| Summary: | <p>Abstract</p> <p>Background</p> <p>Previous studies have demonstrated that intrathecal administration of the substance P amino-terminal metabolite substance P<sub>1-7 </sub>(SP<sub>1-7</sub>) and its C-terminal amidated congener induced antihyperalgesic effects in diabetic mice. In this study, we studied a small synthetic dipeptide related to SP<sub>1-7 </sub>and endomorphin-2, i.e. Phe-Phe amide, using the tail-flick test and von Frey filament test in diabetic and non-diabetic mice.</p> <p>Results</p> <p>Intrathecal 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 σ<sub>1 </sub>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.</p> <p>Conclusions</p> <p>These results suggest that the spinal σ<sub>1 </sub>receptor system might contribute to diabetic mechanical allodynia and thermal hyperalgesia, which could be potently attenuated by Phe-Phe amide.</p>
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