Study On Analgesic Property, Effective Ingredients And Mechanism Of Lamiophlomis Rotata

Lamiophlomis rotata (Benth.) Kudo, a Tibetan herbal painkiller, has been widelyused for the management of pain in China and listed in China Pharmacopoeia, withshanzhiside methyl ester and8-O-acetylshanzhiside methyl ester represented as its majorand quality control indexed ingredients. This study aimed to systemically study theanalgesic property of Lamiophlomis rotata, indentify whether shanzhiside methyl esterand8-O-acetylshanzhiside methyl ester are principle effective ingredients, and explorewhether Lamiophlomis rotata produces analgesia through direct activation of spinalglucagon-like peptide-1receptors (GLP-1Rs). Our results demonstrated the Lamiophlomisrotata aqueous extract was not effective in acute nociception. But it effectively blockedformalin-induced tonic pain, peripheral nerve injury-and bone cancer-induced mechanicalallodynia by50-80%with ED50values of130-250mg/kg, close to the human dosage andregimen. A7-day multidaily gavage Lamiophlomis rotata aqueous extract did not lead toapparent analgesic tolerance. By using the activity-tracking method, we have identifiedtotal iridoid glucosides, rather than total flavonoids including rutin, are effectiveingredients entirely responsible for the analgesic property of Lamiophlomis rotata, whileboth shanzhiside methyl ester and8-O-acetylshanzhiside methyl ester representedprinciple iridoid glucosides. Finally, our results provided evidence that Lamiophlomisrotata produced analgesia completely through direct activation of spinal GLP-1Rsdemonstrated at both the spinal and cellular levels. Shanzhiside methyl ester and8-O-acetylshanzhiside methyl ester were nearly equally potent, and appears to bereversible and orthosteric agonists with full intrinsic efficacy of rat and human GLP-1Rswithout species difference, presumably acting at the same binding site as exenatide andexendin(9-39). Our results further support the notion that activation of spinal GLP-1Rs leads to specific analgesia in chronic pain states at the animal level, and suggest thatGLP-1R might have been a human-validated target molecule for the treatment of chronicpain.