GLP-1 and its derived peptides mediate pain relief through direct TRPV1 inhibition without affecting thermoregulation

Abstract

Hormonal regulation during food ingestion and its association with pain prompted the investigation of the impact of glucagon-like peptide-1 (GLP-1) on transient receptor potential vanilloid 1 (TRPV1). Both endogenous and synthetic GLP-1, as well as a GLP-1R antagonist, exendin 9–39, reduced heat sensitivity in naïve mice. GLP-1-derived peptides (liraglutide, exendin-4, and exendin 9–39) effectively inhibited capsaicin (CAP)-induced currents and calcium responses in cultured sensory neurons and TRPV1-expressing cell lines. Notably, exendin 9–39 alleviated CAP-induced acute pain, as well as chronic pain induced by complete Freund’s adjuvant (CFA) and spared nerve injury (SNI), in mice without causing hyperthermia associated with other TRPV1 inhibitors. Electrophysiological analyses revealed that exendin 9–39 binds to the extracellular side of TRPV1, functioning as a noncompetitive inhibitor of CAP. Exendin 9–39 did not affect proton-induced TRPV1 activation, suggesting its selective antagonism. Among the exendin 9–39 fragments, exendin 20–29 specifically binds to TRPV1, alleviating pain in both acute and chronic pain models without interfering with GLP-1R function. Our study revealed a novel role for GLP-1 and its derivatives in pain relief, suggesting exendin 20–29 as a promising therapeutic candidate. People often consume more sweet and fatty foods when they’re hurting, a pattern observed in both humans and animals. This research investigates how eating can lessen pain, focusing on a hormone named glucagon-like peptide-1 (GLP-1), which is created in the stomach after eating. Researchers carried out tests on mice, using different techniques to see how GLP-1 and its byproducts influence pain perception through their impact on a specific pain receptor located in sensory nerves. The main discovery is that GLP-1 and its byproducts provide a potential new technique for pain relief by directly inhibiting the TRPV1 receptor, which could result in new pain management strategies without the negative effects linked with current treatments. The scientists conclude that targeting the GLP-1 pathway could be a promising approach to developing safer pain medications. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.