Critically, systemic administration of eCB degradation inhibitors simultaneously ‌rescued‌ chronic ISDN-induced headache and anxiety comorbidity, which are separately abolished by CB1R antagonist application in PrLs and ovBNSTs, demonstrating that eCB potentiation in the vAI-PrL and dAI-ovBNST circuits is indispensable for alleviating headache and anxiety, respectively. Here, CNR1 is linked to Headache.