The GLP-1 receptor herbal agonist morroniside attenuates neuropathic pain via spinal microglial expression of IL-10 and β-endorphin

Objectives: To assess the protective effect of the glucagon-like peptide-1 receptor (GLP-1R) agonist morroniside against neuropathic pain and its downstream mechanisms of activating microglial GLP-1R/interleukin-10 (IL-10)/beta-endorphin antinociceptive pathway. Methods: Spinal nerve ligation-induced neuropathic pain rats were intrathecally injected with morroniside, with mechanical paw withdrawal threshold being assessed. The expression of spinal and cultured microglia IL-10 and beta-endorphin were detected with qRT-PCR. Key findings: Morroniside alleviated mechanical allodynia in neuropathic rats, which was blocked by inhibiting or depleting microglia. In addition, neutralizing spinal IL-10 or beta-endorphin with specialized antibodies or blocking the m-opioid receptor was able to fully reverse the morroniside-induced mechanical antiallodynia. Morroniside treatment stimulated the gene expression of IL-10 and beta-endorphin in the spinal lumbar enlargements of neuropathic rats as well as in primary cultured microglia. Furthermore, pretreatment with the IL-10 antibody blocked morroniside-stimulated beta-endorphin expression in the spinal cords of neuropathic rats and cultured primary microglia, whereas the beta-endorphin antibody failed to affect morroniside-stimulated gene expression of IL-10. Conclusions: These results reveal that morroniside produces therapeutic effects in neuropathy through spinal microglial expression of IL-10 and subsequent beta-endorphin after activation of GLP-1R. (C) 2020 Elsevier Inc. All rights reserved.