Peripheral GALR2 activation by the metabolically stabilized spexin analog LIT-01-144 produces potent opioid‑independent antinociception
Abstract
Chronic pain constitutes a major global health burden, and current management remains largely dependent on opioid analgesics, which are associated with opioid use disorder. Accordingly, there is a pressing need to identify non-opioid therapeutic strategies. Galanin receptors (GALR1–3) have been implicated in pain modulation, but their individual roles remain insufficiently defined because of the absence of subtype-selective ligands. Recently, spexin has been identified as an endogenous peptide that selectively activates GALR2 and GALR3, offering a new scaffold for developing pharmacological tools targeting these receptor subtypes. In this study, we designed and characterized LIT-01-144, a modified spexin analog incorporating N-terminal fluorocarbon functionalization to improve metabolic stability while preserving receptor selectivity. In vitro pharmacological profiling demonstrated high potency at GALR2 and GALR3, with negligible activity at GALR1. Pharmacokinetic analyses showed a substantially prolonged plasma half-life relative to native spexin and no evidence of central nervous system penetration. In vivo, intracerebroventricular administration of LIT-01-144 produced robust antinociception at doses tenfold lower than those required for spexin. Although systemic administration had no detectable effect in naïve mice, it significantly attenuated pain-related behaviors in a model of persistent inflammatory pain. This effect was mediated specifically by GALR2 and was independent of opioid receptor signaling. In situ hybridization further showed an increase in Galr2 + neurons in dorsal root ganglia of inflamed mice. Collectively, these findings highlight GALR2 as a promising peripheral target for developing non-opioid analgesics and demonstrate the potential of LIT-01-144 as a valuable tool for understanding GALR2-mediated mechanisms of pain modulation.
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BibTeX
@article{berthome2026peripheral,
title = {{Peripheral GALR2 activation by the metabolically stabilized spexin analog LIT-01-144 produces potent opioid‑independent antinociception}},
author = {Yann Berthomé and Glenn-Marie Le Coz and Valérie Utard and Qiuxiang Gu and Rosine Fellmann-Clauss and Nathalie Petit-Demoulière and Raphaëlle Quillet and Claire Gavériaux-Ruff and Sridevi M. Ramanoudjame and Lucie Estéoulle and Nicolas Humbert and François Daubeuf and Patrick Gizzi and Stéphanie Riché and Xavier Leroy and Dominique Bonnet and Frédéric Simonin},
journal = {Biomedicine and Pharmacotherapy},
year = {2026},
month = oct,
doi = {10.1016/j.biopha.2026.119987},
url = {https://hal.science/hal-05845252v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Peripheral GALR2 activation by the metabolically stabilized spexin analog LIT-01-144 produces potent opioid‑independent antinociception
AU - Yann Berthomé
AU - Glenn-Marie Le Coz
AU - Valérie Utard
AU - Qiuxiang Gu
AU - Rosine Fellmann-Clauss
AU - Nathalie Petit-Demoulière
AU - Raphaëlle Quillet
AU - Claire Gavériaux-Ruff
AU - Sridevi M. Ramanoudjame
AU - Lucie Estéoulle
AU - Nicolas Humbert
AU - François Daubeuf
AU - Patrick Gizzi
AU - Stéphanie Riché
AU - Xavier Leroy
AU - Dominique Bonnet
AU - Frédéric Simonin
PY - 2026
DA - 2026/10/17
JO - Biomedicine and Pharmacotherapy
DO - 10.1016/j.biopha.2026.119987
UR - https://hal.science/hal-05845252v1
AB - Chronic pain constitutes a major global health burden, and current management remains largely dependent on opioid analgesics, which are associated with opioid use disorder. Accordingly, there is a pressing need to identify non-opioid therapeutic strategies. Galanin receptors (GALR1–3) have been implicated in pain modulation, but their individual roles remain insufficiently defined because of the absence of subtype-selective ligands. Recently, spexin has been identified as an endogenous peptide that selectively activates GALR2 and GALR3, offering a new scaffold for developing pharmacological tools targeting these receptor subtypes. In this study, we designed and characterized LIT-01-144, a modified spexin analog incorporating N-terminal fluorocarbon functionalization to improve metabolic stability while preserving receptor selectivity. In vitro pharmacological profiling demonstrated high potency at GALR2 and GALR3, with negligible activity at GALR1. Pharmacokinetic analyses showed a substantially prolonged plasma half-life relative to native spexin and no evidence of central nervous system penetration. In vivo, intracerebroventricular administration of LIT-01-144 produced robust antinociception at doses tenfold lower than those required for spexin. Although systemic administration had no detectable effect in naïve mice, it significantly attenuated pain-related behaviors in a model of persistent inflammatory pain. This effect was mediated specifically by GALR2 and was independent of opioid receptor signaling. In situ hybridization further showed an increase in Galr2 + neurons in dorsal root ganglia of inflamed mice. Collectively, these findings highlight GALR2 as a promising peripheral target for developing non-opioid analgesics and demonstrate the potential of LIT-01-144 as a valuable tool for understanding GALR2-mediated mechanisms of pain modulation.
SN - 0753-3322
SN - 1950-6007
ER -