Intrathecal administration of adrenomedullin induces mechanical allodynia and neurochemical changes in spinal cord and DRG

Abstract

This study investigated the effect of adrenomedullin (AM) on mechanical pain sensitivity and its possible mechanisms. Intrathecal injection of AM receptor agonist AM_1-50 (20 μg) once per day briefly reduced mechanical pain threshold on days 1 and 2 but induced prolonged mechanical allodynia on day 3. However, AM_1-50 did not change mechanical pain sensation when the AM receptor antagonist AM_22-52 (20 μg) was intrathecally co-administered. Daily administration of AM_1-50 (20 μg) for 3 days increased expression of phosphorylated extracellular signal-regulated protein kinase (pERK) and neuronal nitric oxide synthase (nNOS) in the spinal dorsal horn. The AM-induced increase in pERK and nNOS was inhibited by the co-administration of AM_22-52. The chronic administration of AM_1-50 also increased expression of microglial maker Iba1 and astrocytic marker GFAP (glial fibrillary acidic protein) in the spinal dorsal horn in an AM_22-52-sensitive manner. Furthermore, the application of AM_1-50 (10 nM, 3 h) to dorsal root ganglion (DRG) explant cultures induced an increase in the expression of transient receptor potential vanilloid 1 (TRPV1). The treatment with AM_1-50 did not change TRPV1 expression in DRG in the presence of AM_22-52 (2 μM). These results suggest that the increased AM bioactivity induced mechanical allodynia and may contribute to the mechanical pain hypersensitivity under pathological conditions. The mechanisms may involve the activation of ERK signaling pathway and spinal glia as well as the recruitment of nNOS and TRPV1 in the spinal dorsal horn or DRG. The present study indicates that inhibition of the activation AM receptor might provide a fruitful strategy to relieving chronic pain.

Keywords: Adrenomedullin (AM); Dorsal root ganglion (DRG); Glia; Spinal dorsal horn; Transient receptor potential vanilloid 1 (TRPV1); pERK.