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

虽然脊髓是调控伤害性感觉的重要区域，但脊髓血管紧张素II(AngII)在伤害性信息传递中的作用尚不清楚。因此，为了阐明Ang II在脊髓伤害性传递中的作用，我们研究了鞘内注射(I.T.)给小鼠注射血管紧张素转换酶。IT。给予血管紧张素转换酶后，小鼠的行为反应包括抓挠、咬和舔。腹腔注射吗啡可剂量依赖性地抑制血管紧张素Ⅱ诱导的行为反应，提示行为反应与伤害性感受有关。大鼠伤害性行为也被I.T.剂量依赖地抑制。联合应用血管紧张素Ⅱ1型(AT1)受体拮抗剂氯沙坦和p38 MAPK抑制剂SB203580。然而，AT2受体拮抗剂、ERK1/2磷酸化上游抑制剂U0126和JNK抑制剂SP600125对Ang II诱导的伤害性行为无影响。Western印迹分析表明，I.T.注射血管紧张素Ⅱ可诱导脊髓背角p38MAPK的磷酸化，该作用可被氯沙坦抑制，但不影响ERK1/2和JNK。给予血管紧张素转换酶诱导大鼠伤害性行为，并通过AT1受体激活p38MAPK信号通路。这一观察结果表明，AngII可能在脊髓伤害性信息的传递中起神经递质和/或神经调节剂的作用。

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.