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It has been well established that neurogenic inflammation is one of the major pathological processes underlying inflammatory pain, but there are few effective anti-inflammatory drugs to alleviate such pain. The present study shows that minocycline, a widely used glial activation inhibitor, is effective in reducing neurogenic inflammation. Patch-clamp recordings showed that small sized dorsal root ganglion ( DRG) neurons were dramatically excited following intradermal capsaicin injection in the rat hind paw, evidenced by decreased rheobase and membrane threshold. Pretreatment with minocycline (30 mg/kg for 1 day, intraperitoneal injection) blocked the increased neuronal excitability. Western blot and immunostaining of DRG revealed the activation of satellite glial cells ( SGCs) following capsaicin injection. The up-regulation of glial fibrillary acidic protein ( GFAP) was significantly inhibited by minocycline pre-administration. Measurement of tumor necrosis factor α ( TNF- α) and its receptor, TNF- α receptor 1 ( TNFR1), showed that minocycline mainly blocked the up-regulation of TNF- α in SGCs and TNFR1s in neurons following capsaicin injection. The pivotal role of TNF- α in neurogenic inflammation was further supported by the findings that incubation DRG with TNF- α mimicked the increased excitability of DRG neurons induced by capsaicin injection, and that TNF- α application enhanced cutaneous vasodilation in the hind paws induced by antidromic electrical stimulation of dorsal roots. Based on these results, we propose that minocycline is a potential therapeutic drug that can reduce neuronal excitability and neurogenic inflammation by working on SGCs to inhibit the expression of TNF- α. [ABSTRACT FROM AUTHOR]

Abstract: Ketamine, a widely used pediatric anesthetic, has been associated with enhanced neuronal toxicity in the developing brain, but mechanisms and neuronal susceptibility to neurotoxic insult leading to neuronal cell death remain poorly defined. One of the main goals of this study was to determine whether there is a duration of ketamine-induced anesthesia below which no significant ketamine-induced neurodegeneration can be detected. Newborn rhesus monkeys (postnatal day 5 or 6) were administered ketamine intravenously for 3, 9 or 24h to maintain a steady anesthetic plane, followed by a 6-h withdrawal period. The 9- and 24-h durations were selected as relatively long and extremely long exposures, respectively, while the 3-h treatment more closely approximates a typical duration of pediatric general anesthesia. Animals were subsequently perfused under anesthesia and brain tissue was processed for analyses using silver and Fluoro-Jade C stains and caspase-3 immunostain. The results indicated that no significant neurotoxic effects occurred if the anesthesia duration was 3h. However, ketamine infusions for either 9 or 24h significantly increased neuronal cell death in layers II and III of the frontal cortex. Although a few caspase-3- and Fluoro-Jade C-positive neuronal profiles were observed in some additional brain areas including the hippocampus, thalamus, striatum and amygdala, no significant differences were detected between ketamine-treated and control monkeys in these areas after 3, 9 or 24h of exposure. These data show that treatment with ketamine up to 3h is without adverse effects as determined by nerve cell death. However, anesthetic durations of 9h or greater are associated with significant brain cell death in the frontal cortex. Thus, the threshold duration below which no neurotoxicity would be expected is somewhere between 3 and 9h. [Copyright &y& Elsevier]