BackgroundAlthough the mechanism of fentanyl-induced cough is unclear, several lines of evidence suggest that allergic mediators, such as histamine, may play a role in the production of fentanyl-induced coughs. The aim of this study was to explore the effects of fentanyl on cough sensitivity to inhaled citric acid and on histamine release in BALF in mice.MethodsThe cough reflex was induced by the inhalation of citric acid. Male ICR mice were exposed to a nebulized solution of citric acid at a concentration of 0.1 M under conscious and identical conditions using a body plethysmograph. The number of coughs produced per 3-min period of exposure to citric acid was counted. Histamine content in BALF was analyzed by HPLC post-column derivatization and fluorescence detection.ResultsIntravenous administration of fentanyl increased the number of citric acid-induced coughs. The fentanyl-induced enhancement of the number of citric acid-induced coughs was abolished in mice that had been pretreated with moguisteine, a rapidly adapting receptor (RAR) antagonist or fexofenadine, a histamine H1 receptor antagonist. Fentanyl significantly increased the concentration of histamine in BALF.ConclusionThe results of this study suggest that fentanyl enhances the excitability of RARs to cause cough, and enhancement of histamine release in the airways may some how be related to this change.

BackgroundPrevious studies have demonstrated that intrathecal administration of the substance P amino-terminal metabolite substance P1-7 (SP1-7) and its C-terminal amidated congener induced antihyperalgesic effects in diabetic mice. In this study, we studied a small synthetic dipeptide related to SP1-7 and endomorphin-2, i.e. Phe-Phe amide, using the tail-flick test and von Frey filament test in diabetic and non-diabetic mice.ResultsIntrathecal treatment with the dipeptide increased the tail-flick latency in both diabetic and non-diabetic mice. This effect of Phe-Phe amide was significantly greater in diabetic mice than non-diabetic mice. The Phe-Phe amide-induced antinociceptive effect in both diabetic and non-diabetic mice was reversed by the σ1 receptor agonist (+)-pentazocine. Moreover, Phe-Phe amide attenuated mechanical allodynia in diabetic mice, which was reversible by (+)-pentazocine. The expression of spinal σ1 receptor mRNA and protein did not differ between diabetic mice and non-diabetic mice. On the other hand, the expression of phosphorylated extracellular signal-regulated protein kinase 1 (ERK1) and ERK2 proteins was enhanced in diabetic mice. (+)-Pentazocine caused phosphorylation of ERK1 and ERK2 proteins in non-diabetic mice, but not in diabetic mice.ConclusionsThese results suggest that the spinal σ1 receptor system might contribute to diabetic mechanical allodynia and thermal hyperalgesia, which could be potently attenuated by Phe-Phe amide.

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