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조현정Hyunjung Jo

가천대학교 의과대학

Exp. Mol. Med., 01 November 2024 | https://doi.org/10.1038/s12276-024-01342-8 GLP-1 and its derived peptides mediate pain relief through direct TRPV1 inhibition without affecting thermoregulation

Eun Jin Go ^1,5, Sung-Min Hwang^1,5, Hyunjung Jo ^1,5, Md. Mahbubur Rahman ¹, Jaeik Park ¹, Ji Yeon Lee ², Youn Yi Jo ², Byung-Gil Lee ³, YunJae Jung³, Temugin Berta ⁴, Yong Ho Kim ^1,* and Chul-Kyu Park ^1,*

¹Gachon Pain Center and Department of Physiology, College of Medicine, Gachon University, Incheon 21999, Republic of Korea.
²Department of Anesthesiology and Pain Medicine, Gil Medical Center, Gachon University, Incheon 21565, Republic of Korea.
³Lee Gil Ya Cancer and Diabetes Institute Gachon University, Incheon 21999, Republic of Korea.
⁴Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, Cincinnati, OH, USA.
⁵These authors contributed equally: Eun Jin Go, SungMin Hwang, Hyunjung Jo.

^*Corresponding authors: correspondence to Yong Ho Kim or Chul-Kyu Park

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.

논문정보

형식Research article
게재일2024년 11월 (BRIC 등록일 2024-11-01)
연구진국내(교신)+국외 연구진
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