The dipeptide Phe-Phe amide attenuates signs of hyperalgesia, allodynia and nociception in diabetic mice using a mechanism involving the sigma receptor system

Ohsawa Masahiro, Carlsson Anna, Asato Megumi, Koizumi Takayuki, Nakanishi Yuki, Fransson Rebecca, Sandström Anja, Hallberg Mathias, Nyberg Fred, Kamei, Kamei Junzo

Description

Previous studies have demonstrated that intrathecal administration of the substance P amino-terminal metabolite substance P 1-7 (SP 1-7 ) and its C-terminal amidated congener induced antihyperalgesic effects in diabetic mice. In this study, we studied a small synthetic dipeptide related to SP 1-7 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 σ 1 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 σ 1 receptor system might contribute to diabetic mechanical allodynia and thermal hyperalgesia, which could be potently attenuated by Phe-Phe amide.

Sujets

• Allodynia
• Analgesic
• Diabetes
• Hyperalgesia
• Opioid receptor

Informations

• Publié par: biomed
• Publié le: 01 janvier 2011
• Nombre de lectures: 7
• Langue: English

Extrait

Ohsawaet al.Molecular Pain2011,7:85 http://www.molecularpain.com/content/7/1/85

MOLECULAR PAIN

R E S E A R C HOpen Access The dipeptide PhePhe amide attenuates signs of hyperalgesia, allodynia and nociception in diabetic mice using a mechanism involving the sigma receptor system 1 21 11 3 Masahiro Ohsawa , Anna Carlsson , Megumi Asato , Takayuki Koizumi , Yuki Nakanishi , Rebecca Fransson , 3 22 1* Anja Sandström , Mathias Hallberg , Fred Nybergand Junzo Kamei

Abstract Background:Previous studies have demonstrated that intrathecal administration of the substance P amino terminal metabolite substance P 17 (SP 17 ) and its Cterminal amidated congener induced antihyperalgesic effects in diabetic mice. In this study, we studied a small synthetic dipeptide related to SP 1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 thes 1 receptor agonist (+)pentazocine. Moreover, PhePhe amide attenuated mechanical allodynia in diabetic mice, which was reversible by (+)pentazocine. The expression of spinals1 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 spinals 1 receptor system might contribute to diabetic mechanical allodynia and thermal hyperalgesia, which could be potently attenuated by PhePhe amide. Keywords:Allodynia, Antinociception, Diabetes, Hyperalgesia, Opioid receptors, PhePhe amide,s?σ? 1 receptor, Substance P 17

Background Diabetes is a global disease with an estimated worldwide prevalence of 2.8% in 2000, and this is predicted to climb to 4.4% in 2030 [1]. Diabetic neuropathy is seen in about 60% of all diabetic patients [2]. While the symptoms of diabetic polyneuropathy include hyperalge sia (hypersensitivity to noxious stimuli), hypoalgesia (loss of pain sensation) is also possible [3]. This pain is poorly relieved by opiates and the treatment regimen is

* Correspondence: [e-mail] 1 Department of Pathophysiology & Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 441, Ebara 2chome, Shinagawa ku, Tokyo 1428501, Japan Full list of author information is available at the end of the article

usually based on the use of antiepileptics and antide pressants, which often have inadequate effects and are associated with a high prevalence of side effects [4]. There is a great need for new strategies for the treat ment of diabetic neuropathy. We recently demonstrated that substance P 17 (SP 17 ; HArgProLysProGlnGlnPheOH), administered spinally, could attenuate thermal hyperalgesia in diabetic mice [5]. SP 17 is formed from substance P (SP; HArg ProLysProGlnGlnPhePheGlyLeuMetNH 2 ). SP was discovered as a neuropeptide by Von Euler and Gaddum in 1931 [6] and is involved in pain signaling, peripheral inflammation and the maintenance of hyper algesia [7]. SP is enzymatically degraded into several

© 2011 Ohsawa et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.