• Bin Zhu, Nian Gong, Hui Fan, Chong-Sheng Peng, Xiu-Juan Ding, Yi Jiang, and Yong-Xiang Wang.
• 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.).
• Anesthesiology. 2014 Oct 1;121(4):835-51.

BackgroundLamiophlomis 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).MethodsFormalin 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.ResultsThe 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.ConclusionsResults 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.

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