Lee Hsin-Jung, Chang Lu-Yang, Ho Yu-Cheng, Teng Shu-Fang, Hwang Ling-Ling, Mackie Ken, Chiou Lih-Chu
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Neuropharmacology. 2016 Jun;105:577-586. doi: 10.1016/j.neuropharm.2016.02.018. Epub 2016 Feb 18.
The orexin system consists of orexin A/hypocretin 1 and orexin B/hypocretin 2, and OX1 and OX2 receptors. Our previous electrophysiological study showed that orexin A in the rat ventrolateral periaqueductal gray (vlPAG) induced antinociception via an OX1 receptor-initiated and endocannabinoid-mediated disinhibition mechanism. Here, we further characterized antinociceptive effects of orexins in the mouse vlPAG and investigated whether this mechanism in the vlPAG can contribute to stress-induced analgesia (SIA) in mice. Intra-vlPAG (i.pag.) microinjection of orexin A in the mouse vlPAG increased the hot-plate latency. This effect was mimicked by i.pag. injection of WIN 55,212-2, a CB1 agonist, and antagonized by i.pag. injection of the antagonist of OX1 (SB 334867) or CB1 (AM 251), but not OX2 (TCS-OX2-29) or opioid (naloxone), receptors. [Ala(11), D-Leu(15)]-orexin B (i.pag.), an OX2 selective agonist, also induced antinociception in a manner blocked by i.pag. injection of TCS-OX2-29, but not SB 334867 or AM 251. Mice receiving restraint stress for 30 min showed significantly longer hot-plate latency, more c-Fos-expressing orexin neurons in the lateral hypothalamus and higher orexin levels in the vlPAG than unrestrained mice. Restraint SIA in mice was prevented by i.pag. or intraperitoneal injection of SB 334867 or AM 251, but not TCS-OX2-29 or naloxone. These results suggest that during stress, hypothalamic orexin neurons are activated, releasing orexins into the vlPAG to induce analgesia, possibly via the OX1 receptor-initiated, endocannabinoid-mediated disinhibition mechanism previously reported. Although activating either OX1 or OX2 receptors in the vlPAG can lead to antinociception, only OX1 receptor-initiated antinociception is endocannabinoid-dependent.
食欲素系统由食欲素A/下丘脑泌素1和食欲素B/下丘脑泌素2以及OX1和OX2受体组成。我们之前的电生理研究表明，大鼠腹外侧导水管周围灰质（vlPAG）中的食欲素A通过OX1受体启动和内源性大麻素介导的去抑制机制诱导抗伤害感受。在此，我们进一步研究了食欲素在小鼠vlPAG中的抗伤害感受作用，并探讨了vlPAG中的这一机制是否有助于小鼠的应激诱导镇痛（SIA）。向小鼠vlPAG内微量注射（i.pag.）食欲素A可延长热板潜伏期。向i.pag.注射CB1激动剂WIN 55,212-2可模拟此效应，而向i.pag.注射OX1拮抗剂（SB 334867）或CB1拮抗剂（AM 251）可拮抗此效应，但OX2拮抗剂（TCS-OX2-29）或阿片受体拮抗剂（纳洛酮）则无此作用。OX2选择性激动剂[Ala(11), D-Leu(15)]-食欲素B（i.pag.）也可诱导抗伤害感受，其作用方式可被i.pag.注射TCS-OX2-29阻断，但不能被SB 334867或AM 251阻断。接受30分钟束缚应激的小鼠与未受束缚的小鼠相比，热板潜伏期明显延长，下丘脑外侧表达c-Fos的食欲素神经元增多，vlPAG中的食欲素水平升高。向i.pag.或腹腔注射SB 334867或AM 251可预防小鼠的束缚应激诱导的镇痛，但TCS-OX2-29或纳洛酮则无此作用。这些结果表明，在应激过程中，下丘脑食欲素神经元被激活，将食欲素释放到vlPAG中以诱导镇痛，可能是通过先前报道的OX1受体启动、内源性大麻素介导的去抑制机制。虽然激活vlPAG中的OX1或OX2受体均可导致抗伤害感受，但只有OX1受体启动的抗伤害感受依赖于内源性大麻素。
