Mechanism Underlying Morroniside Antinociception In Neuropathic Pain

Purpose: Pain is one of the most common clinical symptoms,which appears in many diseases and disorders,The GLP-1R is a 463-amino acid transmembrane-spanning protein in the family of B/secretin G-protein coupled receptors.It mediates the effects of the endogenous GLP-1 and oxyntomodulin.Previous studies have proved that the iridoid with closed-circle can relieve pain by activating GLP-1 receptors.Morroniside is one of the iridoid with open-circle that can be extracted from Chinese traditional medicine Cornus offcinalis or Sambucus nigra.Morroniside widely reported has protective and prothetic effect on nerve cells.Our major reasearch is whether morroniside,the iridoid with open-circle can activate GLP-1 receptors to relieve neuropathic pain as other iridoids.Methods: In vivo,we used rat model of neuropathic pain(ligate L5/L6 spinal nerves and assess mechanical allodynia),intrathecal injection and intragastric administration are used respectively.After injection of morroniside and GLP-1 receptor antagonist exendin(9-39),observe the influence of mechanical pain in model animals.In vitro,hydrogen peroxide-induced oxidative damage model are used in N9 cells and HEK293 cells.The functions of morroniside were estimated by measuring viability using MTT assay.Results: Intrathecal injection and intragastric administration of morroniside both can suppress mechanical allergic reactions induced by peripheral nerve injury depend on concentrations.The antiallodynic effect persisted throughout the 7-day intrathecal administration,suggesting morroniside dose not induce apparent antiallodynia tolerance.Analgesic effect induced by intrathecal injection and intragastric administration of morroniside both can be blocked by GLP-1R antagonist exendin(9-39).Morroniside protect N9 cells absolutely against hydrogen peroxide-induced oxidative damage,and this protection is moved to right by GLP-1R antagonist exendin(9-39).Morroniside has a protective effect on HEK293 cells with GLP-1R but has not on HEK293 T without GLP-1R.Morroniside can activate GLP-1 receptors directly without inhibition of GLP-1 decomposition.Conclusion: Morroniside has analgesic effect in neuropathic pain through activating GLP-1 receptors without inducing apparent antiallodynic tolerance.