A role for adrenomedullin as a pain-related peptide in the rat.
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.
Ma
Weiya
W
Douglas Hospital Research Center, and Department of Psychiatry, McGill University, Montreal, QC, Canada H4H 1R3.
Chabot
Jean-Guy
JG
Quirion
Remi
R
D053607:Adrenomedullin / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001665:Binding Sites; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005727:Ganglia, Spinal / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D007278:Injections, Spinal; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009619:Nociceptors / Q000378:metabolism; D010146:Pain / Q000139:chemically induced / Q000378:metabolism; D010770:Phosphotransferases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D058261:Receptor Activity-Modifying Proteins; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide / Q000378:metabolism; D015398:Signal Transduction
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D058261:Receptor Activity-Modifying Proteins; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide; D053607:Adrenomedullin; D010770:Phosphotransferases; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin