The effect of selective adenosine A3 receptor (A3AR) agonism on migraine-like dural-responsive trigeminocervical neurons
Editor’s note: The research described below comes from a recipient of a 2025 MSC Travel Grant supporting travel to the 67th Annual Scientific Meeting of the American Headache Society. These grants reimburse travel expenses for those who have had their abstract for a presentation or poster accepted at a meeting.
By Mohammed Gamal Eltrabily, PhD, M.B.B.CH, postdoctoral fellow, American University, US.
What is the research gap that your study addresses?
Migraine is a complex condition. Despite the availability of pharmacological options for migraine management, these agents are not efficient in many patients. This condition points out the necessity of identifying new targets for migraine treatment by studying the role of different neurotransmitter receptors in migraine models. My study focuses on the potential of adenosine receptor type 3 (A3AR) agonism as a promising measure for targeted migraine therapeutic intervention.
What is your research hypothesis?
Specific A3AR agonists decrease the activity of trigeminocervical complex (TCC) neurons induced by electrical stimulation of the dura matter in a preclinical migraine model.
What methodology did you use to address your research hypothesis?
In Sprague Dawley rats, both male and female, in vivo electrophysiological extracellular recordings of TCC neurons were performed, measuring ongoing spontaneous activity, and somatosensory responses to dural electrical stimulation and cutaneous innocuous (brushing) and noxious (pinching) stimulation of receptive fields within the ophthalmic trigeminal division (V1). We assessed the effects of two highly selective A3AR agonists (Cl-IB-MECA and MRS5980; 1mg/kg each) compared to naratriptan (3mg/kg; positive control) or saline (vehicle control) and measured neuronal outcomes over 180 minutes.
What are the main results of your study?
In both male and female animals, Cl-IB-MECA and MRS5980 attenuated TCC neuronal responses to dural electrical stimulation (both A-delta and C fiber responses) and ongoing spontaneous firing without significant changes in cutaneous-induced responses. The results were similar to those obtained in animals treated with naratriptan. MRS5980, a highly selective A3AR agonist, did not affect arterial blood pressure although Cl-IB-MECA caused a sustained decrease in blood pressure, which could be likely due to off-target activity.
What conclusions did you reach based on your results?
These data provide preclinical support that A3AR agonism modulates dural-responsive TCC neuronal activity. It may therefore have a potential role in migraine-related mechanisms and provides strong support for A3AR as a novel target for therapeutic development.
What are the limitations of your study?
As a preclinical model, electrical stimulation of the dura matter has been associated with migraine and therefore we evaluated the effect of systemic A3AR agonist administration on neural activity in this context. However, further validation is necessary in models of trigeminovascular neuronal sensitization and other conditions that contribute to migraine pathophysiology, such as stress and food deprivation.
What is the relevance of your study to migraine?
This study dissects the role of A3AR in modulating trigeminal processing in a migraine-like condition. This supports its potential as a target for therapeutic intervention in migraine treatment. The fact that these agents were effective in females as well strengthen their possible use clinically as migraine is more common among females. Therefore, this work introduces a promising approach for more efficient pharmacological management in migraine.