Acetaminophen reduces lipopolysaccharide-induced fever by inhibiting cyclooxygenase-2

Ruud, Linda Engström; Wilhelms, Daniel Bjӧrk; Eskilsson, Anna; Vasilache, Ana Maria; Elander, Louise; Engblom, David; Blomqvist, Anders

doi:10.1016/j.neuropharm.2013.03.012

Cited by 56 publications

(30 citation statements)

References 37 publications

(39 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…APAP has been shown to induce hypothermia independently of cannabinoids and TRPV1, and AM404 does not mediate this response 12. COXs have an effect at high concentration, acting on the COX-2 dependent-induced PGE2 production that occurs in brain endothelial cells upon inflammatory challenge 46,47. However, COX-2, although constitutive, is induced upon inflammation and this is not the case in our group of healthy volunteers who had a C-reactive protein within normal range.…”

Section: Discussionmentioning

confidence: 99%

Paracetamol sharpens reflection and spatial memory: a double-blind randomized controlled study in healthy volunteers

Pickering¹,

Macian²,

Dubray³

et al. 2016

DDDT

View full text Add to dashboard Cite

BackgroundAcetaminophen (APAP, paracetamol) mechanism for analgesic and antipyretic outcomes has been largely addressed, but APAP action on cognitive function has not been studied in humans. Animal studies have suggested an improved cognitive performance but the link with analgesic and antipyretic modes of action is incomplete. This study aims at exploring cognitive tests in healthy volunteers in the context of antinociception and temperature regulation. A double-blind randomized controlled study (NCT01390467) was carried out from May 30, 2011 to July 12, 2011.MethodsForty healthy volunteers were included and analyzed. Nociceptive thresholds, core temperature (body temperature), and a battery of cognitive tests were recorded before and after oral APAP (2 g) or placebo: Information sampling task for predecisional processing, Stockings of Cambridge for spatial memory, reaction time, delayed matching of sample, and pattern recognition memory tests. Analysis of variance for repeated measures adapted to crossover design was performed and a two-tailed type I error was fixed at 5%.ResultsAPAP improved information sampling task (diminution of the number of errors, latency to open boxes, and increased number of opened boxes; all P<0.05). Spatial planning and working memory initial thinking time were decreased (P=0.04). All other tests were not modified by APAP. APAP had an antinociceptive effect (P<0.01) and body temperature did not change.ConclusionThis study shows for the first time that APAP sharpens decision making and planning strategy in healthy volunteers and that cognitive performance and antinociception are independent of APAP effect on thermogenesis. We suggest that cognitive performance mirrors the analgesic rather than thermic cascade of events, with possibly a central role for serotonergic and cannabinoid systems that need to be explored further in the context of pain and cognition.

show abstract

Section: Discussionmentioning

confidence: 99%

Paracetamol sharpens reflection and spatial memory: a double-blind randomized controlled study in healthy volunteers

Pickering¹,

Macian²,

Dubray³

et al. 2016

DDDT

View full text Add to dashboard Cite

show abstract

“…If so, even very low levels of PGE 2 in the right tissues at the right time points are sufficient to ameliorate some of the defects resulting from total lack of COX-2 enzyme activity, such as fetal survival and kidney pathology [7]. The hypothesis that very low levels of PGE 2 synthesis capacity is enough for normal fetal survival whereas high levels are needed for the generation of fever is further supported by the fact that mice heterozygous for COX-2 display a markedly attenuated febrile response [14], but are born at the expected ratio.…”

Section: Discussionmentioning

confidence: 99%

“…Although COX-1 is involved in the early phase of some responses to inflammation and in neuroinflammation [8–11], it is dispensable for systemic inflammatory symptoms such as fever, anorexia and hyperalgesia, which are instead dependent on COX-2 [12]. In fever, which is a highly conserved trait of acute inflammation, prostaglandin E2 is the critical prostanoid [13–18] and inhibition of prostaglandin synthesis is the main mechanism of action for common antipyretic drugs such as aspirin and paracetamol [14, 19, 20]. In acute inflammation, most of the PGE 2 production is catalyzed by COX-2 [21] and mPGES-1 [22].…”

