Glucagon-like Peptide-1 Receptor Agonists as Modulators of Pain-Related Mechanisms: A Systematic Review of Experimental and Translational Evidence

Background/Objectives: Glucagon-like peptide-1 receptor agonists, widely used for diabetes and obesity, have recently attracted interest because of their potential effects on biological pathways involved in nociception and neuroinflammation. This systematic review synthesized experimental and translational evidence regarding the influence of GLP-1RAs on pain-related mechanisms, rather than on clinical pain outcomes. Methods: A systematic review was conducted according to PRISMA guidelines and registered in PROSPERO (CRD420261367538). Fourteen experimental studies were included, the majority of which were preclinical. Methodological quality was assessed using the CAMARADES checklist, and risk of bias was evaluated using the SYRCLE tool. Results: Most included studies were conducted in animal models or experimental systems. Across these studies, GLP-1 receptor activation was associated with reduced neuroinflammation, inhibition of microglial activation, decreased pro-inflammatory cytokine production, increased IL-10 levels, and modulation of TRPV1/TRPA1 channels. Additional effects included enhancement of endogenous opioid signaling, activation of PI3K/Akt pathways, and attenuation of central sensitization. Overall study quality was moderate, with an unclear-to-moderate risk of bias. Conclusions: Current experimental evidence suggests that GLP-1RAs modulate multiple biological pathways involved in nociception, neuroinflammation, and pain-related signaling. However, these findings primarily derive from mechanistic and preclinical studies and should not be interpreted as evidence of clinical efficacy for pain treatment.