Hypothermic activity of acetaminophen; Involvement of GABAA receptor, theoretical and experimental studies

Document Type: Original Article

Authors

Pharmaceutical Sciences Research Center, School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran

Abstract

Objective(s):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.
Materials and 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.
Conclusion:Results suggest hypothermic action of acetaminophen may be mediate by its effect at GABAA benzodiazepine receptor.

Keywords


1. Ayoub S, Botting R. Acetaminophen-induced hypothermia in mice is mediated by a prostaglandin endoperoxide synthase 1 gene-derived protein. Proc Natl Acad Sci 2004; 101:11165-11169.

2. Dippel DW, van Breda EJ, van der Worp HB, van Gemert HM, Meijer RJ, Kapelle LJ, et al. Effect of paracetamol (acetaminophen) and ibuprofen on body temperature in acute ischemic stroke PISA, a phase II double blind, randomized, placebo controlled trial. BMC Cardiovasc Disord 2003; 3:2-9.

3. Denes E, Amaniou M, Rogez JP, Weinbreck P, Merle L. Acetaminophen-induced hypothermia, an AIDS related side-effect? About 4 cases. Ann Med Intern 2002; 153:411-413.

4. Li S, Dou W, Tang Y, Goorha S, Ballou LR, Blatteis CM. Acetaminophen: antipyretic or hypothermic in mice? In either case, PGHS-1b (COX-3) is irrelevant. Prostaglandins Other Lipid Mediat 2008; 85:89-99.

 5. Corley G, Rawls S. Opioid, cannabinoid CB1 and NOP receptors do not mediate APAP-induced hypothermia in rats. Pharmacol Biochem Behav 2009; 92:503-507.

6. Hilal-Danden R, Brunton L. Goodman & Gilman’s Manual of Pharmacology and Therapeutics. New York: McGraw-Hill; 2014. p. 599-600.

7. Botting R, Ayoub S. COX-3 and the mechanism of action of paracetamol/acetaminophen. Prostaglandins Leukot Essent Fatty Acids 2005; 72: 85-87.

8. Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, et al. COX-3, a cyclooxygenase-1variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure and expression. Proc Natl Acad Sci 2002; 99:13926-13931.

9. Bailey DJ, Tetzlaff JE, Cook JM, He X, Helmstetter FJ. Effects of hippocampal injections of a novel ligand selective for the alpha 5 beta 2 gamma 2 subunits of the GABA/ benzodiazepine receptor on Pavlovian conditioning. Neurobiol Learn Mem 2002; 78:1-10.

10. Sarnowska A, Beresewicz M, Zabłocka B, Domańska-Janik K.  Diazepam neuroprotection in excitotoxic and oxidative stress involves a mitochondrial mechanism additional to the GABAAR and hypothermic effects. Neurochem Int 2009; 55:164-173.

 11. Vinkers CH, Klanker M, Groenink L, Korte SM, Cook JM, Van Linn ML, Hopkins SC, Olivier B.  Dissociating anxiolytic and sedative effects of GABAAergic drugs using temperature and locomotor responses to acute stress. Psychopharmacology (Berl) 2009; 204:299-311.

12. Schmitt FC, Buchheim K, Meierkord H. Anticonvulsant properties of hypothermia in experimental status epilepticus. Neurobiol Dis 2006; 23:689-696.

13. Inamasu J, Nakatsukasa M, Suzuki M. Therapeutic hypothermia for out-of-hospital cardiac arrest: An update for neurosurgeons. World Neur Surg 2010; 74:120-128.

14. Massey TE, Walker RM, McElligott TF, Racz WJ. Acetaminophen induced hypothermia in mice: Evidence for a central action of the parent compound. Toxicology 1982; 25:187-200.

15. Trudell JR, Bertaccini E. Comparative modeling of a GABAA alpha1 receptor using three crystal structures as templates. J Mol Graphics Model 2004; 23:39-49.

16. Olsen R, Sieghart W. GABAA receptors: Subtypes provide diversity of function and pharmacology. Neuropharmacology 2009; 56:141-148.

 17. Olsen RW.  Allosteric ligands and their binding sites define γ-aminobutyric acid (GABA) type A receptor subtypes. Adv Pharmacol 2015; 73:167-202.

18. Sieghart W.  Allosteric modulation of GABAA receptors via multiple drug-binding sites. Adv Pharmacol 2015; 72:53-96.

19. Chebib M, Johnston GA. GABA-activated ligand gated ion channels: medicinal chemistry and molecular biology. J Med Chem 2000; 43:1427-1447.

20. Jembrek MJ, Vlainic J. GABA receptors: pharmacological potential and pitfalls. Curr Pharm Des 2015; 21:4943-4959.

21. Cirone J, Rosahl TW, Reynolds DS. Gamma-aminobutyric acid type A receptor beta 2 subunit mediates the hypothermic effect of etomidate in mice. Anesthesiology 2004; 100:1438-1445.

22. Gray JA, Roth B. Molecular targets for treating cognitive dysfunction in schizophrenia. Schizophr Bul 2007; 33:1100-1119.

23. Jackson HC, Nutt DJ. Strain differences in sensitivity to the hypothermic effects of benzodiazepine receptor ligands in mice. Psychopharmacology 1992; 109:365-368.

24. Yakushiji T, Shirasaki T, Akaike N. Non-competitive inhibition of GABAA responses by a new class of quinolones and non-steroidal antiinfla-mmatories in dissociated frog sensory neurones. Br J Pharmacol 1992; 105:13-18.

25. Hall E, Andrus P, Fleck T. Neuroprotective properties of the benzodiazepine receptor, partial agonist PNU-101017 in the gerbil forebrain ischemia model. J Cereb Blood Flow Metab 1997; 17:875-883.

26. Madenoglu H, Kaçmaz M, Aksu R. Effects of naloxone and flumazenil on antinociceptive action of acetaminophen in rats. Curr Ther Res 2010; 71:111-117.

27. Breese GR, Knapp DJ, Overstreet DE. Repeated lipopolysaccharide (LPS) or cytokine treatments sensitize ethanol withdrawal induced anxiety like behavior. Neuropsychopharmacology 2008; 33:867-876.

28. Saito O, Aoe T, Yamamoto T. Analgesic effects of nonsteroidal antiinflammatory drugs, acetaminophen and morphine in a mouse model of bone cancer pain. J Anesth 2005; 19:218-224.

29. Jackson H, Nutt D. Body temperature discri-minates between full and partial benzodiazepine receptor agonists. Eur J Pharmacol 1990; 185:243-246.