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.