Fundamental & clinical pharmacology
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Fundam Clin Pharmacol · Jun 2013
Randomized Controlled TrialParacetamol and opioid pathways: a pilot randomized clinical trial.
Previous studies suggest that the antinociceptive action of paracetamol (acetaminophen, APAP) might involve descending inhibitory pain pathways and the opioidergic system: this study explores this issue in humans with naloxone, the opioid antagonist. After ethical approval, 12 healthy male volunteers were included in this randomized, controlled, double-blind, crossover, four-arm study. They were administered intravenous paracetamol (APAP 1 g) or saline (placebo, pl) followed at 100 min with IV naloxone (Nal 8 mg) or saline, every week for 4 weeks. ⋯ AUC (0-150) of APAP/pl is significantly different from pl/pl (-3452%.min (95%CI -4705 to -2199) vs. -933% min (95%CI -2273 to 407; P = 0.015) but not from APAP/Nal (-1731% min (95%CI -3676 to 214; P = 0.08) and other treatments. AUC (90-150) is not significantly different. This pilot study shows for the first time in human volunteers that naloxone does not inhibit paracetamol antinociception, suggesting no significant implication of the opioid system in paracetamol mechanism of action: this needs be confirmed on a larger number of subjects.
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Fundam Clin Pharmacol · Jun 2013
The mechanisms of antihyperalgesic effect of topiramate in a rat model of inflammatory hyperalgesia.
Recent studies have shown that topiramate, a structurally novel anticonvulsant, exerts antinociceptive activity in animal models of neuropathic, acute somatic, and visceral pain. This study was aimed to examine: (i) the effects of systemically and locally peripherally administered topiramate in the rat inflammatory pain model and (ii) the potential role and site(s) of gamma-aminobutyric acid (GABA), opioid, and adrenergic receptors in topiramate's antihyperalgesia. Rats received intraplantar (i.pl.) injections of the pro-inflammatory compound carrageenan. ⋯ Local peripheral topiramate (0.03-0.34 mg/paw; i.pl.) also produced significant dose-dependent antihyperalgesia, which was significantly depressed by local peripheral yohimbine (0.05-0.2 mg/paw; i.pl.) but not by local peripheral bicuculline (0.15 mg/paw; i.pl.) or naloxone (0.1 mg/paw; i.pl.). The results suggest that topiramate produces systemic and local peripheral antihyperalgesia in an inflammatory pain model, which is, at least partially, mediated by central GABAA and opioid receptors and by peripheral and most probably central α2-adrenergic receptors. These findings contribute to better understanding of topiramate's action in pain states involving inflammation.