The Dipeptide Phe-Phe Amide Attenuates Signs of Hyperalgesia, Allodynia and Nociception in Diabetic Mice Using a Mechanism Involving the Sigma Receptor System

• Published in: Molecular pain Vol. 7; no. 1; p. 85
• Main Authors: Ohsawa, Masahiro, Carlsson, Anna, Asato, Megumi, Koizumi, Takayuki, Nakanishi, Yuki, Fransson, Rebecca, Sandström, Anja, Hallberg, Mathias, Nyberg, Fred, Kamei, Junzo
• Format: Journal Article
• Language: English
• Published: Los Angeles, CA SAGE Publications 31.10.2011; BioMed Central Ltd; Sage Publications Ltd; BioMed Central; SAGE Publishing
• Subjects: Allodynia; Amides; Animals; Antinociception; Blotting, Western; Complications and side effects; Congeners; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - metabolism; Diabetic neuropathy; Diagnosis; Dipeptides - therapeutic use; Endomorphin-2; Extracellular signal-regulated kinase; Health aspects; Hyperalgesia; Hyperalgesia - drug therapy; Kinases; Latency; Ligands; Male; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - genetics; Mice; Mice, Inbred ICR; mRNA; Nociception - drug effects; Opioid receptors; Pain; Pain perception; Pentazocine; Pentazocine - pharmacology; Peptides; Phe-Phe amide; Phosphorylation; Phosphorylation - drug effects; Protein kinase; Proteins; Receptors, sigma - agonists; Receptors, sigma - genetics; Receptors, sigma - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; Rodents; Sp1 protein; Statistical analysis; Studies; Substance P; Substance P1-7; σ1 receptor; Sweden; Japan; Allodynia; Phe-Phe amide; σ?σ?1 receptor; Substance P1-7; Opioid receptors; Antinociception; Diabetes; Hyperalgesia; σ1 receptor
• ISSN: 1744-8069; 1744-8069
• DOI: 10.1186/1744-8069-7-85

Background: Previous 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. Results: 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 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. Conclusions: These 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.