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Abstract: The present study was designed to investigate the anti-allodynic effects of current analgesic agents, such as pregabalin, amitriptyline, mexiletine, morphine, and diclofenac, in a rat model of streptozotocin (STZ)-induced diabetic neuropathy. Diabetic rats developed a sustained decrease in withdrawal threshold response to the von Frey test within 8 weeks after a single injection of STZ (45 mg/kg, i.v.). The anti-allodynic effects of analgesic agents were examined after a single oral or subcutaneous administration at 3 and 7 weeks after beginning of STZ-treatment. Pregabalin (3–30 mg/kg, p.o.), an antiepileptic agent, dose-dependently blocked the mechanical allodynia in rats treated both at 3 and 7 weeks. Mexiletine (10–100 mg/kg, p.o.), a sodium channel blocker, dose-dependently ameliorated mechanical allodynia in rats treated at 3 weeks; however, the efficacy was diminished at 7 weeks. Morphine (1–10 mg/kg, s.c.) was effective in rats treated at 3 weeks; however, it was ineffective at 7 weeks. Conversely, an antidepressant amitriptyline (0.3–3 mg/kg, p.o.) improved mechanical allodynia in rats treated at 7 weeks, whereas it was ineffective at 3 weeks. Diclofenac, a non-steroidal anti-inflammatory drug, was ineffective at both time points. These results demonstrate that, except for diclofenac, the standard analgesic agents tested can effectively alleviate the mechanical allodynia seen in STZ-induced diabetic neuropathy. Their efficacies varied depending on the duration of the diabetic condition, suggesting that temporal changes in pharmacodynamic factors could affect the responsiveness of this model to analgesic agents. [Copyright &y& Elsevier]

Abstract: AS1069562 is the (+)-isomer of indeloxazine, which had been clinically used as a cerebral activator for the treatment of cerebrovascular diseases with serotonin and norepinephrine reuptake inhibition (SNRI) and neuroprotection. Here, we compared the analgesic effects of repeated treatment with AS1069562 and duloxetine, a selective SNRI, on pain-related behavior in a rat model of streptozotocin (STZ)-induced diabetic neuropathy. Further, we also evaluated the effects on the expression of neurotrophic factors and nerve conduction velocity. AS1069562 and duloxetine by single daily administration for 4 weeks significantly improved mechanical allodynia in STZ-induced diabetic rats and did not affect plasma glucose level or body weight. Interestingly, the analgesic effect of AS1069562 continued after a consecutive 1-week treatment discontinuation, although the plasma concentration of AS1069562 was reduced to undetectable levels. In contrast, the efficacy of duloxetine disappeared after treatment discontinuation. Expression analysis demonstrated that AS1069562 significantly restored decreased insulin-like growth factor 1 and fibroblast growth factor 2 mRNA levels in dorsal root ganglion and spinal cord, respectively, whereas duloxetine did not affect the expression levels of neurotrophic factors. In addition, AS1069562 reversed the slowing of nerve conduction velocity. The results of this study indicate that the analgesic effect of repeated dosing of AS1069562 but not duloxetine is persistent even after a 1-week drug discontinuation in STZ-induced diabetic rats. Restoration of neurotrophic factors may be involved in the curative-like pharmacological effect of this agent. Thus, AS1069562 may potentially offer a better treatment option for patients with painful diabetic neuropathy than duloxetine via different mechanisms. [Copyright &y& Elsevier]

Abstract: FK1706, a derivative of FK506, is a non-immunosuppressive immunophilin ligand with significant neurotrophic activity mediated via FKBP-52 and the RAS/RAF/MAPK signaling pathway. Here, we tested the effect of FK1706 on painful diabetic neuropathy in rat model of diabetes induced by streptozotocin (STZ). FK1706 ameliorated mechanical allodynia in this model at doses over 0.32mg/kg, p.o., even if treatment was initiated after neuropathy was established, and did not affect plasma glucose levels. Furthermore, this improvement continued at least 4 weeks after the last administration. In morphological analysis, FK1706 treatment also restored intraepidermal nerve fiber density in footpad skin to almost normal levels. Gabapentin also improved mechanical allodynia in the same model, but efficacy disappeared the day after administration stopped. Allodynia responses were potentiated by co-administration of both compounds. Thus, FK1706 ameliorated painful diabetic neuropathy via a different mechanism from gabapentin and improved morphological outcomes, indicating that FK1706 improves painful diabetic neuropathy by modifying the underlying disease pathology. [Copyright &y& Elsevier]