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Acetaminophen is a widely used antipyretic analgesic, reducing fever caused by bacterial and viral infections and by clinical trauma such as cancer or stroke. In rare cases in humans, e.g., in febrile children or HIV or stroke patients, acetaminophen causes hypothermia while therapeutic blood levels of the drug are maintained. In C57͞BL6 mice, acetaminophen caused hypothermia that was dose related and maximum (>2°C below normal) with a dose of 300 mg͞kg. The reduction and recovery of body temperature was paralleled by a fall of >90% and a subsequent rise of prostaglandin (PG)E 2 concentrations in the brain. In cyclooxygenase (COX)-2 ؊/؊ mice, acetaminophen (300 mg͞kg) produced hypothermia accompanied by a reduction in brain PGE 2 levels, whereas in COX-1 ؊/؊ mice, the hypothermia to this dose of acetaminophen was attenuated. The brains of COX-1 ؊/؊ mice had Ϸ70% lower levels of PGE2 than those of WT animals, and these levels were not reduced further by acetaminophen. The putative selective COX-3 inhibitors antipyrine and aminopyrine also reduced basal body temperature and brain PGE 2 levels in normal mice. We propose that acetaminophen is a selective inhibitor of a COX-1 variant and this enzyme is involved in the continual synthesis of PGE 2 that maintains a normal body temperature. Thus, acetaminophen reduces basal body temperature below normal in mice most likely by inhibiting COX-3.

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Inhibition of cyclooxygenase (COX)-derived prostaglandins (PGs) by nonsteroidal anti-inflammatory drugs (NSAIDs)mediates leukocyte killing of bacteria. However, the relative contribution of COX1 versus COX2 to this process, as well as the mechanisms controlling it in mouse and humans, are unknown. Indeed, the potential of NSAIDs to facilitate leukocyte killing of drug-resistant bacteria warrants investigation. Therefore, we carried out a series of experiments in mice and humans, finding that COX1 is the predominant isoform active in PG synthesis during infection and that its prophylactic or therapeutic inhibition primes leukocytes to kill bacteria by increasing phagocytic uptake and reactive oxygen intermediate-mediated killing in a cyclic adenosine monophosphate (cAMP)-dependent manner. Moreover, NSAIDs enhance bacterial killing in humans, exerting an additive effect when used in combination with antibiotics. Finally, NSAIDs, through the inhibition of COX prime the innate immune system to mediate bacterial clearance of penicillinresistant Streptococcus pneumoniae serotype 19A, a well-recognized vaccine escape serotype of particular concern given its increasing prevalence and multi-antibiotic resistance. Therefore, these data underline the importance of lipid mediators in host responses to infection and the potential of inhibitors of PG signaling pathways as adjunctive therapies, particularly in the context of antibiotic resistance. IntroductionAntibiotic resistance arising from the selective pressure generated by excessive/inappropriate antibiotic use in human and veterinary practices poses major challenges to the management of infection, particularly with the scarcity of new antibacterial drugs. 1 For this reason, there is considerable interest in developing strategies to counteract multidrug microbial resistance either as an independent pharmaceutical entity or as an adjunct to existing treatment regimes. Cyclooxygenase (COX) metabolizes phospholipase A 2 -liberated arachidonic acid to PGH 2 , which serves as a substrate for downstream synthases to generate prostaglandins (PGs) and thromboxane A 2 . 2 Two isoforms of COX exist, with constitutively expressed COX1 suggested to make PGs to aid physiologic processes while COX2 is inducible at sites of inflammation believed to generate pathophysiologic PGs. 3 During inflammation in response to infection, PGs of the E/D series elevate cyclic adenosine monophosphate (cAMP) by activating EP2/EP4 or DP1 receptors, 4 respectively. Elevating cAMP inhibits 2 pivotal steps in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated bacterial killing, namely the phosphorylation as well as the translocation of the cytosolic p47phox subunit to cell membrane. [5][6][7][8] Moreover, by signaling through EP2, PGE 2 inhibits Fc␥R-mediated phagocytosis. 9 Therefore, as nonsteroidal antiinflammatory drugs (NSAIDs) inhibit PG synthesis, 10 it is not surprising that targeting COX pathways of arachidonic acid metabolism is attracting current attention as a means of facil...

