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Abstract 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.

Objective: The capitulum of Chrysanthemum indicum (Compositae) is the source of a crude drug used in Japanese traditional Kampo and traditional Chinese medicine. Previous research showed that C. indicum flowers promote adipocyte differentiation through the activation of peroxisome proliferator-activated receptor (PPAR)-γ that may be an important mechanism for controlling systemic insulin resistance or other biological functions. Materials and Methods: The capitulum of C. indicum was extracted with methanol, and its PPAR-γ agonistic activity was measured using luciferase assay. The active ingredients were isolated by the activity-guided fractionations. Results: We isolated (Z)-tonghaosu and (E)-tonghaosu, and (E)-tonghaosu had PPAR-γ agonistic constituents by the activity-guided fractionation from the capitulum of C. indicum. The isomer (Z)-tonghaosu did not show PPAR-γ-agonistic activity. Conclusion: (E)-tonghaosu is one of the active ingredients as PPAR-γ agonist in the capitulum of C. indicum. Abbreviations used: ANOVA: One-way analysis of variance; DMEM: Dulbecco's modified minimum essential medium; FBS: Fetal bovine serum; HPLC: High-performance liquid chromatography; MCI: Methanol extract of the capitulum of Chrysanthemum indicum; NMR: Nuclear magnetic resonance; PPAR: Peroxisome proliferator-activated receptor. [ABSTRACT FROM AUTHOR]

Abstract: We previously demonstrated that intrathecal treatment with substance P metabolite substance P1–7 induced anti-hyperalgesia in diabetic mice. In the present study, we have used a synthetic analog of this peptide, the substance P1–7 amide, showing higher binding affinitiy than the native heptapeptide, for studies of the tail-flick response in diabetic and non-diabetic mice. Intrathecal injection of substance P1–7 amide produced prolongation of the tail-flick latency in both diabetic and non-diabetic mice, an effect that was more pronounced in diabetic mice than non-diabetic mice. Moreover, the observed antinociceptive potency of the substance P1–7 amide was higher in both diabetic and non-diabetic mice in comparison with the native substance P1–7. The antinociceptive effect of substance P1–7 amide was reversed by naloxone but not by the selective opioid receptor antagonist β-funaltrexamine, naltrindole or nor-binaltorphimine, selective for the μ-, δ- or κ-opioid receptor, respectively. In addition, the antinociceptive effect induced by substance P1–7 amide was partly reversed by the σ1 receptor agonist (+)-pentazocine, suggesting a possible involvement of the σ1 receptor for the action of this peptide. These results suggest that the actions of substance P1–7 amide mimic the effects of the native substance P fragment but with higher potency and that the mechanisms for its action may involve the σ1 receptor system. [ABSTRACT FROM AUTHOR]

Abstract: Diabetic neuropathy is one of the most common complications of diabetes and causes various problems in daily life. Several investigations have noted that many factors in the spinal cord are involved in the symptoms of painful diabetic neuropathy, and there are very few effective therapeutic regimens. In the present study, we sought to elucidate the role of the RhoA/Rho kinase (ROCK) pathway in thermal hyperalgesia in diabetic mice. The intracellular localization of RhoA and the expression of eNOS were measured by western blotting. Thermal hyperalgesia was assessed by the tail-flick test and mechanical allodynia was assessed by automated von Frey filament test in streptozotocin(STZ)-induced diabetic mice. The spinal cord of STZ-treated diabetic mice showed increased membrane-bound RhoA compared to non-diabetic control. Treatment with the RhoA inhibitor exoenzyme C3, Clostridium botulinum, and the ROCK inhibitor Y27632 attenuated thermal hyperalgesia and mechanical allodynia in diabetic mice. Moreover, daily treatment with simvastatin attenuated all of those changes in diabetic mice. The expression of eNOS and NO metabolite contents in the spinal cord was decreased in diabetic mice, and these changes were normalized by treatment with simvastatin. The present results show that HMG-CoA reductase inhibitors have an inhibitory effect on thermal hyperalgesia in diabetic mice, which is mediated by an increase in NO production through the inhibition of RhoA/ROCK pathways. These results suggest that ROCK inhibitors and HMG-CoA inhibitors may be attractive compounds to relieve the symptoms of painful diabetic neuropathies. [Copyright &y& Elsevier]

Abstract: Sensory abnormality is one of the serious complications in diabetes. Since the effective therapeutic regimen to ameliorate the diabetic sensory abnormality is very few, the present study was then designed to investigate the effect of zinc l-carnosine on the changes of nociceptive threshold in diabetic mice. Zinc l-carnosine (75–300 mg/kg, p.o.) was administered once daily from 1 day after streptozotocin treatment. Diabetic mice showed shorter tail-flick latency at 1–4 weeks after streptozotocin treatment and longer tail-flick latency at 6–9 weeks after its treatment. The shortened tail-flick latency in early stage of diabetic mice was ameliorated by treatment with zinc l-carnosine. Moreover, zinc l-carnosine also slowed the onset of hypoalgesia in diabetic mice. Tail-flick latency in non-diabetic mice was not affected by the zinc l-carnosine treatment, indicating that zinc l-carnosine did not affect normal nociceptive transmission. Moreover, l-carnosine, but not zinc sulfate, ameliorated the abnormal sensory perception in diabetic mice. Interestingly, the ameliorative effect of zinc l-carnosine on the abnormal sensory perception in diabetic mice is much stronger than that of l-carnosine. These results provide the evidence of the ameliorative potential of zinc l-carnosine on the progressive diabetic neuropathy. Moreover, l-carnosine combined with zinc shows more potent amelioration of abnormal sensory perception in diabetic mice than by itself. [Copyright &y& Elsevier]

