Angiotensin-(1-7) induces peripheral antinociception through mas receptor activation in an opioid-independent pathway

The G protein-coupled receptor Mas was recently described as an angiotensin-(1-7) [Ang-(1-7)] receptor. In the present study, we demonstrate an antinociceptive effect of Ang-(1-7) for the first time. Additionally, we evaluated the anatomical localization of Mas in the dorsal root ganglia using immunofluorescence. This is the first evidence indicating that this receptor is present in sensitive neurons. The antinociceptive effect was demonstrated using the rat paw pressure test. For this test, sensitivity is increased by intraplantar injection of prostaglandin E(2). Ang-(1-7) administered locally into the right hind paw elicited a dose-dependent antinociceptive effect. Because the higher dose of Ang-(1-7) did not produce an effect when injected into the contralateral paw, this effect was considered local. The specific antagonist for the Mas receptor, A-779, inhibited the peripheral antinociception induced by exposure to 4 μg/paw Ang-(1-7) in a dose-dependent manner. The highest dose completely reversed the antinociceptive effect induced by Ang-(1-7), suggesting that the Mas receptor is an obligatory component in this process and that other angiotensin receptors may not be involved. When injected alone, the antagonist was unable to induce hyperalgesia or antinociception. Alternatively, naloxone was unable to inhibit the antinociceptive effect induced by Ang-(1-7), suggesting that endogenous opioid peptides may not be involved in this response. These data provide the first anatomical basis for the physiological role of Ang-(1-7) in the modulation of pain perception via Mas receptor activation in an opioid-independent pathway. Taken together, these results provide new perspectives for the development of a new class of analgesic drugs.