Ahangar Nematollah, Esam Zohreh, Bekhradnia Ahmadreza, Ebrahimzadeh Mohammad Ali
Pharmaceutical Sciences Research Center, School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
Iran J Basic Med Sci. 2016 May;19(5):470-5.
The mechanism of hypothermia action of acetaminophen (APAP) remains unclear even 125 years after its synthesis. Acetaminophen produces hypothermia. The mechanism of this reduction in core body temperature is not clear but evidence shows that it is not dependent on opioid and cannabinoid receptors. Because of strong documents about the roles of GABA and benzodiazepine receptors in hypothemic activity of some drugs such as diazepam, we determined if these receptors also contributes to the hypothermic effect of APAP.
Diazepam (5 mg/kg, IP) was used for induction of hypothermia. Flumazenil (10 mg/kg, IP) or picrotoxin (2 mg/kg, IP) used for reversal of this effect. Rats injected with APAP (100, 200 or 300 mg/kg, IP). Baseline temperature measurements were taken with a digital thermometer via rectum. To evaluate the structural correlation between APAP and benzodiazepine receptor ligands, numerous models are selected and studied at HF/6-31G* level of theory. Relative energies, enthalpies and Gibbs free energies were calculated for all selected drugs.
Diazepam induced hypothermia was reversed by flumazenil or picrotoxin. Rats injected with APAP displayed dose- and time-related hypothermia. For combined administration, the hypothermic effect of APAP (200 mg/kg) was strongly reduced by pretreatment with picrotoxin or flumazenil P<0.0001and P<0.01, respectively. Selective structural data, bond length, dihedral angles, and related distance in pharmacophore of APAP and BZDR models were the same. Some significant structural analogues were obtained between these drugs.
Results suggest hypothermic action of acetaminophen may be mediate by its effect at GABAA benzodiazepine receptor.
对乙酰氨基酚（APAP）合成125年后，其低温作用机制仍不清楚。对乙酰氨基酚可产生低温效应。核心体温降低的机制尚不清楚，但有证据表明这并不依赖于阿片类和大麻素受体。鉴于有大量文献表明γ-氨基丁酸（GABA）和苯二氮䓬受体在某些药物（如地西泮）的低温活性中起作用，我们研究了这些受体是否也对APAP的低温效应有影响。
使用地西泮（5mg/kg，腹腔注射）诱导低温。使用氟马西尼（10mg/kg，腹腔注射）或印防己毒素（2mg/kg，腹腔注射）来逆转这种效应。给大鼠注射APAP（100、200或300mg/kg，腹腔注射）。通过直肠用数字温度计测量基线体温。为评估APAP与苯二氮䓬受体配体之间的结构相关性，选择了众多模型并在HF/6-31G*理论水平上进行研究。计算所有选定药物的相对能量、焓和吉布斯自由能。
氟马西尼或印防己毒素可逆转地西泮诱导的低温。注射APAP的大鼠表现出剂量和时间相关的低温。对于联合给药，预先使用印防己毒素或氟马西尼可使APAP（200mg/kg）的低温效应显著降低，分别为P<0.0001和P<0.01。APAP和苯二氮䓬受体模型的药效团中的选择性结构数据、键长、二面角和相关距离相同。在这些药物之间获得了一些显著的结构类似物。
结果表明对乙酰氨基酚的低温作用可能是通过其对GABAA苯二氮䓬受体的作用介导的。
