Caspani Ombretta, Reitz Marie-Céline, Ceci Angelo, Kremer Andreas, Treede Rolf-Detlef
Department of Neurophysiology, Centre for Biomedicine and Medical Technology Mannheim (CBTM), Heidelberg University, Ludolf-Krehl-Str. 13, D-68167 Mannheim, Germany.
Department of Neurophysiology, Centre for Biomedicine and Medical Technology Mannheim (CBTM), Heidelberg University, Ludolf-Krehl-Str. 13, D-68167 Mannheim, Germany.
Pharmacol Biochem Behav. 2014 Sep;124:290-6. doi: 10.1016/j.pbb.2014.06.018. Epub 2014 Jun 27.
Depression and anxiety are common comorbidities of neuropathic pain (NP). Pharmacological preclinical studies on NP have given abundant information on the effects of drugs on reflex measures of stimulus-evoked pain. However, few preclinical studies focus on relief of comorbidities evoked by NP. In this study, we investigated the effects of tramadol on nociceptive reflex, depression-associated and anxiety-related behaviors in a NP model in rats. We used chronic constriction injury (CCI) of the sciatic nerve as an animal model of neuropathic pain. We performed electronic von Frey tests (evF) to measure mechanical sensitivity, elevated plus maze tests (EPM) to record anxiety-related behaviors and forced swimming tests (FST) to evaluate depression-associated behaviors. In the evF, CCI rats showed a decrease of 82% of the paw withdrawal threshold (PWT) compared to sham (P<0.001). Tramadol increased the PWT by 336% in CCI rats (P<0.001) and by 16% in sham (P<0.05). On the EPM, CCI rats spent 45% less time than sham on the open arms of the maze (P<0.05). Tramadol increased the time spent on the open arms of CCI rats by 67% (P<0.05) and had no significant effect on sham. During the FST, CCI rats showed 28% longer immobility than sham (P<0.01). Tramadol reduced the immobility time in CCI rats by 22% (P<0.001), while having no effect on sham. Tramadol reversed the changes in mechanical sensitivity as well as anxiety-related and depression-associated behaviors that are caused by injury of the sciatic nerve with only minor effects in the absence of injury. These data suggest that tramadol relieves chronic pain and its indirect consequences and comorbidities, and that this study also is a model for pharmacological studies seeking to investigate the effect of drugs on the major disabling symptoms of NP.
抑郁症和焦虑症是神经性疼痛（NP）常见的共病。关于NP的临床前药理学研究已经提供了大量关于药物对刺激诱发疼痛的反射测量影响的信息。然而，很少有临床前研究关注NP诱发的共病的缓解情况。在本研究中，我们调查了曲马多对大鼠NP模型中伤害性反射、与抑郁相关及与焦虑相关行为的影响。我们使用坐骨神经慢性缩窄损伤（CCI）作为神经性疼痛的动物模型。我们进行电子von Frey测试（evF）以测量机械敏感性，进行高架十字迷宫测试（EPM）以记录与焦虑相关的行为，并进行强迫游泳测试（FST）以评估与抑郁相关的行为。在evF测试中，与假手术组相比，CCI大鼠的爪部撤离阈值（PWT）降低了82%（P<0.001）。曲马多使CCI大鼠的PWT提高了336%（P<0.001），使假手术组的PWT提高了16%（P<0.05）。在EPM测试中，CCI大鼠在迷宫开放臂上花费的时间比假手术组少45%（P<0.05）。曲马多使CCI大鼠在开放臂上花费的时间增加了67%（P<0.05），对假手术组无显著影响。在FST测试中，CCI大鼠的不动时间比假手术组长28%（P<0.01）。曲马多使CCI大鼠的不动时间减少了22%（P<0.001），对假手术组无影响。曲马多逆转了由坐骨神经损伤引起的机械敏感性以及与焦虑相关和与抑郁相关行为的变化，而在无损伤情况下只有轻微影响。这些数据表明曲马多可缓解慢性疼痛及其间接后果和共病，并且本研究也是寻求研究药物对NP主要致残症状影响的药理学研究的一个模型。
