title: Lamiophlomis rotata, an orally available Tibetan herbal painkiller, specifically reduces pain hypersensitivity states through the activation of spinal glucagon-like peptide-1 receptors.
abstract: BACKGROUND
  Lamiophlomis rotata is an orally available Tibetan herb prescribed for the management of pain, with shanzhiside methylester (SM) and 8-O-acetyl-SM as quality control ingredients. This study aimed to evaluate the antinociceptive properties of L. rotata, determine whether SM and 8-O-acetyl-SM are principle effective ingredients, and explore whether L. rotata produces antinociception through activation of spinal glucagon-like peptide-1 receptors (GLP-1Rs).
  
  
  METHODS
  Formalin test, neuropathic pain, and bone cancer pain models were used, and the animal sample size was 5 to 6 in each group. Hydrogen peroxide-induced oxidative damage was also assayed.
  
  
  RESULTS
  The L. rotata aqueous extract blocked formalin-induced tonic hyperalgesia and peripheral nerve injury- and bone cancer-induced mechanical allodynia by 50 to 80%, with half-effective doses of 130 to 250 mg/kg, close to the human dosage. The herb was not effective in alleviating acute nociceptive pain. A 7-day gavage with L. rotata aqueous extract did not lead to antiallodynic tolerance. Total iridoid glycosides, rather than total flavonoids, were identified by the activity-tracking method as effective ingredients for antihyperalgesia, whereas both SM and 8-O-acetyl-SM were principal components. Further demonstrations using the GLP-1R antagonist and gene silencer against GLP-1R at both the spinal and the cellular levels indicated that L. rotata inhibited pain hyperactivity by activation of spinal GLP-1Rs, and SM and 8-O-acetyl-SM appeared to be orthosteric, reversible, and fully intrinsic agonists of both rat and human GLP-1Rs.
  
  
  CONCLUSIONS
  Results support the notion that the activation of spinal GLP-1Rs leads to specific antinociception in pain hypersensitivity and further suggest that GLP-1R is a human-validated target molecule for the treatment of chronic pain.
authors.affiliation: From the King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai, China (B.Z., N.G., H.F., C.-S.P., Y.-X.W.); and Suzhou Yihua Biopharm Technology Co., Suzhou, Jiangsu, China (X.-J.D., Y.J.).
authors.forename: Bin
authors.initials: B
authors.lastname: Zhu
authors.forename: Nian
authors.initials: N
authors.lastname: Gong
authors.forename: Hui
authors.initials: H
authors.lastname: Fan
authors.forename: Chong-Sheng
authors.initials: CS
authors.lastname: Peng
authors.forename: Xiu-Juan
authors.initials: XJ
authors.lastname: Ding
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
authors.forename: Yong-Xiang
authors.initials: YX
authors.lastname: Wang
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage* / Q000302:isolation & purification; D000818:Animals; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage* / Q000302:isolation & purification; D000067757:Glucagon-Like Peptide-1 Receptor; D057809:HEK293 Cells; D006358:Hot Temperature / Q000009:adverse effects; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism*; D016716:PC12 Cells; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D028321:Plant Preparations / Q000008:administration & dosage / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D018609:Tibet
chemical_list: D000700:Analgesics; D004365:Drugs, Chinese Herbal; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D028321:Plant Preparations; D018027:Receptors, Glucagon