The role of angiotensin II in nociceptive transmission in the spinal cord

虽然脊髓是一个重要的区域调制的伤害性感受，脊髓血管紧张素II（AngII）在伤害性传递的作用仍然不清楚。因此，为了阐明Ang II在脊髓伤害性传递中的作用，我们研究了鞘内（i.t.）将AngII施用到小鼠中。I.T. AngII的给药产生了由抓、咬和舔组成的行为反应。腹腔注射吗啡可剂量依赖性地抑制AngII诱导的行为反应，提示该行为反应与伤害性感受有关。i.t.也呈剂量依赖性地抑制伤害性行为。联合给药氯沙坦（AngII 1型（AT 1）受体拮抗剂）和SB 203580（p38 MAPK抑制剂）。然而，AT 2受体拮抗剂PD 123319、ERK 1/2磷酸化上游抑制剂U 0126和JNK受体激动剂SP 600125对Ang II诱导的伤害性行为没有影响。Western blot分析显示，i.t.注射AngII可诱导脊髓背角p38 MAPK的磷酸化，而对ERK 1/2和JNK无明显影响。给予AngII诱导伤害性行为，伴随着通过AT 1受体介导的p38 MAPK信号转导的激活。这一观察结果表明，血管紧张素Ⅱ可能作为一种神经递质和/或神经调质在脊髓传递伤害性信息。

Though the spinal cord is an important area for the modulation of nociception, the role of spinal angiotensin II (AngII) in nociceptive transmission remains unclear. Therefore, in order to elucidate the role of Ang II in nociceptive transmission in the spinal cord, we examined the effect of intrathecal (i.t.) administration of AngII into mice. I.t. administration of AngII produced a behavioral response consisting of scratching, biting and licking. The behavior induced by AngII was dose-dependently inhibited by intraperitoneal injection of morphine, suggesting that the behavioral response is related to nociception. The nociceptive behavior was also inhibited dose-dependently by i.t. co-administration of losartan, an AngII type 1 (AT1) receptor antagonist, and SB203580, a p38 MAPK inhibitor. However, AT2receptor antagonistPD123319, the upstream inhibitor of ERK1/2 phosphorylation U0126, and the JNK inhibitorSP600125 had no effect on Ang II-induced nociceptive behavior. Western blot analysis showed that the i.t. injection of AngII induced phosphorylation of p38 MAPK in the lumbar dorsal spinal cord, which was inhibited by losartan, without affecting ERK1/2 and JNK.Our data show that i.t. administration of AngII induces nociceptive behavior accompanied by the activation of p38 MAPK signaling mediated through AT1receptors. This observation indicates that AngII may act as a neurotransmitter and/or neuromodulator in the spinal transmission of nociceptive information.