The dipeptide Phe-Phe amide attenuates signs of hyperalgesia, allodynia and nociception in diabetic mice using a mechanism involving the sigma receptor system
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.
R E S E A R C HOpen Access The dipeptide PhePhe 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 P17(SP17) and its Cterminal amidated congener induced antihyperalgesic effects in diabetic mice. In this study, we studied a small synthetic dipeptide related to SP17and endomorphin2, i.e. Phe Phe amide, using the tailflick test and von Frey filament test in diabetic and nondiabetic mice. Results:Intrathecal treatment with the dipeptide increased the tailflick latency in both diabetic and nondiabetic mice. This effect of PhePhe amide was significantly greater in diabetic mice than nondiabetic mice. The PhePhe amideinduced antinociceptive effect in both diabetic and nondiabetic mice was reversed by thes1receptor agonist (+)pentazocine. Moreover, PhePhe 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 nondiabetic 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 nondiabetic mice, but not in diabetic mice. Conclusions:These results suggest that the spinals1receptor system might contribute to diabetic mechanical allodynia and thermal hyperalgesia, which could be potently attenuated by PhePhe amide. Keywords:Allodynia, Antinociception, Diabetes, Hyperalgesia, Opioid receptors, PhePhe amide,s?σ?1receptor, Substance P17
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: kamei@hoshi.ac.jp 1 Department of Pathophysiology & Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 441, Ebara 2chome, Shinagawa ku, Tokyo 1428501, 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 P17(SP17; HArgProLysProGlnGlnPheOH), administered spinally, could attenuate thermal hyperalgesia in diabetic mice [5]. SP17is formed from substance P (SP; HArg ProLysProGlnGlnPhePheGlyLeuMetNH2). 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