A role for adrenomedullin as a pain-related peptide in the rat.

Abstract

Adrenomedullin (AM) belongs to the calcitonin gene-related peptide (CGRP) family and is a well known potent vasodilator. We show here that AM is a powerful pain-inducing neuropeptide. AM-like immunoreactivity is widely distributed in both CGRP-containing and lectin IB4-binding nociceptors in dorsal root ganglion and axon terminals in the superficial dorsal horn of the rat spinal cord. Specific binding sites for the radioligand, [(125)I]AM13-52 as well as immunoreactivity for receptor markers such as the calcitonin receptor-like receptor and three receptor-activity-modifying proteins are localized in the superficial dorsal horn, demonstrating the existence of AM/CGRP receptors in this region. Intrathecal injection of rat AM1-50, dose- and time-dependently, induced long-lasting heat hyperalgesia and increased the phosphorylation of Akt and GSK3beta in the dorsal horn. Pre- and posttreatments with the AM receptor antagonist AM22-52 and PI3 kinase inhibitors (LY294002 and Wortmannin) significantly blocked or reversed AM-induced heat hyperalgesia. Pre- and posttreatments with AM22-52 and Wortmannin also significantly blocked or reversed intraplantar capsaicin-induced heat hyperalgesia. Taken together, our results demonstrate that AM acts as a pain-inducing peptide in the dorsal horn. By activating specific receptors (likely AM2) and the PI3K/Akt/GSK3beta signaling pathway, AM could play a significant role in long-lasting heat hypersensitivity and inflammatory heat hyperalgesia.

• Authors: Weiya Ma, Jean-Guy Chabot, Remi Quirion
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 103 Issue 43 Pg. 16027-32 (Oct 24 2006) ISSN: 0027-8424 [Print] United States
• PMID: 17043245 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• Receptor Activity-Modifying Proteins
• Receptors, Adrenomedullin
• Receptors, Peptide
• Adrenomedullin
• Phosphotransferases
• Calcitonin Gene-Related Peptide
• Capsaicin

Topics

• Adrenomedullin (administration & dosage, immunology, metabolism, pharmacology)
• Animals
• Behavior, Animal (drug effects)
• Binding Sites
• Calcitonin Gene-Related Peptide (metabolism)
• Capsaicin (pharmacology)
• Enzyme Activation (drug effects)
• Ganglia, Spinal (metabolism)
• Inflammation (chemically induced, metabolism)
• Injections, Spinal
• Intracellular Signaling Peptides and Proteins (metabolism)
• Male
• Membrane Proteins (metabolism)
• Nociceptors (metabolism)
• Pain (chemically induced, metabolism)
• Phosphotransferases (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptor Activity-Modifying Proteins
• Receptors, Adrenomedullin
• Receptors, Peptide (metabolism)
• Signal Transduction