title: Hypothermic activity of acetaminophen; involvement of GABAA receptor, theoretical and experimental studies.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Results suggest hypothermic action of acetaminophen may be mediate by its effect at GABAA benzodiazepine receptor.
authors.affiliation: Pharmaceutical Sciences Research Center, School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Nematollah
authors.initials: N
authors.lastname: Ahangar
authors.affiliation: Pharmaceutical Sciences Research Center, School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Zohreh
authors.initials: Z
authors.lastname: Esam
authors.affiliation: Pharmaceutical Sciences Research Center, School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Ahmadreza
authors.initials: A
authors.lastname: Bekhradnia
authors.affiliation: Pharmaceutical Sciences Research Center, School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Mohammad Ali
authors.initials: MA
authors.lastname: Ebrahimzadeh
keywords: Abinitio study; Acetaminophen; Benzodiazepine receptor; GABAA; Hypothermia