title: Geniposide and its iridoid analogs exhibit antinociception by acting at the spinal GLP-1 receptors.
abstract: 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).
authors.affiliation: King's Lab, Shanghai Jiao Tong University, School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Nian
authors.initials: N
authors.lastname: Gong
authors.affiliation: King's Lab, Shanghai Jiao Tong University, School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Fan
authors.affiliation: King's Lab, Shanghai Jiao Tong University, School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Ai-Niu
authors.initials: AN
authors.lastname: Ma
authors.affiliation: King's Lab, Shanghai Jiao Tong University, School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: King's Lab, Shanghai Jiao Tong University, School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China. Electronic address: yxwang@sjtu.edu.cn.
authors.forename: Yong-Xiang
authors.initials: YX
authors.lastname: Wang
mesh_terms: D000700:Analgesics / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002491:Central Nervous System Agents / Q000494:pharmacology; D000077270:Exenatide; D005557:Formaldehyde; D000067757:Glucagon-Like Peptide-1 Receptor; D057809:HEK293 Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000737:chemistry; D006801:Humans; D057888:Iridoid Glucosides / Q000008:administration & dosage / Q000737:chemistry; D039823:Iridoids / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D059225:Nociception / Q000187:drug effects* / Q000502:physiology; D016716:PC12 Cells; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects* / Q000503:physiopathology; D014688:Venoms / Q000008:administration & dosage
chemical_list: C512409:1,10-anhydrogenipin; D000700:Analgesics; D002491:Central Nervous System Agents; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D006575:Heterocyclic Compounds, 3-Ring; D057888:Iridoid Glucosides; D039823:Iridoids; D010446:Peptide Fragments; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; C007835:geniposide; D005557:Formaldehyde; C078040:catalpol; C058966:geniposidic acid; C083773:exendin (9-39); D000077270:Exenatide; C059516:loganin
keywords: Antinociception; Geniposide; Glucagon-like peptide-1 receptors; Iridoid