Background and purpose: Annexin-A1 (ANXA1), a glucocorticoid-regulated protein, mediates several of the antiinflammatory actions of the glucocorticoids. Previous studies demonstrated that ANXA1 is involved in pain modulation. The current study, using ANXA1 knockout mice (ANXA1 À/À ), is aimed at addressing the site and mechanism of the modulatory action of ANXA1 as well as possible involvement of ANXA1 in mediating the analgesic action of glucocorticoids. Experimental approach: The acetic acid-induced writhing response was performed in ANXA1À/À and wild-type (ANXA1 þ / þ ) mice with spinal and brain levels of prostaglandin E 2 (PGE 2 ) examined in both genotypes. The effect of the ANXA1 peptomimetic Ac2-26 as well as methylprednisolone on the writhing response and on spinal cord PGE 2 of ANXA1 þ / þ and ANXA1 À/À was compared. The expression of proteins involved in PGE 2 synthesis, cytosolic phospholipase A 2 (cPLA 2 ) and cyclooxygenases (COXs), in the spinal cord of ANXA1 þ / þ and ANXA1 À/À was also compared. Key results: ANXA1 À/À mice exhibited a significantly greater writhing response and increased spinal cord levels of PGE 2 compared with ANXA1 þ / þ mice. Ac2-26 produced analgesia and reduced spinal PGE 2 levels in ANXA1 þ / þ and ANXA1 À/À mice, whereas methylprednisolone reduced the writhing response and spinal PGE 2 levels in ANXA1mice. The expression of cPLA 2 , COX-1, COX-2 and COX-3 in spinal cord tissues was upregulated in ANXA1 À/À compared with ANXA1 þ / þ . Conclusions and implications: We conclude that ANXA1 protein modulates nociceptive processing at the spinal level, by reducing synthesis of PGE 2 by modulating cPLA 2 and/or COX activity. The analgesic activity of methylprednisolone is mediated by spinal ANXA1.

ABSTRACT:In recent years, there has been increasing interest in hypothermia induced by paracetamol for therapeutic purposes, which, in some instances, has been reported as a side effect. Understanding the mechanism by which paracetamol induces hypothermia is therefore an important question. In this study, we investigated whether the novel metabolite of paracetamol, N-(4-hydroxyphenyl)arachidonylamide (AM404), which activates the cannabinoid (CB) and transient receptor potential vanilloid-1 (TRPV1) systems, mediates the paracetamolinduced hypothermia. The hypothermic response to 300 mg/kg paracetamol in CB 1 receptor (CB 1 R) and TRPV1 knockout mice was compared to wild-type mice. Hypothermia induced by paracetamol was also investigated in animals pretreated with the CB 1 R or TRPV1 antagonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperdinyl-1H-pyrazole-3-carboxamide trifluoroacetate salt (AM251) or 4-chloro-3-methoxycinnamanilide (SB366791), respectively. In CB 1 R or TRPV1 knockout mice, paracetamol induced hypothermia to the same extent as in wild-type mice. In addition, in C57BL/6 mice pretreated with AM251 or SB366791, paracetamol induced hypothermia to the same extent as in control mice. AM404 failed to induce hypothermia at pharmacological doses. Inhibition of fatty acid amide hydrolase (FAAH), which is involved in the metabolism of paracetamol to AM404, did not prevent the development of hypothermia with paracetamol. Paracetamol also induced hypothermia in FAAH knockout mice to the same extent as wild-type mice. We conclude that paracetamol induces hypothermia independent of cannabinoids and TRPV1 and that AM404 does not mediate this response. In addition, potential therapeutic value of combinational drug-induced hypothermia is supported by experimental evidence.

Paracetamol (acetaminophen), is a centrally-acting antipyretic analgesic drug, which can also lower body temperature. Despite a century of clinical use, its mechanism of pharmacological action has not been completely elucidated. Previously, we demonstrated significant attenuation in the paracetamol induced hypothermia in parallel with its inhibitory action on the synthesis of brain prostaglandin E2 (PGE2) in cyclooxygenase-1 (COX-1) knockout mice in comparison to wild-type mice. The above reported pharmacological actions by paracetamol were completely retained in COX-2 knockout mice. We thus concluded that the mechanism of hypothermic action of paracetamol is dependent on inhibition of a COX-1 gene-derived enzyme. In the current investigation, we provide further support for this notion by demonstrating that the paracetamol-induced hypothermia is not mediated through inhibition of COX-1 as neither the COX-1 selective inhibitor, SC560, nor the COX-1/COX-2 dual inhibitor, indomethacin, induced hypothermia at pharmacologically active doses in mice. In addition, using a COX-2-dependent and PGE2-mediated model of endotoxin-induced fever, paracetamol induced anti-pyretic and hypothermic actions in COX-1 wild-type mice. These effects were fully or partially attenuated in COX-1 knockout mice after prophylactic or therapeutic administration, respectively. Therapeutically-administered paracetamol also reduced hypothalamic PGE2 biosynthesis in febrile COX-1 wild-type mice, but not in febrile COX-1 knockout mice. In conclusion, we provide further evidence which suggests that the hypothermic and now anti-pyretic actions of paracetamol are mediated through inhibition of a COX-1 variant enzyme.