Methods and findings in experimental and clinical pharmacology
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Methods Find Exp Clin Pharmacol · Jan 2010
Comparative StudySimilar and different effects of capsaicin and resiniferatoxin on substance P release and transient receptor potential vanilloid type 1 expression of cultured rat dorsal root ganglion neurons.
The purpose of this study was to investigate the effects of capsaicin (CAP) and resiniferatoxin (RTX) on substance P (SP) release and transient receptor potential vanilloid type 1 (TRPV1) expression of cultured rat dorsal root ganglion (DRG) neurons. Dissociated DRG cells of embryonic 15-day-old Wistar rat were cultured for 3 days and then exposed to CAP (1 micromol/L, 10 micromol/L) or RTX (10 nmol/L, 100 nmol/L) for 10 min. At 3 days of culture growth, SP release increased significantly after 10 min of stimulation with CAP or RTX as compared with controls. ⋯ Preprotachykinin (PPT) mRNA, TRPV1 mRNA and TRPV1 protein expression decreased in CAP-treated cultures and RTX cultures treated with the higher concentration, whereas RTX cultures treated with the lower concentration were not affected. The results indicate that CAP and high concentrations of RTX are more neurotoxic to cultured rat DRG neurons while the inability of the neurons to express SP or TRPV1 after acute exposure to the lower concentration of RTX could be partially reversed after a period of incubation. The efficacy and therapeutic potential of the reversible action of RTX are more applicable as strategies for pain or neurogenic inflammation therapy.
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Methods Find Exp Clin Pharmacol · Jan 2010
Clinical TrialIn vitro and in vivo characterization of tapentadol metabolites.
Tapentadol is a novel, centrally acting analgesic combining micro-opioid receptor (MOR) agonism and noradrenaline (NA) reuptake inhibition in a single molecule. Many classic opioids form active metabolites that contribute to analgesia and/or side effects, and the involved cytochrome P450 enzyme complex can give rise to pharmacokinetic drug-drug interactions and variability in drug efficacy due to enzyme polymorphisms. Here we report on the relevance of tapentadol metabolites. ⋯ The absence or presence of analgesia correlated with moderate activity (0.5 microM < K(i) < 1.1 microM) at the NA transporter or MOR. However, the systemic exposure for these metabolites found in humans after therapeutic oral doses of tapentadol was far below their respective K(i) values at these binding sites (by a factor of > 45). Thus, it is highly unlikely that tapentadol forms metabolites that contribute in any relevant degree to its analgesic activity.