Department of Anatomy and K.K. Leung Brain Research Centre, Preclinical School of Medicine, Fourth Military Medical University, China.
Pain Physician. 2012 Jul-Aug;15(4):311-26.
Acrolein signaling is important during spinal cord injury; whether it is involved in somatic and emotional pain is not clear. Hydralazine is a potent antihypertensive drug and can scavenge acrolein efficiently.
We hypothesized that hydralazine decreases spinal level acrolein and renders analgesic effects with some side effects, which was tested in the current study.
Subcutaneous injection of formalin was used to induce somatic and emotional pain responses. The spinal neuronal activation (FOS expression) and acrolein expression were evaluated at 2 hours after subcutaneous formalin injection. The possible side effects of hydralazine on the murine central nervous system or cardiovascular system were evaluated at one hour after hydralazine injection with open field, elevated plus maze and rotarod tests, or telemetrical measurement of mean artery blood pressure and heart rate.
The subcutanous injection of formalin into the left hind paw induced significant somatic and emotional pain responses, evaluated by the biphasic spontaneous flinch/licking of the injected hind paw and interphase ultrasonic vocalizations during the one hour window after formalin injection. The spinal acrolein level was significantly increased and neurons were activated at 2 hours after formalin injection. Intraperitoneal injection of hydralazine (at 0.1, 1 or 10 mg/kg of body weight) at one hour before formalin challenging dose-dependently attenuated the formalin induced pain responses with an analgesic 50% effect dose ranging from 0.2 to 1 mg/kg of body weight. Furthermore, the neuronal activation and elevated acrolein expression were dose-dependently inhibited by hydralazine pretreatment. The side effects of intraperitoneal hydralazine on locomotion, anxiety, and motor coordination at one hour after hydralazine administration had negative results. The main side effects of hydralazine were an insignificant decrease of blood pressure and a significant increase of heart rates at high dose (10 mg/kg of body weight).
This study is limited because the analgesic effect of hydralazine was tested on only one type of acute inflammatory pain model; however, its effect on chronic inflammatory or neuropathic pain needs to be further investigated.
Based on the above findings, hydralazine may find its new application of analgesia within a safe dose window (around one mg/kg of body weight) without causing severe side effects.
丙烯醛信号在脊髓损伤中很重要；它是否参与躯体和情绪疼痛尚不清楚。肼屈嗪是一种有效的降压药物，能有效地清除丙烯醛。
我们假设肼屈嗪降低脊髓水平的丙烯醛并产生镇痛作用，但具有一些副作用，本研究对此进行了测试。
皮下注射甲醛用于诱导躯体和情绪疼痛反应。在皮下注射甲醛后 2 小时评估脊髓神经元激活（FOS 表达）和丙烯醛表达。在皮下注射甲醛后 1 小时，通过旷场试验、高架十字迷宫试验和转棒试验，或通过遥测测量平均动脉血压和心率，评估肼屈嗪对小鼠中枢神经系统或心血管系统的可能副作用。
左后足底皮下注射甲醛可引起明显的躯体和情绪疼痛反应，通过注射后足底的双相自发退缩/舔舐和甲醛注射后 1 小时内的间歇超声发声来评估。在甲醛注射后 2 小时，脊髓丙烯醛水平显著升高，神经元被激活。在甲醛挑战剂量前 1 小时腹腔注射肼屈嗪（0.1、1 或 10 mg/kg 体重）剂量依赖性地减轻了甲醛引起的疼痛反应，镇痛 50%效应剂量范围为 0.2 至 1 mg/kg 体重。此外，肼屈嗪预处理可剂量依赖性地抑制神经元激活和丙烯醛表达升高。腹腔注射肼屈嗪后 1 小时对运动、焦虑和运动协调的副作用呈阴性结果。肼屈嗪的主要副作用是高剂量（10 mg/kg 体重）时血压轻微下降和心率显著增加。
本研究的局限性在于肼屈嗪的镇痛作用仅在一种急性炎症性疼痛模型中进行了测试；然而，其对慢性炎症性或神经性疼痛的作用需要进一步研究。
根据上述发现，肼屈嗪在安全剂量范围内（约 1 毫克/公斤体重）可能会发现新的镇痛应用，而不会引起严重的副作用。
