μ-Opioid Receptor Dynamics in the Parameningeal Tissue During Migraine Attacks

Objective: The possible impact of meningeal μ-opioid receptor (μOR) binding in migraine remains unknown. This study investigated μOR availability in the cranial parameninges involved in migraine initiation via nociceptor activation. Methods: We used positron emission tomography with [¹¹C] carfentanil, and measured μOR availability in meninges and adjacent skull bone (parameningeal tissue [PMT]) under resting and sustained thermal pain threshold stress challenge conditions. μOR availability was compared between individuals with migraine in interictal and ictal phases and healthy controls. Furthermore, we examined the relationship between μOR availability and headache intensity, as well as the potential influence of sex on this measure. Results: A total of 36 patients with interictal episodic migraine (8 also assessed ictally), 7 patients with ictal chronic migraine, and 22 healthy controls were included in the analysis. Both the episodic migraine and chronic migraine groups showed lower μOR availability in the parietal PMT than healthy controls during the ictal resting phase. No significant differences were observed during the interictal phase. Exploratory analyses on the effects of sex indicated that both healthy women and migraine patients of both sexes showed lower μOR availability in the frontal PMT compared with healthy men in the ictal sustained thermal pain threshold stress condition. Furthermore, the interictal μOR availability in the frontal PMT was negatively associated with headache intensity in the preceding month. Interpretation: The observed variability in PMT μOR availability across the different cortical regions and migraine episodes, along with its association with pain intensity, underscores the critical role of extracerebral mechanisms in migraine pathophysiology. ANN NEUROL 2025;98:777–787.