Li Shu-Fa, Zhang Yuan-Yuan, Li You-Yan, Wen Song, Xiao Zhi
Endocrinology Department, Linyi People's Hospital, Linyi, Shangdong 276000, People's Republic of China.
Zunyi Medical College, Zunyi, Guizhou 563003, People's Republic of China.
Pharmacol Biochem Behav. 2014 Dec;127:49-55. doi: 10.1016/j.pbb.2014.10.007. Epub 2014 Oct 24.
The 5-HT7 receptor is the most recently discovered receptor for 5-hydroxytryptamine (5-HT), and only little is known about the analgesic potential of this receptor. Adenosine triphosphate (ATP) modulates pain transmission by activating P2X/P2Y receptors, in which the P2X3 subtype is an important target for this effect. This study examined the antihyperalgesic effect of the 5-HT7 receptors in the ventrolateral midbrain periaqueductal gray (vlPAG), a crucial site for endogenous pain inhibition. This study also explored the importance of the interactions between the 5-HT7 and P2X3 receptors in this effect. To address this issue, neuropathic pain was induced through chronic constriction injury (CCI) of the sciatic nerve in Sprague-Dawley (SD) rats. The expression level and distribution of the 5-HT7 receptor were evaluated through Western blot and immunohistochemistry. The mechanical withdrawal threshold (MWT) was measured by using an electronic pressure meter test. Different doses (3, 6, and 12μmol) of AS-19, a selective agonist of the 5-HT7 receptor, were administered in the vlPAG of CCI rats. The effects of pretreatment with the selective 5-HT7 receptor antagonist SB-269970 or the selective P2X3 receptor antagonist A-317491 on the analgesic effect of AS-19 were observed. Results showed that CCI decreased the MWT values of the rats. The injury also increased the protein level of the 5-HT7 receptor in the vlPAG of neuropathic pain rats. AS-19 microinjection significantly elevated the MWT values in a dose-dependent manner, but SB-269970 pretreatment attenuated the antihyperalgesic effect of AS-19. Furthermore, the antihyperalgesic effect of the 5-HT7 receptor was partially but significantly blocked by A-317491 pretreatment. These data indicate that the 5-HT7 receptor in the vlPAG exerts an antihyperalgesic effect on rats with neuropathic pain. The 5-HT7 and P2X3 receptors interact in the vlPAG and exhibit an analgesic action through the enhanced function of the endogenous analgesic system.
5-羟色胺7（5-HT7）受体是5-羟色胺（5-HT）最近发现的受体，关于该受体的镇痛潜力知之甚少。三磷酸腺苷（ATP）通过激活P2X/P2Y受体来调节疼痛传递，其中P2X3亚型是这种作用的重要靶点。本研究考察了腹外侧中脑导水管周围灰质（vlPAG）中5-HT7受体的抗痛觉过敏作用，vlPAG是内源性疼痛抑制的关键部位。本研究还探讨了5-HT7和P2X3受体之间相互作用在该效应中的重要性。为解决这一问题，通过对Sprague-Dawley（SD）大鼠坐骨神经进行慢性压迫损伤（CCI）来诱导神经性疼痛。通过蛋白质免疫印迹法和免疫组织化学法评估5-HT7受体的表达水平和分布。使用电子压力计测试测量机械缩足阈值（MWT）。将不同剂量（3、6和12μmol）的5-HT7受体选择性激动剂AS-19注射到CCI大鼠的vlPAG中。观察选择性5-HT7受体拮抗剂SB-269970或选择性P2X3受体拮抗剂A-317491预处理对AS-19镇痛作用的影响。结果显示，CCI降低了大鼠的MWT值。该损伤还增加了神经性疼痛大鼠vlPAG中5-HT7受体的蛋白水平。AS-19微量注射以剂量依赖性方式显著提高了MWT值，但SB-269970预处理减弱了AS-19的抗痛觉过敏作用。此外，A-317491预处理部分但显著地阻断了5-HT7受体的抗痛觉过敏作用。这些数据表明，vlPAG中的5-HT7受体对神经性疼痛大鼠发挥抗痛觉过敏作用。5-HT7和P2X3受体在vlPAG中相互作用，并通过增强内源性镇痛系统的功能发挥镇痛作用。
