Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
Department of Health Care Medical Research, Venture Business Laboratory, Kanazawa University, Kanazawa 920-1192, Japan.
Neuropeptides. 2017 Oct;65:71-76. doi: 10.1016/j.npep.2017.05.002. Epub 2017 May 23.
We have previously demonstrated that the intrathecal (i.t.) administration of angiotensin (Ang) II into mice produces a nociceptive behaviour consisting of scratching, biting and licking accompanied by the phosphorylation of p38 MAPK in the spinal cord, which was mediated through AT1 receptors. Both the p38 MAPK phosphorylation and subsequent nociceptive behaviour were attenuated by the i.t. co-administration of Ang (1-7), an N-terminal fragment of Ang II, that acted via Mas receptors. On the other hand, a C-terminal fragment of Ang II, namely Ang III, was also shown to induce a nociceptive behaviour by acting upon AT1 receptors on spinal astrocytes and neurons, and was found to be more potent than Ang II. However, the inhibitory effect of Ang (1-7) on the Ang III-induced nociceptive behaviour remains unclear. Thus, here we examined whether Ang (1-7) can attenuate the Ang III-induced nociceptive behaviour and activation of spinal p38 MAPK. The i.t. administration of Ang (1-7) (1-100fmol) dose-dependently attenuated the Ang III (1pmol)-induced nociceptive behaviour in mice. Moreover, the inhibitory effect of Ang (1-7) at a dose of 100fmol was prevented by A779 (30fmol), a Mas receptor antagonist. Western blot analysis showed that the phosphorylation of p38 MAPK induced by the i.t. administration of Ang III (1pmol) was also attenuated by Ang (1-7) (100fmol), and this inhibition was prevented by A779 (30fmol). Furthermore, we showed that in the lumbar superficial dorsal horn, Mas receptors are expressed in neurons and microglia but absent from astrocytes. Together, these results suggest that the i.t. administration of Ang (1-7) attenuates the nociceptive behaviour and accompanying p38 MAPK phosphorylation induced by Ang III, and that this effect is likely mediated through Mas receptors on spinal neurons.
我们之前已经证明，向小鼠鞘内（i.t.）给予血管紧张素（Ang）II 会产生一种疼痛行为，包括抓挠、咬和舔，并伴随着脊髓中 p38 MAPK 的磷酸化，这是通过 AT1 受体介导的。Ang（1-7），即 Ang II 的 N 端片段，与 AT1 受体共同鞘内给药，可减轻 p38 MAPK 磷酸化和随后的疼痛行为。另一方面，Ang II 的 C 端片段，即 Ang III，也被证明通过作用于脊髓星形胶质细胞和神经元上的 AT1 受体引起疼痛行为，并且比 Ang II 更有效。然而，Ang（1-7）对 Ang III 诱导的疼痛行为的抑制作用仍不清楚。因此，在这里，我们研究了 Ang（1-7）是否可以减轻 Ang III 诱导的疼痛行为和脊髓 p38 MAPK 的激活。Ang（1-7）（1-100fmol）的鞘内给予剂量依赖性地减轻了小鼠中 Ang III（1pmol）诱导的疼痛行为。此外，Mas 受体拮抗剂 A779（30fmol）阻止了 Ang（1-7）（100fmol）的抑制作用。Western blot 分析表明，Ang III（1pmol）鞘内给予引起的 p38 MAPK 磷酸化也被 Ang（1-7）（100fmol）减弱，而 A779（30fmol）可阻止这种抑制。此外，我们表明，在腰椎浅层背角中，Mas 受体存在于神经元和小胶质细胞中，但不存在于星形胶质细胞中。总之，这些结果表明，Ang（1-7）的鞘内给予减轻了 Ang III 诱导的疼痛行为和伴随的 p38 MAPK 磷酸化，并且这种作用可能是通过脊髓神经元上的 Mas 受体介导的。
