic Pain: Marcela Romero-Reyes, DDS, PhD, FAHS

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"I’d like to say I’m very fortunate, because as a care provider, I'm an orofacial pain specialist who also does basic science, so I’m able to experience firsthand the needs of the patients, particularly those with trigeminal neuropathic pain disorders. I'm able to see this translation of the need to go from clinical care to the bench, and back."

Migraine, a complex and often debilitating neurological disorder, is among the leading causes of disability worldwide. Although several treatment options are available, many patients continue to experience inadequate relief, highlighting the need for new therapeutic targets to improve migraine management. One emerging candidate is the adenosine A3 receptor (A3AR), a Gi protein-coupled receptor broadly distributed in the central nervous system. In prior preclinical studies, results have shown that A3AR agonism can alleviate neuropathic pain via modulation of spinal dorsal horn neurons, though its role in trigeminally related nociception and migraine remains limited.

Researchers recently assessed the effects of selective A3AR agonists on migraine-like trigeminal neuronal activity in a preclinical migraine model. Presented at the 2025 American Headache Society (AHS) Annual Meeting, held June 19-22 in Minneapolis, Minnesota, findings from the study provided additional preclinical evidence that A3AR agonism modulates dural-responsive trigeminocervical neurons, inhibiting neuronal activity. Overall, the data indicated that A3AR may play a role in migraine-related mechanisms and highlighted its promise as a novel therapeutic target, though additional studies in models of trigeminovascular-neuronal sensitization may be needed to validate these results.^1,2

Orofacial pain specialist Marcela Romero-Reyes, DDS, PhD, FAHS, sat down with NeurologyLive^® at AHS 2025 to specifically discuss her team’s research on targeting the A3AR for post-traumatic trigeminal neuropathic pain, which she presented in a session. During the interview, Romero-Reyes, clinical professor and the director of the Brotman Facial Pain Clinic at University of Maryland School of Dentistry, explained that this approach builds on research showing that modulating key pronociceptive pathways can reduce central sensitization in pain models. She also pointed out previous data that suggest A3AR was generally safe and may provide a novel, nonaddictive, and well-tolerated therapeutic strategy for patients with chronic pain conditions.

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REFERENCES
1. Romero-Reyes M. A New Target for the Management of Trigeminal Neuropathic Pain. Presented at: 2025 AHS Annual Meeting; June 19-22; Minneapolis, MN. Hot Topic in Basic Science Talk 2.
2. Gamal-Eltrabily M, Romero-Reyes M, Salvemini D, Akerman S. The effect of selective adenosine A3 receptor (A3AR) agonism on migraine-like dural-responsive trigeminocervical neurons. Presented at: 2025 AHS Annual Meeting; June 19-22; Minneapolis, MN. Abstract P-223.