CGRP receptor antagonism impairs microglial anti-inflammatory function: IL-4 supplementation as a compensatory strategy for migraine.

Calcitonin gene-related peptide (CGRP) is a key therapeutic target for migraine, yet its dual role in central neuroimmune regulation remains incompletely understood. This study reveals a critical paradox: while CGRP directly promotes anti-inflammatory activation of microglia in vitro, treatment with the CGRP receptor antagonist BIBN4096BS in a chronic migraine mouse model rapidly alleviated pain but was not accompanied by an increase in microglial anti-inflammatory markers, including CD206 and p-STAT6. This finding suggests that complete CGRP blockade may inadvertently attenuate a masked endogenous pro-repair tone. To supplement this signaling, we introduced IL-4 intervention. IL-4 not only restored microglial anti-inflammatory function via STAT6 pathway activation but also produced synergistic analgesic effects when combined with the CGRP antagonist, superior to either monotherapy. STAT6 overexpression further enhanced the anti-inflammatory effect of the CGRP and IL-4 combination, while STAT6 knockdown completely reversed this protective effect. These findings demonstrate that CGRP antagonism, while providing rapid analgesia, may come at the cost of suppressing neuroimmune repair. Combining CGRP antagonism with STAT6 pathway activation may offer a strategy to simultaneously block vasogenic pain and support immune homeostasis, providing a new conceptual framework for migraine therapy.