Triptans reprogram Schwann cells to drive medication-overuse headache via β-glycan/TGF-β3 signaling

Abstract Medication-overuse headache (MOH) is one of the leading causes of chronic daily headache worldwide and arises from the repeated use of acute anti-migraine medications, including triptans. However, the cellular substrates and intracellular pathways driving this paradoxical chronification remain unknown. Here, using Schwann cell-selective silencing of the 5-HT 1B/D receptor, we observed that acute triptan administration counteracts CGRP-induced, endosome-confined cAMP accumulation, preventing the development of periorbital mechanical allodynia in mice. In contrast, prolonged 5-HT 1B/D activation in Schwann cells induces epigenetic and transcriptomic dysregulation associated with MOH in mice. Specifically, intronic hypermethylation-driven overexpression of BETAGLYCAN promotes activation of a non-canonical TGF-β-dependent signaling cascade. The resulting TGF-β3 upregulation establishes a feed-forward loop that sustains proalgesic paracrine communication between Schwann cells and primary sensory neurons. Analysis of plasma levels from patients with MOH confirmed elevated TGF-β3 levels specifically associated with triptan-dependent MOH, supporting the translational relevance of these findings. Together, our data identify Schwann cell 5-HT 1B/D signaling as a dual mediator of both the acute anti-migraine efficacy and the maladaptive mechanisms underlying MOH. These results provide a conceptual framework for strategies aimed at preserving the therapeutic benefits of triptans while limiting the adverse consequences of chronic administration. One Sentence Summary Schwann cell 5-HT1B/D receptor signaling mediates the dual effects of triptans by acutely inhibiting CGRP-driven nociceptive pathways while chronically promoting epigenetically driven TGF-β3-dependent proalgesic signaling that causes medication-overuse headache.