ABSTRACT
Endogenous angiotensin (Ang) II and/or an Ang II-derived peptide, acting on Ang type 1 (AT(1)) and Ang type 2 (AT(2)) receptors, can carry out part of the nociceptive control modulated by periaqueductal gray matter (PAG). However, neither the identity of this putative Ang-peptide, nor its relationship to Ang II antinociceptive activity was clarified. Therefore, we have used tail-flick and incision allodynia models combined with an HPLC time course of Ang metabolism, to study the Ang III antinociceptive effect in the rat ventrolateral (vl) PAG using peptidase inhibitors and receptor antagonists. Ang III injection into the vlPAG increased tail-flick latency, which was fully blocked by Losartan and CGP 42,112A, but not by divalinal-Ang IV, indicating that Ang III effect was mediated by AT(1) and AT(2) receptors, but not by the AT(4) receptor. Ang III injected into the vlPAG reduced incision allodynia. Incubation of Ang II with punches of vlPAG homogenate formed Ang III, Ang (1-7) and Ang IV. Amastatin (AM) inhibited the formation of Ang III from Ang II by homogenate, and blocked the antinociceptive activity of Ang II injection into vlPAG, suggesting that aminopeptidase A (APA) formed Ang III from Ang II. Ang III can also be formed from Ang I by a vlPAG alternative pathway. Therefore, the present work shows, for the first time, that: (i) Ang III, acting on AT(1) and AT(2) receptors, can elicit vlPAG-mediated antinociception, (ii) the conversion of Ang II to Ang III in the vlPAG is required to elicit antinociception, and (iii) the antinociceptive activity of endogenous Ang II in vlPAG can be ascribed preponderantly to Ang III.
Subject(s)
Analgesics/pharmacology , Angiotensin III/metabolism , Nociceptors/drug effects , Pain/metabolism , Periaqueductal Gray/metabolism , Analgesics/metabolism , Angiotensin II/pharmacology , Angiotensin III/pharmacology , Angiotensin Receptor Antagonists , Animals , Disease Models, Animal , Drug Interactions/physiology , Efferent Pathways/drug effects , Efferent Pathways/metabolism , Glutamyl Aminopeptidase/biosynthesis , Losartan/pharmacology , Male , Microinjections , Neural Inhibition/drug effects , Neural Inhibition/physiology , Nociceptors/metabolism , Oligopeptides/pharmacology , Pain/drug therapy , Pain/physiopathology , Pain Measurement , Pain Threshold/drug effects , Pain Threshold/physiology , Peptides/pharmacology , Periaqueductal Gray/drug effects , Rats , Rats, Wistar , Receptors, Angiotensin/metabolismABSTRACT
In the past few years the classical concept of the renin-angiotensin system (RAS) has experienced substantial conceptual changes. The identification of the renin/prorenin receptor, the angiotensin-converting enzyme homologue ACE2 as an angiotensin peptide processing enzyme, Mas as a receptor for Ang-(1-7) and the possibility of signaling through ACE, have contributed to switch our understanding of the RAS from the classical limited-proteolysis linear cascade to a cascade with multiple mediators, multiple receptors, and multi-functional enzymes. In this review we will focus on the recent findings related to RAS and, in particular, on its role in diabetes by discussing possible interactions between RAS mediators, endothelium function, and insulin signaling transduction pathways as well as the putative role of ACE2-Ang-(1-7)-Mas axis in disease pathogenesis.