Anti-allodynic effect of angiotensin (1-7) on streptozotocin-induced diabetic neuropathic pain

[Speaker] Ryota Yamagata:1
[Co-author] Wataru Nemoto:1, Yoshiki Ogata:1, Osamu Nakagawasai:1, Koichi Tan-No:1
1:Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Japan

[Background] We have reported that intrathecal (i.t.) administration of an N-terminal fragment of angiotensin (Ang) II, Ang (1-7), attenuates Ang II-induced nociceptive behavior accompanied by the inhibition of p38 MAPK phosphorylation via Mas receptors [Eur. J. Pain, 18:1471-1479 (2014)]. In addition, expression of spinal Ang converting enzyme is increased in streptozotocin (STZ)-induced type 1 diabetes mice, which in turn leads to an activation of Ang II production system. Moreover, this activate of Ang II production system causes tactile allodynia accompanied by the phosphorylation of p38 MAPK through AT1 receptors [Mol. Pharmacol., 90:205-13 (2016)]. However, the inhibitory effect of Ang (1-7) on the STZ-induced diabetic neuropathic pain remains unclear. Thus, here we examined the effect of Ang (1-7) on diabetic neuropathic pain using STZ-induced type 1 diabetes mice.
[Methods] All experiments were performed using male ddY mice weighing 26-30 g. STZ (200 mg/kg) was dissolved in 0.1 N citrate buffer (pH 4.5) and a single intravenous injection was given to mice promptly thereafter to induce diabetes. Tactile allodynia was measured using von Frey Filament test. Phosphorylation of spinal ERK, JNK and p38 MAPK, and localization of Mas receptors were analyzed by Western blotting and immunohistochemistry, respectively.
[Results] STZ-induced tactile allodynia was inhibited by i.t. administration of Ang (1-7). The inhibitory effect of Ang (1-7) was significantly reversed by co-administration of A779, a Mas receptor antagonist. Anti-allodynic effect of Ang (1-7) was also prevented by i.t. preadministration of glibenclamide, an ATP-dependent potassium channel inhibitor. Western blot analysis showed that the expressions of phospho-p38 MAPK, -ERK 1/2 and -JNK were increased in spinal cord of STZ mice. Among them, i.t. injection of Ang (1-7) inhibited only phosphorylation of p38 MAPK, which was partially reversed by A779. Furthermore, spinal Mas receptors were expressed in neurons and microglia but absent from astrocytes.
[Conclusions] Our data show that Ang (1-7) inhibits STZ-induced tactile allodynia accompanied by the inhibition of p38 MPAK phosphorylation via Mas receptors, which expressed in neurons and microglia. In addition, it seems that anti-allodynic effect of Ang (1-7) is may be partially mediated through spinal ATP-dependent potassium channels.
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