Angiotensin III modulates the nociceptive control mediated by the periaqueductal gray matter.
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.
Pelegrini-da-Silva
A
A
Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Av Bandeirantes, 3900, ZIP 14049-900 Ribeirão Preto, São Paulo, Brazil.
Rosa
E
E
Guethe
L M
LM
Juliano
M A
MA
Prado
W A
WA
Martins
A R
AR
D000700:Analgesics / Q000378:metabolism / Q000494:pharmacology*; D000804:Angiotensin II / Q000494:pharmacology; D000805:Angiotensin III / Q000378:metabolism* / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D004195:Disease Models, Animal; D004347:Drug Interactions / Q000502:physiology; D004525:Efferent Pathways / Q000187:drug effects / Q000378:metabolism; D043384:Glutamyl Aminopeptidase / Q000096:biosynthesis; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008845:Microinjections; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000494:pharmacology; D010487:Periaqueductal Gray / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011945:Receptors, Angiotensin / Q000378:metabolism
D000700:Analgesics; D057911:Angiotensin Receptor Antagonists; D009842:Oligopeptides; D010455:Peptides; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D000805:Angiotensin III; C060894:CGP 42112A; C016977:amastatin; D043384:Glutamyl Aminopeptidase; D019808:Losartan