Santos Priscila L, Brito Renan G, Oliveira Marlange A, Quintans Jullyana S S, Guimarães Adriana G, Santos Márcio R V, Menezes Paula P, Serafini Mairim R, Menezes Irwin R A, Coutinho Henrique D M, Araújo Adriano A S, Quintans-Júnior Lucindo J
Department of Physiology, Federal University of Sergipe, São Cristóvão, SE, Brazil.
Department of Pharmacy, Federal University of Sergipe, São Cristóvão, SE, Brazil.
Phytomedicine. 2016 Aug 15;23(9):948-57. doi: 10.1016/j.phymed.2016.06.007. Epub 2016 Jun 11.
Citronellal (CT) is a monoterpene with antinociceptive acute effect. β-Cyclodextrin (βCD) has enhanced the analgesic effect of various substances.
HYPOTHESIS/PURPOSE: To evaluate the effect of CT both complexed in β-cyclodextrin (CT-βCD) and non-complexed, in a chronic muscle pain model (CMP) in mice.
The complex containing CT in βCD was obtained and characterized in the laboratory. The anti-hyperalgesic effect of CT and CT-βCD was evaluated in a pre-clinical in vivo study in a murine CMP.
The complex was characterized through differential scanning calorimetry, derivative thermogravimetry, moisture determination, infrared spectroscopy and scanning electron microscopy. Male Swiss mice were pre-treated with CT (50mg/kg, po), CT-βCD (50mg/kg, po), vehicle (isotonic saline, po) or standard drug (tramadol4 mg/kg, ip). 60 min after the treatment and then each 1h, the mechanic hyperalgesia was evaluated to obtain the time effect. In addition, the muscle strength using grip strength meter and hyperalgesia were also performed daily, for 7 days. We assessed by immunofluorescence for Fos protein on brains and spinal cords of mice. The involvement of the CT with the glutamatergic system was studied with molecular docking.
All characterization methods showed the CT-βCD complexation. CT-induced anti-hyperalgesic effect lasted until 6h (p <0.001) while CT-βCD lasted until 8h (p <0.001vs vehicle and p <0.001vs CT from the 6th h). CT-βCD reduced mechanical hyperalgesia on all days of treatment (p <0.05), without changing muscle strength. Periaqueductal gray (p <0.01) and rostroventromedular area (p <0.05) showed significant increase in the Fos protein expression while in the spinal cord, there was a reduction (p <0.001). CT showed favorable energy binding (-5.6 and -6.1) to GluR2-S1S2J protein based in the docking score function.
We can suggest that βCD improved the anti-hyperalgesic effect of CT, and that effect seems to involve the descending pain-inhibitory mechanisms, with a possible interaction of the glutamate receptors, which are considered as promising molecules for the management of chronic pain such as CMP.
香茅醛（CT）是一种具有抗伤害感受急性效应的单萜。β-环糊精（βCD）可增强多种物质的镇痛效果。
假设/目的：在小鼠慢性肌肉疼痛模型（CMP）中评估与β-环糊精复合的CT（CT-βCD）和未复合的CT的效果。
在实验室中制备并表征了含CT的βCD复合物。在小鼠CMP的临床前体内研究中评估了CT和CT-βCD的抗痛觉过敏作用。
通过差示扫描量热法、导数热重分析法、水分测定、红外光谱和扫描电子显微镜对复合物进行表征。雄性瑞士小鼠分别用CT（50mg/kg，口服）、CT-βCD（50mg/kg，口服）、赋形剂（等渗盐水，口服）或标准药物（曲马多4mg/kg，腹腔注射）进行预处理。治疗60分钟后，然后每小时评估一次机械性痛觉过敏以获得时间效应。此外，每天使用握力计评估肌肉力量并检测痛觉过敏，持续7天。通过免疫荧光法检测小鼠脑和脊髓中的Fos蛋白。通过分子对接研究CT与谷氨酸能系统的相互作用。
所有表征方法均显示形成了CT-βCD复合物。CT诱导的抗痛觉过敏作用持续至6小时（p<0.001），而CT-βCD持续至8小时（与赋形剂相比，从第6小时起p<0.001；与CT相比，p<0.001）。在治疗的所有天数中，CT-βCD均降低了机械性痛觉过敏（p<0.05），且未改变肌肉力量。中脑导水管周围灰质（p<0.01）和嘴侧延髓腹内侧区（p<0.05）的Fos蛋白表达显著增加，而脊髓中的Fos蛋白表达则降低（p<0.001）。基于对接评分函数，CT与GluR2-S1S2J蛋白显示出良好的能量结合（-5.6和-6.1）。
我们可以认为βCD改善了CT的抗痛觉过敏作用，且该作用似乎涉及下行性疼痛抑制机制，可能与谷氨酸受体相互作用，这些被认为是治疗如CMP等慢性疼痛的有前景的分子。
