title: Shanzhiside methylester, the principle effective iridoid glycoside from the analgesic herb Lamiophlomis rotata, reduces neuropathic pain by stimulating spinal microglial β-endorphin expression.
abstract: Lamiophlomis rotata (L. rotata, Duyiwei) is an orally available Tibetan analgesic herb widely prescribed in China. Shanzhiside methylester (SM) is a principle effective iridoid glycoside of L. rotata and serves as a small molecule glucagon-like peptide-1 (GLP-1) receptor agonist. This study aims to evaluate the signal mechanisms underlying SM anti-allodynia, determine the ability of SM to induce anti-allodynic tolerance, and illustrate the interactions between SM and morphine, or SM and β-endorphin, in anti-allodynia and anti-allodynic tolerance. Intrathecal SM exerted dose-dependent and long-lasting (>4 h) anti-allodynic effects in spinal nerve injury-induced neuropathic rats, with a maximal inhibition of 49% and a projected ED50 of 40.4 μg. SM and the peptidic GLP-1 receptor agonist exenatide treatments over 7 days did not induce self-tolerance to anti-allodynia or cross-tolerance to morphine or β-endorphin. In contrast, morphine and β-endorphin induced self-tolerance and cross-tolerance to SM and exenatide. In the spinal dorsal horn and primary microglia, SM significantly evoked β-endorphin expression, which was completely prevented by the microglial inhibitor minocycline and p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580. SM anti-allodynia was totally inhibited by the GLP-1 receptor antagonist exendin(9-39), minocycline, β-endorphin antiserum, μ-opioid receptor antagonist CTAP, and SB203580. SM and exenatide specifically activated spinal p38 MAPK phosphorylation. These results indicate that SM reduces neuropathic pain by activating spinal GLP-1 receptors and subsequently stimulating microglial β-endorphin expression via the p38 MAPK signaling. Stimulation of the endogenous β-endorphin expression may be a novel and effective strategy for the discovery and development of analgesics for the long-term treatment of chronic pain.
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: Teng-Fei
authors.initials: TF
authors.lastname: Li
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. Electronic address: yxwang@sjtu.edu.cn.
authors.forename: Yong-Xiang
authors.initials: YX
authors.lastname: Wang
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000627:therapeutic use*; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000187:drug effects*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D008911:Minocycline / Q000494:pharmacology; D009437:Neuralgia / Q000188:drug therapy*; D009474:Neurons / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D028321:Plant Preparations / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013127:Spinal Nerves / Q000293:injuries; D001615:beta-Endorphin / Q000235:genetics* / Q000378:metabolism
chemical_list: D000700:Analgesics; D004365:Drugs, Chinese Herbal; D028321:Plant Preparations; D001615:beta-Endorphin; D052216:Glucagon-Like Peptide 1; D008911:Minocycline
keywords: Anti-allodynia; Glucagon-like peptide-1 (GLP-1) receptor; Microglia; Shanzhiside methylester (SM); p38 mitogen-activated protein kinase (MAPK); β-endorphin