sformation of 4aminophenol and HMBA to TRPV1 active lipid metabolites in the brain, including drug absorption from the site of injection, distribution of the drug to the brain and FAAH-dependent fatty acid conjugation to yield the various bioactive metabolites. Our pharmacokinetic findings show that relatively small changes in the chemical structure may have profound effects on the propensity of the molecule to undergo fatty acid conjugation. Indeed, mice receiving equieffective doses of 4-aminophenol and HMBA in the mouse formalin test produced similar brain contents of 4-aminophenol and HMBA. However, the corresponding brain contents of AM404 and arvanil were 411 pmol/l and 3.33 pmol/l, respectively, indicating that the FAAH-mediated conjugation with arachidonic acid was approximately 100 times more efficient for 4-aminophenol than HMBA, two structurally similar primary amines. The hepatotoxicity of 4-aminophenol is very low in rodents and may involve its N-acetylation to paracetamol. However, 4aminophenol has been shown to produce renal tubular necrosis after a single exposure at doses not far from those eliciting antinociception in rodents. This 20832753 selective nephrotoxic effect seems to depend on the extrarenal formation of toxic glutathione conjugates of 4-aminophenol, including 4-amino-3cysteinylphenol, which then accumulates in proximal tubular epithelial cells, although a direct cytotoxic effect of 4-aminophenol on tubular epithelial cells cannot be excluded. The glutathione transferase capacity differs greatly between species and it is particularly high in rats and mice, making predictions of tolerable doses in man very difficult. In contrast to 4aminophenol and paracetamol, HMBA should not generate reactive benzoquinone imines and therefore may display low nephro- and hepatotoxicity. Further animal studies addressing the toxicology and the antinociceptive activity in models of inflammatory pain are warranted before considering 4-aminophenol and HMBA as potential analgesics for parenteral use in man. This study suggests that FAAH-dependent generation of antinociceptive TRPV1 active drug metabolites in the brain represent a novel pharmacological principle for treatment of pain and strengthens that 4-aminophenol is the key FAAH substrate in the bioactivation of paracetamol. 8 Analgesic TRPV1 Active Drug Metabolites in Brain 212141-51-0 Materials and Methods Ethics Statement The animal procedures were approved by the animal ethics committees in Auvergne, France and Lund, Sweden. The behavioural tests were conducted in accordance with the official edict presented by the French 9 Analgesic TRPV1 Active Drug Metabolites in Brain 4-aminophenol. p,0.05, p,0.01 and p,0.001 when compared to vehicle injection, using repeated measures two-way ANOVA followed by Sidak’s multiple comparisons test or Mann-Whitney U test. doi:10.1371/journal.pone.0070690.g011 Assessment of TRPV1 Activity TRPV1 activation was assessed indirectly on rat isolated mesenteric arteries, using nerve-mediated vasorelaxation as readout. Briefly, arterial segments were suspended between two stainless steel wires in temperature-controlled tissue baths, containing aerated physiological salt solution, under a passive load of 2 mN. One of the wires was 12176911 connected to a force-displacement transducer model FT03 C for isometric tension recording. Vasorelaxation was studied in arterial segments submaximally contracted with phenylephrine. Increasing concentrations of AM404, arvanil, olvanil and HP

The MDA levels rose with increasing concentrations of HBs

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