Intrathecal semaglutide attenuates burn injury-induced pain in mice through a spinal GLP-1R-linked enkephalin/δ-opioid receptor pathway.

Authors

Yongtao He, Jie Gao, Yongpeng Liu, Shuyuan Wu, Junzhe Kuang, Dan Chen, Biao Xu, Mengna Zhang, Quan Fang

Published in

Neuropharmacology. Pages 111163. Aug 30, 2026. Epub Aug 30, 2026.

Abstract

Burn injury-induced pain (BIP) is a complex condition whose spinal mechanisms remain incompletely understood. Although spinal glucagon-like peptide-1 receptor (GLP-1R) signaling has been implicated in pain modulation, its contribution to BIP remains unclear. Using a mouse model of second-degree burn injury, we characterized nociceptive behaviors, spinal glial responses, and the temporal and cellular distribution of GLP-1R using immunoblotting, immunofluorescence, and RNAscope in situ hybridization. We then evaluated the antinociceptive effects of intrathecal semaglutide, their sensitivity to pharmacological GLP-1R antagonism, and the functional contribution of endogenous enkephalin/δ-opioid receptor (DOR) signaling. Burn injury increased spinal GLP-1R expression during the peak phase of pain hypersensitivity. GLP-1R immunoreactivity and Glp1r transcripts showed a substantial association with GFAP-positive astrocytic profiles, while detectable signals were also present in microglia and neurons. Intrathecal semaglutide attenuated mechanical allodynia and thermal hyperalgesia, and these effects were reduced by pharmacological GLP-1R antagonism. Acute semaglutide responsiveness was also observed in female mice. Semaglutide increased spinal Penk mRNA and enkephalin immunoreactivity in vivo and increased Penk expression and extracellular enkephalin levels in primary spinal astrocyte-enriched cultures. In spinal tissue, enkephalin immunoreactivity was more frequently associated with GFAP-positive profiles than with Iba1- or NeuN-positive profiles. Moreover, enkephalin neutralization and DOR antagonism attenuated semaglutide-induced antinociception. Together, these findings support a functional spinal enkephalin/DOR pathway linked to intrathecal semaglutide treatment and consistent with GLP-1R involvement in BIP.

PMID:
42669356
Bibliographic data and abstract were imported from PubMed on 31 Aug 2026.

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