Central Mechanism Of AM22-52 And BAM8-22 In Inhibiting LPS Induced Inflammatory Pain In Rats

Adrenomedullin(AM/ADM)belongs to the calcitonin gene-related peptide(CGRP)family and is usually distributed widely as a neuroinducible peptide in the spinal cord dorsal horn(SCDH),cerebral cortex,hippocampus,hypothalamus,brainstem and peripheral dorsal root ganglia(DRG).The rat Mas-related G-protein-coupled receptor subtype C(MrgC)belongs to the G protein-coupled receptors(GPCRs)family and is mainly distributed in the small diameter DRG and trigeminal ganglia(TG).Previous studies have also demonstrated that inhibition of AM receptors or activation of MrgC receptors could relieve the lipopolysaccharide(LPS)-induced inflammatory pain,but its central mechanism of action was not clear.In our study,we selected intrathecal injection of AM22-52(AM receptor antagonist)and bovine adrenal medulla peptide 8-22(BAM8-22,MrgC receptor agonist),and explored the behavioral,Western blot,real-time fluorescence quantitative PCR and immunofluorescence staining techniques to investigate the blocking or AM and activating MrgC receptors were involved in the central mechanisms of inflammatory pain in LPS.The results showed that:(1)intraperitoneal injection of LPS induced a decrease in radiant heat stimulation in rats,and the pain threshold decreased to the lowest after about18 h of LPS injection,and intrathecal injection of AM22-52(10 nmol,20 nmol)showed a dose-dependent reversal of partial heat nociceptive hyperalgesia in rats;intraperitoneal injection of LPS in rats induced an increase in AM expression in SCDH.(2)Intraperitoneal injection of LPS induced elevation of Iba1,GFAP,TNF-α,IL-1β,P2X7 R and p-ERK1/2 in SCDH of rats,and intrathecal injection of AM22-52 inhibited the alteration of these factors.Co-expression of AM with astrocytes in SCDH was also detected experimentally.(3)Intraperitoneal injection of LPS resulted in decreased DRG MrgC expression in rats;intrathecal injection of BAM8-22 inhibited the elevation of Iba1,GFAP,TNF-α,IL-1β,CCL21,P2X7 R,n NOS and p-ERK1/2 in SCDH of rats with LPS-induced inflammatory pain,and had no effect on IL-6 expression.Conclusion: Intrathecal application of AM22-52 and BAM8-22 can inhibit LPS-induced activation of microglia and astrocytes in rats from the CNS,which in turn exerts analgesic effects.