e n v i r o n m e n t a l t o x i c o l o g y a n d p h a r m a c o l o g y 3 7 ( 2 0 1 4 ) 438–447 Available online at www.sciencedirect.com ScienceDirect j o ur nal ho me pa ge: www.elsevier.com/locate/etap Arsenic reduces the antipyretic activity of paracetamol in rats: Modulation of brain COX-2 activity and CB 1 receptor expression Karunakaran Vijayakaran, Kandasamy Kannan, Manickam Kesavan, Subramaniyam Suresh, Palanisamy Sankar, Surendra Kumar Tandan, Souvendra Nath Sarkar ∗ Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar 243122, Bareilly, Uttar Pradesh, India a r t i c l e i n f o Article history: Received 26 September 2013 Received in revised form 17 December 2013 Accepted 19 December 2013 Available online 2 January 2014 Keywords: Arsenic Paracetamol Antipyretic activity Cyclooxygenase CB1 receptor Rat a b s t r a c t We examined whether subacute arsenic exposure can reduce paracetamol-mediated antipyretic activity by affecting COX pathway and cannabinoid CB 1 receptor regulation. Rats were preexposed to elemental arsenic (4 ppm) as sodium arsenite through drinking water for 28 days. Next day pyrexia was induced with lipopolysaccharide and paraceta- mol’s (200 mg/kg, oral) antipyretic activity was assessed. The activities of COX-1 and COX-2, the levels of PGE 2 , TNF- and IL-1 and expression of CB 1 receptors were assessed in brain. Arsenic inhibited paracetamol-mediated antipyretic activity. COX-1 activity was not affected by any treatments. Paracetamol decreased COX-2 activity, levels of PGE 2 , TNF- and IL-1 and caused up-regulation of CB 1 receptors. Arsenic caused opposite effects on these parameters. In the arsenic-preexposed rats, paracetamol-mediated effects were attenuated, while CB 1 receptor up-regulation was reversed to down-regulation. Results suggest that elevated COX- 2 activity and reduced CB 1 expression could be involved in the arsenic-mediated attenuation of the antipyretic activity of paracetamol. © 2013 Elsevier B.V. All rights reserved. 1. Introduction Paracetamol (Acetaminophen) is an extensively used non- steroidal anti-inflammatory drug (NSAID) for treating fever and pain. Paracetamol reduces prostaglandin (PG) synthesis in CNS (Ayoub et al., 2011), indicating inhibition of cyclooxy- genase (COX) activity. Paracetamol displayed 4-fold selectivity for COX-2 inhibition and a standard dose caused almost com- plete COX-2 inhibition in humans, whereas only moderate COX-1 inhibition was observed (Hinz et al., 2008). COX-1 seems to have no role in febrigenesis (Blatteis, 2006; Hopkins, 2007), ∗ Corresponding author. Tel.: +91 581 2300291; fax: +91 581 2303284. E-mail addresses: snsarkar1911@rediffmail.com, snsarkar1911@gmail.com (S.N. Sarkar). while the proposed mechanism of hypothermia through COX- 3 inhibition was rejected (Hinz et al., 2008; Kis et al., 2005; Li et al., 2008). Thus, its antipyretic effect is attributed to COX- 2 inhibition in brain, particularly hypothalamus (Graham and Scott, 2005; Li et al., 2008). Recently, Engström Ruud et al. (2013) demonstrated that paracetamol reduced lipopolysaccharide (LPS)-induced fever by inhibiting COX-2 and not by inhibiting microsomal prostaglandin-E synthase-1 (mPGES-1). Paracetamol’s pharmacodynamics could also be medi- ated through interactions with the endocannabinoid system (Hogestatt et al., 2005). p-Aminophenol, the deacetylated metabolite of paracetamol, conjugates with arachidonic 1382-6689/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.etap.2013.12.015