Geniposide and its iridoid analogs exhibit antinociception by acting at the spinal GLP-1 receptors

Neuropharmacology. 2014 Sep;84:31-45. doi: 10.1016/j.neuropharm.2014.04.007. Epub 2014 Apr 18.


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).

Keywords: Antinociception; Geniposide; Glucagon-like peptide-1 receptors; Iridoid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / administration & dosage*
  • Analgesics / chemistry
  • Analgesics / pharmacology
  • Animals
  • Central Nervous System Agents / pharmacology
  • Exenatide
  • Formaldehyde
  • Glucagon-Like Peptide-1 Receptor
  • HEK293 Cells
  • Heterocyclic Compounds, 3-Ring / administration & dosage
  • Heterocyclic Compounds, 3-Ring / chemistry
  • Humans
  • Iridoid Glucosides / administration & dosage
  • Iridoid Glucosides / chemistry
  • Iridoids / administration & dosage*
  • Iridoids / chemistry
  • Iridoids / pharmacology
  • Male
  • Mice
  • Nociception / drug effects*
  • Nociception / physiology
  • PC12 Cells
  • Peptide Fragments / pharmacology
  • Peptides / administration & dosage
  • Rats
  • Rats, Wistar
  • Receptors, Glucagon / agonists
  • Receptors, Glucagon / antagonists & inhibitors
  • Receptors, Glucagon / metabolism*
  • Spinal Cord / drug effects*
  • Spinal Cord / physiopathology
  • Venoms / administration & dosage


  • 1,10-anhydrogenipin
  • Analgesics
  • Central Nervous System Agents
  • GLP1R protein, human
  • Glp1r protein, mouse
  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Heterocyclic Compounds, 3-Ring
  • Iridoid Glucosides
  • Iridoids
  • Peptide Fragments
  • Peptides
  • Receptors, Glucagon
  • Venoms
  • geniposide
  • Formaldehyde
  • catalpol
  • geniposidic acid
  • exendin (9-39)
  • Exenatide
  • loganin