Adrenomedullin (AM) Is Involved In Neuropathic Pain And Cytological Mechanism In Diabetic Rats

Diabetic neuropathic pain(DNP)is a common chronic complication of diabetes.It is usually characterized by spontaneous pain,induced pain,hyperalgesia which seriously affects the quality of life of patients.The mechanism of DNP is still unclear.Adrenomedullin(AM)is a newly discovered pain-relieving medium.It is a 52-amino acid neuropeptide belonging to the calcitonin gene-related peptide(CGRP)family.Past studies in our laboratory have confirmed that AM is distributed in the superficial dorsal horn of the spinal cord and in the small and middle neurons of the dorsal root ganglia(DRG),and is involved in inflammatory pain and morphine tolerance as well as neuropathic pain caused by nerve damage.However,there are few studies on the role of AM in DNP.In this study,we explored the neuropathology of AM-induced diabetic rats by constructing a rat model of diabetes,detecting changes in behavior,using real-time fluorescent quantitative PCR,Western blotting(WB)and immunofluorescence double-labeled histochemistry.The role of pain and its mechanism experiment result shows:(1)In the process of STZ-induced DNP,the rats' body weight decreased continuously,blood glucose increased significantly,and the mechanical contraction pain threshold(MWT)and heat-shrinking foot reflex latency(TWL)decreased significantly,indicating that the DNP model was successfully established.(2)On day 28 of STZ-induced diabetes,after intrathecal administration of AM receptor antagonist AM22-52,pain hypersensitivity and hyperalgesia were alleviated in rats,indicating that AM was involved in the formation of diabetic neuropathic pain;(3)On day 28 of STZ-induced DNP model,AM and receptor mRNA increased in peripheral DRG and spinal cord of rats,indicating that AM mediates DNP through receptor;(4)On the 28 th day after modeling,intrathecal administration of AM22-52 to block AM receptor inhibited the activation of satellite glial cells and the up-regulation of Nav1.7 and nNOS protein expression in DRG induced by diabetes.AM is co-expressed with Nav1.7 and nNOS in DRG neurons;(5)On day 28 of STZ-induced diabetes,microglia and astrocytes were activated,inflammatory factor TNF-? and IL-1? mRNA and its protein expression are up-regulated in rat spinal dorsal horn;intrathecal AM22-52 blocks AM receptor,inhibits the activation of rat glial cells and upregulation of expression TNF-? and IL-1? proteins in diabetic rats.The above results indicate that DRG and spinal dorsal horn AM increase when DNP occurs,blocking AM receptor signaling can significantly alleviate DNP;AM participates in the regulation of satellite glial cells,nNOS,Nav1.7 and spinal dorsal horn cells in DRG DNP.