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 AM1-50 (20 μg) once per day briefly reduced mechanical pain threshold on days 1 and 2 but induced prolonged mechanical allodynia on day 3. However, AM1-50 did not change mechanical pain sensation when the AM receptor antagonist AM22-52 (20 μg) was intrathecally co-administered. Daily administration of AM1-50 (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 AM22-52. The chronic administration of AM1-50 also increased expression of microglial maker Iba1 and astrocytic marker GFAP (glial fibrillary acidic protein) in the spinal dorsal horn in an AM22-52-sensitive manner. Furthermore, the application of AM1-50 (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 AM1-50 did not change TRPV1 expression in DRG in the presence of AM22-52 (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.

• Authors: Hao Huang, Mei Wang, Yanguo Hong
• Journal: Neuroscience letters (Neurosci Lett) Vol. 690 Pg. 196-201 (01 18 2019) ISSN: 1872-7972 [Electronic] Ireland
• PMID: 30366012 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Aif1 protein, rat
• Calcium-Binding Proteins
• GFAP protein, rat
• Glial Fibrillary Acidic Protein
• Microfilament Proteins
• Peptide Fragments
• TRPV Cation Channels
• Trpv1 protein, rat
• adrenomedullin (1-50)
• adrenomedullin (22-52)
• Adrenomedullin
• Nitric Oxide Synthase Type I
• Extracellular Signal-Regulated MAP Kinases

Topics

• Adrenomedullin (administration & dosage, agonists, antagonists & inhibitors, pharmacology, physiology)
• Animals
• Calcium-Binding Proteins (biosynthesis)
• Cells, Cultured
• Drug Interactions
• Extracellular Signal-Regulated MAP Kinases (biosynthesis)
• Ganglia, Spinal (metabolism)
• Glial Fibrillary Acidic Protein (biosynthesis)
• Hyperalgesia (metabolism, physiopathology)
• Injections, Spinal
• Male
• Microfilament Proteins (biosynthesis)
• Nitric Oxide Synthase Type I (biosynthesis)
• Pain Measurement (drug effects)
• Peptide Fragments (administration & dosage, pharmacology)
• Phosphorylation (drug effects)
• Rats
• Spinal Cord (metabolism)
• Spinal Cord Dorsal Horn (metabolism)
• TRPV Cation Channels (biosynthesis)