From the Institute of Clinical Pharmacology, pharmazentrum Frankfurt/ZAFES, Hospital of the Goethe-University, Frankfurt, Germany.
Anesthesiology. 2014 Feb;120(2):447-58. doi: 10.1097/ALN.0b013e3182a76f74.
Prostacyclin (PGI2) is known to be an important mediator of peripheral pain sensation (nociception) whereas little is known about its role in central sensitization.
The levels of the stable PGI2-metabolite 6-keto-prostaglandin F1α (6-keto-PGF1α) and of prostaglandin E2 (PGE2) were measured in the dorsal horn with the use of mass spectrometry after peripheral inflammation. Expression of the prostanoid receptors was determined by immunohistology. Effects of prostacyclin receptor (IP) activation on spinal neurons were investigated with biochemical assays (cyclic adenosine monophosphate-, glutamate release-measurement, Western blot analysis) in embryonic cultures and adult spinal cord. The specific IP antagonist Cay10441 was applied intrathecally after zymosan-induced mechanical hyperalgesia in vivo.
Peripheral inflammation caused a significant increase of the stable PGI2 metabolite 6-keto-PGF1α in the dorsal horn of wild-type mice (n = 5). IP was located on spinal neurons and did not colocalize with the prostaglandin E2 receptors EP2 or EP4. The selective IP-agonist cicaprost increased cyclic adenosine monophosphate synthesis in spinal cultures from wild-type but not from IP-deficient mice (n = 5-10). The combination of fluorescence-resonance-energy transfer-based cyclic adenosine monophosphate imaging and calcium imaging showed a cicaprost-induced cyclic adenosine monophosphate synthesis in spinal cord neurons (n = 5-6). Fittingly, IP activation increased glutamate release from acute spinal cord sections of adult mice (n = 13-58). Cicaprost, but not agonists for EP2 and EP4, induced protein kinase A-dependent phosphorylation of the GluR1 subunit and its translocation to the membrane. Accordingly, intrathecal administration of the IP receptor antagonist Cay10441 had an antinociceptive effect (n = 8-11).
Spinal prostacyclin synthesis during early inflammation causes the recruitment of GluR1 receptors to membrane fractions, thereby augmenting the onset of central sensitization.
已知前列环素（PGI2）是外周疼痛感觉（伤害感受）的重要介质，但其在中枢敏化中的作用知之甚少。
使用质谱法在周围炎症后测量背角中稳定的 PGI2 代谢物 6-酮-前列腺素 F1α（6-keto-PGF1α）和前列腺素 E2（PGE2）的水平。通过免疫组织化学测定 prostanoid 受体的表达。在胚胎培养物和成年脊髓中使用生化测定（环腺苷单磷酸-、谷氨酸释放测定、Western blot 分析）研究前列环素受体（IP）激活对脊髓神经元的影响。在体内酵母聚糖诱导的机械性痛觉过敏后，将特异性 IP 拮抗剂 Cay10441 鞘内给药。
周围炎症导致野生型小鼠背角中稳定的 PGI2 代谢物 6-酮-PGF1α显著增加（n = 5）。IP 位于脊髓神经元上，不与前列腺素 E2 受体 EP2 或 EP4 共定位。选择性 IP 激动剂 cicaprost 增加了来自野生型而非 IP 缺陷型小鼠的脊髓培养物中环腺苷单磷酸的合成（n = 5-10）。基于荧光共振能量转移的环腺苷单磷酸成像和钙成像的组合显示 cicaprost 诱导了脊髓神经元中环腺苷单磷酸的合成（n = 5-6）。相应地，IP 激活增加了成年小鼠急性脊髓切片中的谷氨酸释放（n = 13-58）。Cicaprost 而非 EP2 和 EP4 的激动剂诱导 GluR1 亚基的蛋白激酶 A 依赖性磷酸化及其向膜的易位。因此，鞘内给予 IP 受体拮抗剂 Cay10441 具有镇痛作用（n = 8-11）。
早期炎症期间脊髓前列环素的合成导致 GluR1 受体募集到膜部分，从而增强了中枢敏化的发生。
