Background & Aims
Migraine stands as the second leading cause of global disability, particularly affecting females under 50 [1]. Nearly 70% of migraine sufferers are dissatisfied with conventional prophylactic therapies [2], prompting exploration into alternative treatment approaches. Recent preclinical investigations have shown that liraglutide (a GLP-1 receptor agonist) is effective against mechanical hypersensitivity associated with chronic migraine [3, 4]. Building on this, the hypothesis that GLP-1 receptor agonists might be useful for migraine prophylaxis arose. To add on existing knowledge, we aimed to investigate the effects of semaglutide and liraglutide, both long-acting GLP-1 receptor agonists, through an extended battery of antinociceptive tests including well-being assessment in a murine model of chronic migraine. In order to increase the translational relevance of our study, propranolol (a well-established migraine prophylactic drug) served as a positive control.
Methods
A model of chronic migraine was established by repeated intraperitoneal (i.p.) administration of nitroglycerin (NTG; 10 mg/kg; every second day over 9 days) in female C57BL/6 mice. Semaglutide (subcutaneous, s.c.), liraglutide (s.c.), and propranolol (i.p.) were given daily all over the study course. To evaluate pain hypersensitivity and the antinociceptive effects of treatments, both stimulus-evoked (orofacial glutamate test) and non-evoked (burrowing test) nociceptive tests were used. The orofacial glutamate test was performed by injecting glutamate solution (s.c.) into the orofacial region. This chemical stimulus induces specific nociceptive behavior that was quantified during 15 min (two hours post-NTG injection, all over the observing period). The burrowing test served as a paradigm for spontaneous nociceptive behavior and overall animal welfare (performed on the 8th day of the protocol). Data were analyzed using one-way/two-way repeated measures ANOVA (Tukey post hoc analysis).
Results
Repeated NTG administration caused significant chemical hypersensitivity and spontaneous nociceptive behavior in treated mice in comparison with the vehicle group (all P < 0.01; P < 0.05; respectively). In the orofacial glutamate test, prophylactic repeated administration of semaglutide (50 and 100 µg/kg/day, s.c.), liraglutide (400 and 800 µg/kg/day, s.c.), as well as propranolol (20 mg/kg/day, i.p.) significantly reduced the development of chemical pain hypersensitivity in female mice with NTG-induced chronic migraine, characterized by a decrease in total time spent in nociceptive behavior (all P < 0.05; two-way repeated measures ANOVA with Tukey post hoc test). In the burrowing test, prophylactic administration of both GLP-1 receptor agonists, contrasting the reference drug, statistically significantly increased the amount of burrowed material in comparison with the NTG-control group (all P < 0.05; one-way ANOVA with Tukey post hoc test).
Conclusions
The presented results showed that GLP-1 receptor agonists, semaglutide and liraglutide, attenuated provoked pain-like behavior in a comparable manner to propranolol, the referent drug, in the chronic migraine model in female C57BL/6 mice. Unlike propranolol, GLP-1 receptor agonists beneficially affect spontaneous pain-like behavior and animal well-being. Assuming the high predictive value of the employed chronic pain model, semaglutide and liraglutide might represent useful alternatives for chronic migraine prophylaxis. Further exploration of GLP-1 agonists in clinical settings is essential to ascertain their potential applicability.
References
[1] Steiner, T.J., Stovner, L.J., Jensen, R., Uluduz, D., Katsarava, Z., 2020. Migraine remains second among the world’s causes of disability, and first among young women: findings from GBD2019. J Headache Pain 21, 137.
[2] Pascual, J., Panni, T., Dell’Agnello, G., Gonderten, S., Novick, D., Evers, S., 2023. Preventive treatment patterns and treatment satisfaction in migraine: results of the OVERCOME (EU) study. J Headache Pain. 24(1):88.
[3] Jing, F., Zou, Q., Wang, Y., Cai, Z., Tang, Y., 2021. Activation of microglial GLP-1R in the trigeminal nucleus caudalis suppresses central sensitization of chronic migraine after recurrent nitroglycerin stimulation. J Headache Pain. 22(1):86.
[4] Jing, F., Zou, Q., Pu, Y., 2023. GLP-1R agonist liraglutide attenuates pain hypersensitivity by stimulating IL-10 release in a nitroglycerin-induced chronic migraine mouse model. Neurosci Lett. 812:137397.
Presenting Author
Katarina Si?ovi?
Poster Authors
Katarina Sicovic
MSc
Faculty of Pharmacy, University of Belgrade
Lead Author
Katarina Nasti?
M. Pharm.
Department of Pharmacology, Faculty of Pharmacy, University of Belgrade
Lead Author
Uroš Pecikoza
M. Pharm
Department of Pharmacology, Faculty of Pharmacy, University of Belgrade
Lead Author
Ana Micov
M. Pharm
Department of Pharmacology, Faculty of Pharmacy, University of Belgrade
Lead Author
Topics
- Specific Pain Conditions/Pain in Specific Populations: Migraine