Section: Introductionmentioning

confidence: 99%

Cyclooxygenase Isoform Exchange Blocks Brain-Mediated Inflammatory Symptoms

et al. 2016

Self Cite

View full text Add to dashboard Cite

Cyclooxygenase-2 (COX-2) is the main source of inducible prostaglandin E2 production and mediates inflammatory symptoms including fever, loss of appetite and hyperalgesia. COX-1 is dispensable for fever, anorexia and hyperalgesia but is important for several other functions both under basal conditions and during inflammation. The differential functionality of the COX isoforms could be due to differences in the regulatory regions of the genes, leading to different expression patterns, or to differences in the coding sequence, resulting in distinct functional properties of the proteins. To study the molecular underpinnings of the functional differences between the two isoforms in the context of inflammatory symptoms, we used mice in which the coding sequence of COX-2 was replaced by the corresponding sequence of COX-1. In these mice, COX-1 mRNA was induced by inflammation but COX-1 protein expression did not fully mimic inflammation-induced COX-2 expression. Just like mice globally lacking COX-2, these mice showed a complete lack of fever and inflammation-induced anorexia as well as an impaired response to inflammatory pain. However, as previously reported, they displayed close to normal survival rates, which contrasts to the high fetal mortality in COX-2 knockout mice. This shows that the COX activity generated from the hybrid gene was strong enough to allow survival but not strong enough to mediate the inflammatory symptoms studied, making the line an interesting alternative to COX-2 knockouts for the study of inflammation. Our results also show that the functional differences between COX-1 and COX-2 in the context of inflammatory symptoms are not only dependent on the features of the promoter regions. Instead they indicate that there are fundamental differences between the isoforms at translational or posttranslational levels.

show abstract

“…Despite being one of the most widely used non-prescription analgesics, the mechanism of action of acetaminophen is not fully understood. Acetaminophen has been reported to open the transient receptor potential A1 ion channel on sensory neurons in the dorsal horn (Andersson et al 2011), and also to inhibit cyclooxygenase (COX) 2 or 3 (Chandrasekharan et al 2002; Ruud et al 2013). Therefore, acetaminophen appears to be centrally-active analgesic rather than an anti-inflammatory agent, despite its wide use in the treatment of inflammatory pain in humans.…”

Section: Discussionmentioning

confidence: 99%

Interactions between imidazoline I2 receptor ligands and acetaminophen in adult male rats: antinociception and schedule-controlled responding

Siemian

Zhang

et al. 2015

Psychopharmacology

View full text Add to dashboard Cite

Rationale Recent evidence suggests that imidazoline I2 receptor ligands are suitable for combination therapy with opioids. Quantitative analysis of I2 receptor ligands combined with non-opioid drugs is necessary for justification of alternative pain therapies. Objective This study systematically examined the anti-hyperalgesic and response rate-suppressing effects of selective I2 receptor ligands (2-BFI and phenyzoline) alone and in combination with acetaminophen. Methods Von Frey and Hargreaves tests were used to examine the anti-hyperalgesic effects of drugs in complete Freund’s adjuvant (CFA)-induced inflammatory pain in rats. Food-reinforced schedule-controlled responding was used to assess the rate-suppressing effects of study drugs. Dose-addition and isobolographic analyses were used to assess drug-drug interactions for all assays. Results 2-BFI (3.2–17.8 mg/kg, i.p.), phenyzoline (17.8–100 mg/kg, i.p.), and acetaminophen (56–178 mg/kg, i.p.) all dose-dependently produced significant antinociceptive effects. When studied as combinations, 2-BFI and acetaminophen produced infra-additive to additive interactions while phenyzoline and acetaminophen produced additive to supra-additive interactions. The same drug combinations suppressed response rate in a supra-additive manner. Conclusions Quantitative analysis of the anti-hyperalgesic and response rate-suppressing effects suggests that I2 receptor ligands are not well suited to combination therapy with acetaminophen.

show abstract

Acetaminophen reduces lipopolysaccharide-induced fever by inhibiting cyclooxygenase-2

Cited by 56 publications

References 37 publications

Paracetamol sharpens reflection and spatial memory: a double-blind randomized controlled study in healthy volunteers

Paracetamol sharpens reflection and spatial memory: a double-blind randomized controlled study in healthy volunteers

Cyclooxygenase Isoform Exchange Blocks Brain-Mediated Inflammatory Symptoms

Interactions between imidazoline I2 receptor ligands and acetaminophen in adult male rats: antinociception and schedule-controlled responding

Contact Info

Product

Resources

About