摘要
作为经典的苯并二氮类(Benzodiazepines)药物之一,地西泮(Diazepam)有着很广泛的药理学作用,临床上常用作治疗焦虑症,癫痫,睡眠障碍和肌肉僵直等。苯并二氮类药物的大多数作用是通过其与γ-氨基丁酸(GABA)_A受体上的苯并二氮结合位点所介导的,常见的有抗焦虑,抗惊厥,肌松和致健忘的作用。近年来,大量证据已经表明GABA在痛觉的传递过程中起着很重要的作用,然而地西泮对痛觉的影响一直未确定。所以通过两种不同的疼痛模型,我们研究了地西泮对痛觉的作用并且探讨了其痛觉作用的机制。
采用小鼠热甩尾试验和福尔马林实验,我们研究了地西泮对小鼠的镇痛作用。在热甩尾实验中,腹腔注射地西泮(1 mg/kg)显著地引起了小鼠甩尾潜伏期的延长,且这种延长作用能被提前腹腔注射氟马西尼(一种GABA_A受体上的苯并二氮结合位点的特异性拮抗剂),荷包牡丹碱(一种GABA_A受体的竞争性拮抗剂)和印方己毒素(一种氯离子通道阻断剂)所阻断。在小鼠福尔马林实验中,腹腔注射低剂量的地西泮(0.25和0.5 mg/kg)明显地减少了第二相总的舔/咬足时间,但第一相的时间并没有显著性变化。另外与小鼠热甩尾实验得到的结果一样,腹腔注射荷包牡丹碱和印方己毒素均能不同程度地逆转地西泮的镇痛作用。因此根据我们的实验结果,我们认为一定剂量的地西泮能够产生抗疼痛作用,属于一种弱效的镇痛药物;而且实验结果也证明了地西泮的抗疼痛作用是通过体内的γ-氨基丁酸A(GABA_A)受体所介导的。
As one of benzodiazepine drugs, diazepam has a wide spectrum of pharmacological effects in clinic and usually used as treatment of anxiety, epilepsies sleep disorders and muscle rigor and so on. Most of benzodiazepines effects are mediated by interaction with benzodiazepine binding site of GABA_A receptors. Recently, several lines of evidence had indicated that neurotransmission involving the GABAergic system plays an important role in the modulation of pain pathways. Besides the effect of diazepam on pain was unclear, we investigated its effects and approached the mechanisms on pain with two different nocicepiton tests.
The antinociceptive effects of diazepam were investigated using tail-immersion test and the formalin test in mice. Intraperitoneal (i.p.) injection of diazepam (1 mg/kg) significantly increased the tail-withdrawal latency in the tail-immersion test. The diazepam induced prolongation of tail-withdrawal latency could be reversed by systemic administrations of flumazenil(a special antagonist of benzodiazepine binding site associated with GABA_A receptors), bicuculline(a competitive antagonist of GABA_A receptor), and picrotoxin (a blocker of chlorine ion channel), respectively. In the formalin test, low doses of diazepam (0.5 mg/kg and 0.25 mg/kg, i.p.) markedly decreased the cumulative licking/biting time of the second phase (10-45 min), whereas the first phase (0-10 min) was not affected. In addition, the reduction of the cumulative licking/biting time of the second phase was abolished by pretreatment with bicuculline or picrotoxin. Therefore, these data indicated that intraperitoneal administration of diazepam could produce antinociceptive effects, and endogenous GABA and GABA_A receptors may be involved in the antinociception of diazepam.
引文
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