title: Morroniside, a secoiridoid glycoside from Cornus officinalis, attenuates neuropathic pain by activation of spinal glucagon-like peptide-1 receptors.
abstract: Iridoid glycosides containing the double bond scaffold of cyclopentapyran are reversible and orthosteric agonists of glucagon-like peptide-1 (GLP-1) receptors and exert anti-nociceptive and neuroprotective actions. Morroniside, derived from the medicinal herb Cornus officinalis, is an atypical secoiridoid containing a six-membered cyclic inner ether fragment. Here we investigated whether morroniside was an orthosteric GLP-1 receptor agonist and had anti-hypersensitivity activities in a model of neuropathic pain.
  
  
  
  We used a model of neuropathic pain, induced by tight ligation of L5/L6 spinal nerves in rats. Hydrogen peroxide-induced oxidative damage was also assayed in N9 microglial cells and human HEK293 cells stably expressing GLP-1 receptors.
  
  
  
  Morroniside protected against hydrogen peroxide-induced oxidative damage in N9 microglial and HEK293 cells that expressed mouse or human GLP-1 receptors, but not in HEK293T cells without GLP-1 receptors. The GLP-1 receptor orthosteric antagonist exendin(9-39) also concentration-dependently shifted the concentration-protective response curves of morroniside and exenatide to the right without affecting maximal protection, with similar pA2values. Furthermore, morroniside given by oral gavage or intrathecally in neuropathic rats dose-dependently attenuated mechanical allodynia, with comparable Emaxvalues and ED50s of 335 mg·kg-1and 7.1 μg and completely blocked thermal hyperalgesia. Daily intrathecal injections of morroniside over 7 days did not induce anti-allodynic tolerance. Pretreatment with intrathecal exendin(9-39) completely blocked systemic and intrathecal morroniside-induced mechanical anti-allodynia.
  
  
  
  Our data demonstrated that morroniside was an orthosteric agonist of GLP-1 receptors and produced antihypersensitivity in a neuropathic pain model by activation of spinal GLP-1 receptors.
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Xu
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai, China.
authors.forename: Hai-Yun
authors.initials: HY
authors.lastname: Wu
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai, China.
authors.forename: Nian
authors.initials: N
authors.lastname: Gong
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai, China.
authors.forename: Yi-Rui
authors.initials: YR
authors.lastname: Wang
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai, China.
authors.forename: Yong-Xiang
authors.initials: YX
authors.lastname: Wang
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D029768:Cornus / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism*; D006027:Glycosides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008968:Molecular Conformation; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D000700:Analgesics; D000067757:Glucagon-Like Peptide-1 Receptor; D006027:Glycosides; C488401:morroniside; D000097789:Glucagon-Like Peptide-1 Receptor Agonists