Abstract: Neuropathy accompanied by abnormal sensory perception is the most common complication in insulin-dependent and -independent diabetes mellitus. Since there are very few effective therapeutic regimens for sensory abnormalities in diabetes, we examined the effect of cytidine 5′-diphosphocholine (CDP)-choline on the thermal nociceptive threshold in streptozotocin-induced diabetic mice using the tail-flick test. Diabetic mice showed a shorter tail-flick latency at 1–4 weeks after streptozotocin treatment and a longer tail-flick latency after 8–12 weeks. This hyper- and hypoalgesia in diabetic mice was almost completely inhibited by daily treatment with CDP-choline (100mg/kg/day, p.o.) beginning on the day of streptozotocin treatment. Daily treatment with CDP-choline beginning 5 weeks after streptozotocin treatment attenuated the development of hypoalgesia. Diabetic mice showed a significant increase in Na+-K+-ATPase activity at 3 weeks after streptozotocin treatment, whereas Na+-K+-ATPase activity was decreased at 12 weeks after treatment. These alterations were normalized by daily treatment with CDP-choline (100mg/kg/day, p.o.) beginning the day of streptozotocin treatment. These results provide evidence to support the therapeutic potency of CDP-choline on the development of thermal hyper- and hypoalgesia and the progression of thermal hypoalgesia in diabetic mice. Moreover, these effects of CDP-choline may result from the normalization of Na+-K+-ATPase activity. [Copyright &y& Elsevier]

Abstract: Hypoalgesia is one of the serious complications in diabetes. Since there are few therapeutic treatments for this diabetic hypoalgesia, the present study was designed to examine the effect of acetyl-L-carnitine (ALC) on the changes of nociceptive threshold in diabetic mice. For prophylactic study, ALC was administered once daily from 1 day after the streptozotocin treatment. Diabetic mice showed shorter tail-flick latency at 1–4 weeks after the streptozotocin treatment and longer tail-flick latency at 6–9 weeks after the streptozotocin treatment. The shortened tail-flick latency in early stage of diabetic mice was not affected by prophylactic treatment with ALC. On the other hand, ALC dose-dependently improved the hypoalgesia in diabetic mice. For therapeutic study, ALC was administered once daily from 7 weeks after the streptozotocin treatment, when tail-flick latency was already prolonged. The therapeutic treatment with ALC also ameliorated the prolonged tail-flick latency in diabetic mice. Both prophylactic and therapeutic treatment with ALC did not affect the tail-flick latency in non-diabetic mice, indicating ALC did not affect the general nociceptive transmission. These results provide evidence of the prophylactic and therapeutic potential of ALC on the progressive diabetic neuropathy. [Copyright &y& Elsevier]

Goshajinkigan (GJG), a traditional Japanese Kampo formula, has been shown to exhibit several pharmacological actions, including antinociceptive effects. Processed aconite root (PA), which is considered to be an active ingredient of GJG, has also been demonstrated to have an ameliorative effect on pain, such as diabetic peripheral neuropathic pain. We recently identified neoline as the active ingredient of both GJG and PA that is responsible for its effects against oxaliplatin-induced neuropathic pain in mice. In the present study, we investigated whether GJG, PA, and neoline could inhibit Nav1.7 voltage-gated sodium channel (VGSC) current and whether neoline could ameliorate mechanical hyperalgesia in diabetic mice. To assess the electrophysiological properties of GJG extract formulation, powdered PA, and neoline on Nav1.7 VGSCs, whole-cell patch clamp recording was performed using human HEK293 cells expressing Nav1.7 VGSCs. In addition, the ameliorative effects of neoline on diabetic peripheral neuropathic pain were evaluated using the von Frey test in streptozotocin (STZ)-induced diabetic model mice. GJG extract formulation significantly inhibited Nav1.7 VGSC peak current. Powdered PA also inhibited Nav1.7 VGSC peak current. Like GJG and PA, neoline could inhibit Nav1.7 VGSC current. When diabetic mice were treated with neoline by intraperitoneal acute administration, the mechanical threshold was increased in diabetic mice, but not in non-diabetic mice, in a behavioral study. These results suggest that neoline might be a novel active ingredient of GJG and PA that is one of responsible ingredients for ameliorating mechanical hyperalgesia in diabetes via the inhibition of Nav1.7 VGSC current at least. Image 1 [ABSTRACT FROM AUTHOR]