Geniposide and its iridoid analogs exhibit antinociception by acting at the spinal GLP-1 receptors
| Autor: | Ai-Niu Ma, Nian Gong, Yong-Xiang Wang, Qi Xiao, Hui Fan |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Male
Nociception Agonist endocrine system medicine.medical_specialty medicine.drug_class Iridoid Glucosides PC12 Cells Glucagon-Like Peptide-1 Receptor Mice Cellular and Molecular Neuroscience chemistry.chemical_compound Formaldehyde Internal medicine Receptors Glucagon medicine Animals Humans Iridoids Rats Wistar Receptor Pharmacology Analgesics Venoms Chemistry Loganin digestive oral and skin physiology Antagonist Peptide Fragments Catalpol Rats HEK293 Cells Endocrinology Spinal Cord Genipin Exenatide Peptides Heterocyclic Compounds 3-Ring hormones hormone substitutes and hormone antagonists Central Nervous System Agents medicine.drug |
| Zdroj: | Neuropharmacology. 84:31-45 |
| ISSN: | 0028-3908 |
| DOI: | 10.1016/j.neuropharm.2014.04.007 |
| Popis: | We recently discovered that the activation of the spinal glucagon-like peptide-1 receptors (GLP-1Rs) by the peptidic agonist exenatide produced antinociception in chronic pain. We suggested that the spinal GLP-1Rs are a potential target molecule for the management of chronic pain. This study evaluated the antinociceptive activities of geniposide, a presumed small molecule GLP-1R agonist. Geniposide produced concentration-dependent, complete protection against hydrogen peroxide-induced oxidative damage in PC12 and HEK293 cells expressing rat and human GLP-1Rs, but not in HEK293T cells that do not express GLP-1Rs. The orthosteric GLP-1R antagonist exendin(9-39) right-shifted the concentration–response curve of geniposide without changing the maximal protection, with identical pA2 values in both cell lines. Subcutaneous and oral geniposide dose-dependently blocked the formalin-induced tonic response but not the acute flinching response. Subcutaneous and oral geniposide had maximum inhibition of 72% and 68%, and ED50s of 13.1 and 52.7 mg/kg, respectively. Seven days of multidaily subcutaneous geniposide and exenatide injections did not induce antinociceptive tolerance. Intrathecal geniposide induced dose-dependent antinociception, which was completely prevented by spinal exendin(9-39), siRNA/GLP-1R and cyclic AMP/PKA pathway inhibitors. The geniposide iridoid analogs geniposidic acid, genipin methyl ether, 1,10-anhydrogenipin, loganin and catalpol effectively inhibited hydrogen peroxide-induced oxidative damage and formalin pain in an exendin(9-39)-reversible manner. Our results suggest that geniposide and its iridoid analogs produce antinociception during persistent pain by activating the spinal GLP-1Rs and that the iridoids represented by geniposide are orthosteric agonists of GLP-1Rs that function similarly in humans and rats and presumably act at the same binding site as exendin(9-39). |
| Databáze: | OpenAIRE |
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