The involvement of a cyclooxygenase 1 gene-derived protein in the antinociceptive action of paracetamol in mice

Ayoub, Samir S.; Colville‐Nash, Paul; Willoughby, D. A.; Botting, Regina M.

doi:10.1016/j.ejphar.2006.03.061

Cited by 68 publications

(67 citation statements)

References 40 publications

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“…This hypothesis was reached by demonstrating potent reduction of prostaglandin biosynthesis in brain tissues but not in peripheral tissues (Flower and Vane, 1972). Reduction of central nervous system PGE 2 by paracetamol is supported by other studies (Malmberg and Yaksh, 1994;Muth-Selbach et al, 1999;Ayoub et al, 2006).…”

Section: Discussionsupporting

confidence: 58%

“…For measurement of PGE 2 concentrations, whole brains were removed from the skull, immediately washed with 10 g/ml indomethacin, and snap-frozen in liquid nitrogen. Prostaglandins were extracted using a protocol described previously (Ayoub et al, 2004(Ayoub et al, , 2006. In brief, frozen brain tissues were pulverised with a nitrogen bomb.…”

Section: Methodsmentioning

confidence: 99%

“…The compound weakly inhibits activities of cyclooxygenase-1 (COX-1) and COX-2 enzymes (Mitchell et al, 1993). However, it significantly reduces central nervous system prostaglandin synthesis (Feldberg et al, 1972;Flower and Vane, 1972;Ayoub et al, 2006), indicating inhibition of a COX activity. We recently demonstrated that the hypothermic action of paracetamol in normothermic mice is dependent on the inhibition of a COX-1-derived protein.…”

Section: Introductionmentioning

confidence: 99%

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Paracetamol-Induced Hypothermia Is Independent of Cannabinoids and Transient Receptor Potential Vanilloid-1 and Is Not Mediated by AM404

Ayoub

Pryce²,

Seed³

et al. 2011

Drug Metab Dispos

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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.

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Section: Discussionsupporting

confidence: 58%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Paracetamol-Induced Hypothermia Is Independent of Cannabinoids and Transient Receptor Potential Vanilloid-1 and Is Not Mediated by AM404

Ayoub

Pryce²,

Seed³

et al. 2011

Drug Metab Dispos

Self Cite

View full text Add to dashboard Cite

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“…However as antipyretic activity was not affected in COX-1 knockout mice and reason why PCM have propensity towards central COX-1 than peripheral COX1 is not known, it has been suggest that PCM might act through other actions also. 9,21 Other researchers have suggested the role of COX-2 and COX-3 enzyme inhibition as well. However, ADRs of PCM are different than selective COX-2 enzyme inhibitors and pain is neither mediated by COX-3 enzyme nor it is discovered in humans.…”

Section: Discussionmentioning

confidence: 99%

Anti-hyperalgesic effect of paracetamol in rat model of thermal hyperalgesia: implications for the treatment of neuropathic pain

Bankar

Dudhgaonkar

2013

Int J Basic Clin Pharmacol

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Background: Neuropathic pain conditions are prevalent in general population and difficult to treat. Most currently available therapies do not provide adequate benefit in all treated patients. Though Paracetamol is available for more than 100 years and have huge safety data, it is still not included in any treatment guidelines for neuropathic pain, as very few studies have evaluated its effects in neuropathic pain conditions. The aim of this study was to evaluate antihyperalgesic activity of paracetamol and to compare it with antihyperalgesic effect of amitriptyline and gabapentin in rat model of thermal hyperalgesia. Methods: Male albino wistar rats weighing 200-250 g of body weight and 4-6 months old were used. After anaesthetizing rats with 2% halothane, mild thermal injury was induced using hot plate analgesiometer. Drugs were administered intraperitoneally 30 minutes after thermal injury. Paw withdrawal latencies were measured at 30, 60, 90 and 120 minutes after drug administration. Statistical analysis done using GraphPad Prism version 5.01 and one way ANOVA followed by post hoc Dunnett's test or Tukey's test were used. Results: Paracetamol showed both dose as well as time dependent antihyperalgesic activity. Gabapentin demonstrated significantly more antihyperalgesic activity compared to amitriptyline (p< 0.05) and paracetamol (p< 0.01). Conclusions: Paracetamol showed antihyperalgesic activity however, it was less as compared to drugs like gabapentin and amitriptyline. Considering the excellent safety profile of paracetamol, it might be useful adjuvant drug for treatment of neuropathic pain conditions. [Int J Basic Clin Pharmacol 2013; 2(3.000): 290-297

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“…Paracetamol seems to have only a weak inhibitory effect on prostaglandin production in cell culture, with IC 50 values mostly around 100 μM [20]. In animals, paracetamol reduced prostaglandin in cerebrospinal fluid [21], the spinal cord [22] and the brain [23,24]. Interestingly, AM404 was shown to be an inhibitor of COX on isolated COX-1 and COX-2 and in LPSinduced prostaglandin E 2 formation in RAW264.7 macrophages [2].…”

Section: Cox Enzymementioning

confidence: 99%

Paracetamol: Update on its Analgesic Mechanism of Action

Mallet¹,

Eschalier²,

Daulhac³

2017

Pain Relief - From Analgesics to Alternative Therapies

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Paracetamol is the most widely used over-the-counter medication in the world. The mechanism of action of its analgesic effect was often considered as based on the mobilization of the cyclooxygenases and more recently on serotonergic pathways. A new metabolic pathway involving the generation of an active metabolite, AM404 (N-(4-Hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide), in the brain by the fatty acid amide hydrolase (FAAH) enzyme, was recently identified. This chapter describes experimental data that have shown the involvement of this metabolic pathway in the analgesic action of paracetamol and its relationship with the cyclooxygenase and serotonergic systems. It also explains how new targets and systems, such as the cannabinoid and vanilloid systems and the calcium channel receptor Cav3.2, play a role in the action of paracetamol. Finally, it suggests how research on the mechanism of the clinically relevant effects of this long-established analgesic could lead to new therapeutic pain strategies.

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The involvement of a cyclooxygenase 1 gene-derived protein in the antinociceptive action of paracetamol in mice

Cited by 68 publications

References 40 publications

Paracetamol-Induced Hypothermia Is Independent of Cannabinoids and Transient Receptor Potential Vanilloid-1 and Is Not Mediated by AM404

Paracetamol-Induced Hypothermia Is Independent of Cannabinoids and Transient Receptor Potential Vanilloid-1 and Is Not Mediated by AM404

Anti-hyperalgesic effect of paracetamol in rat model of thermal hyperalgesia: implications for the treatment of neuropathic pain

Paracetamol: Update on its Analgesic Mechanism of Action

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