GLP-1 receptor activation attenuates chronic migraine-like behaviour: Sex-specific modulation of opioid- and endocannabinoid-related pathways
- Design
- Animal study · Mixed outcome
- Match to healthy normal-weight adults aged 55–75
- Not human evidenceVERY_INDIRECT: the subjects are male and female mice in a nitroglycerin model of chronic migraine, not people.
- Could weight loss explain it?
- UnlikelyBody weight and glucose tolerance were monitored and the GLP-1RAs left them unchanged, while propranolol raised glucose in males, so the antinociceptive effect cannot be attributed to weight loss or improved glycaemia; the outcome is a behavioural pain measure. No formal mediation analysis was done.
- Study tier
- Study tier 4VERY_LOW: a preclinical animal study, which the model places at its lowest tier; no animal numbers, doses, confidence intervals or p values are reported.
- Assessment
- Version 3 · Checked against the source by AI · Nov 6, 2026
Study facts come from the paper. Population match, weight-loss explanation and study tier are our judgments, made against the reference group of healthy normal-weight adults aged 55–75.
In male and female mice given repeated nitroglycerin to produce chronic migraine-like pain sensitivity, liraglutide, semaglutide and dulaglutide each reduced that sensitivity dose-dependently, about as well as the reference drug propranolol. The GLP-1 drugs did not change body weight or glucose tolerance, while propranolol raised blood glucose in males only. Semaglutide's effect was partly blocked by naloxone and came with sex-specific changes in opioid- and endocannabinoid-related gene expression in the brainstem. This is a preclinical animal study, and the abstract gives no animal numbers, doses or statistical estimates.
01Findings
What the study reported
- Drugs
- Liraglutide, Semaglutide, Dulaglutide
- Comparator
- propranolol (reference drug)
- Primary outcome
- attenuation of nitroglycerin-induced chronic migraine-like hypersensitivity (von Frey, acetone and orofacial glutamate tests)
- Effect
- Liraglutide, semaglutide and dulaglutide dose-dependently attenuated migraine-like hypersensitivity in both sexes, comparable to propranolol; the GLP-1RAs did not affect metabolic parameters while propranolol caused male-specific hyperglycaemia; semaglutide's antinociception was partially blocked by naloxone and came with sex-dimorphic brainstem changes in opioid- and endocannabinoid-related gene expression
- 95% confidence interval
- not reported in abstract
- Follow-up
- Not stated
- Adverse events
- GLP-1RAs did not affect metabolic parameters; propranolol, the comparator, induced male-specific hyperglycaemia
- Limitations
- A preclinical study in a nitroglycerin mouse model of chronic migraine with no animal numbers, doses, confidence intervals or p values reported; the endpoints are behavioural pain tests and brain mRNA measures rather than clinical migraine outcomes, and the mechanistic work used semaglutide alone as the class representative.
Who was studied
- Sex distribution
- male and female mice
- Obesity status
- not reported in abstract
- Diabetes status
- not reported in abstract
- Cvd status
- not reported in abstract
- Ckd status
- not reported in abstract
- Baseline condition
- nitroglycerin-induced chronic migraine-like hypersensitivity in mice
- Inclusion exclusion
- male and female mice given repeated nitroglycerin to induce chronic migraine-like hypersensitivity, then treated with a GLP-1RA or propranolol
Study quality details
- Study design
- Preclinical (animal)
- Sample size
- not extracted
- Randomization
- not reported in abstract
- Blinding
- not stated
- Comparator
- propranolol (reference drug)
- Follow up duration
- not stated
- Outcome type
- mixed
- Replication
- not assessed
- Consistency with other evidence
- not assessed
- Population applicability
- VERY_INDIRECT
- Statistical precision
- no confidence intervals, p values or animal numbers reported; effects described as dose-dependent
- Risk of bias
- not assessed
- Peer review status
- yes
02Funding
Funding and conflicts
- Funding
- Ministry of Science, Technological Development, and Innovation of the Republic of Serbia
- Industry funded
- Unclear
- Manufacturer
- not stated in source
- Sponsor role
- not reported in abstract
- Author conflicts
- not reported in abstract
- Independent replication
- unknown
Funding is shown on every study and never used to score it.
04Source
The source, as retrieved
Abstract
[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.
Where this record came from
| Source | Retrieved | Identifier |
|---|---|---|
| pubmed | Nov 1, 2026 | 42950887 first ingestion |
| pubmed | Nov 1, 2026 | 42950887 duplicate matched on doi |
| owner-review | Nov 6, 2026 | reviewed_by set to Carrie Schluter (2026-11-05) on the owner's own confirmation. The assessment is unchanged and still the auto-classifier's, so its extracted values stay withheld under the 2026-10-18 decision. |
| funding-repair | Nov 6, 2026 | funding_source: 'not reported in abstract' -> 'Ministry of Science, Technological Development, '. IN-067: funding_source, industry_funded and manufacturer re-derived from PubMed's grants metadata, which PASS-SPEC did not admit as a source until v1.3, so the review had replaced a named funder with a placeholder. Judgments, population, effects, prose and conflicts fields are unchanged. Owner decision IN-067 option 1, 2026-11-06. |
| pubmed | Nov 8, 2026 | 42950887 duplicate matched on doi |
| pubmed | Nov 8, 2026 | 42950887 duplicate matched on doi |