GLP‐1 receptor activation attenuates chronic migraine‐like behaviour: Sex‐specific modulation of opioid‐ and endocannabinoid‐related pathways

Background and Purpose Chronic migraine (CM) is a highly disabling condition that remains suboptimally treated. Metabolic disturbances may trigger migraine chronification, whereas impaired endogenous pain inhibition contributes to CM development. Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), used for type 2 diabetes and obesity, show efficacy in chronic pain models. We evaluated the prophylactic effects of liraglutide, semaglutide and dulaglutide compared with propranolol (reference drug), potential opioidergic/endocannabinoid involvement and sex differences in a CM model. Experimental Approach Chronic migraine‐like hypersensitivity was induced by repeated nitroglycerin administration in male and female mice. The prophylactic effects of GLP‐1RAs and propranolol were examined using von Frey, acetone and orofacial glutamate tests. Body weight and glucose tolerance were monitored to evaluate metabolic safety. Potential opioidergic/endocannabinoid involvement in semaglutide‐induced antinociception (selected GLP‐1RA class representative) was assessed by pharmacological blockade and/or quantitative polymerase chain reaction (qPCR) analysis of pain‐related neurobiomarker mRNA expression in brainstem and trigeminal ganglia. Key Results Liraglutide, semaglutide and dulaglutide dose‐dependently attenuated CM‐like hypersensitivity in both sexes, with efficacy comparable to propranolol. GLP‐1RAs did not affect metabolic parameters, whereas propranolol induced male‐specific hyperglycaemia. Semaglutide‐induced antinociception was partially sensitive to naloxone and was associated with sex‐dimorphic, brainstem‐specific transcriptional changes in opioid‐ and endocannabinoid‐related pathways. Semaglutide increased Glp1r, Cnr1 , Pomc, Pcsk1 and Pcsk2 mRNA expression in males, whereas it up‐regulated Glp1r and down‐regulated Faah and Mgll in females. Conclusions and Implications GLP‐1RAs exert class‐wide antinociceptive effects in a preclinical CM model, with semaglutide‐based analyses suggesting sex‐specific modulation of central opioid‐ and endocannabinoid‐related pathways. These findings support further investigation of GLP‐1RAs as prophylactic strategies for migraine, particularly in individuals with metabolic comorbidities.