The Antinociceptive Effects Of α-Aminoamide Sodium Channel Blockers On Neuropathic Pain

There is a substantial body of evidence that suggests altered sodium channel activity contribute to the neuronal hyperexcitability associated with neuropathic pain. The therapeutic potential of sodium channel blockers for pain treatment is well recognized and these compounds do not tend to induce tolerance and dependence. The effects of current available drugs are not subtype-selective for sodium channels, resulting in emergence of severe side effects accompanied with antinociception. Therefore, there is an urgent need to find novel compounds with subtype-selective activity on sodium channels.Newron Pharmaceuticals’analgesic candidate ralfinamide is an a-aminoamide derivative with ion channel blocking properties, exhibiting higher potency towards Nav1.7 than lidocaine and carbamazepine (22-fold and 48-fold respectively). In rat models of inflammatory pain (CFA induced inflammatory pain) and neuropathic pain (chronic constriction injury), Ralfinamide dose-dependently reversed mechanical allodynia. A previous Phase Ⅱ study had indicated that ralfinamide exhibits a significant analgesia with benefits noted in the quality of sleep. The trial had enrolled patients with at least moderate neurppathic pain, e.g. Diabetic Neuropathy, Post-herpetic Neuralgia.The starting dose of ralfinamide of 320 mg/day was well tolerated. No statistically significant or clinically relevant difference between ralfinamide and placebo was detected. However, in SERENA study, a phase Ⅱb/Ⅲ study of ralfinamide in patients with at least moderate Neuropathic Low Back Pain (NLBP), available results did not detect any significant difference between ralfinamide and placebo. It is possible that ralfinamide is selective towards specific pain conditions within different patients.Objective:The purpose of this study is to evaluate the analgesic activity of Ralfinamide and its derivatives in animal models of neuropathic and inflammatory pain as well as physiological pain. In addition, we investigate the side effects of Ralfinamide and its derivatives.Methods:In present study, we investigated the analgesic effect of Ralfinamide and Ralfinamide derivative on the model of spared nerve injury (SNI) and chronic constriction injury (CCI) of neuropathic pain in mice and rats and chemotherapy-evoked neuropathic pain in mice with gabapentin used as a positive control. We also evaluated the anti-allodynic effect of Ralfinamide and its derivative in acute pain test (hot plate and acetic acid writhing test) in mice. The potential adverse effects of Ralfinamide and ralfianmide derivative were investigated by spontaneous activity test and rotarod test. In addition, at doses up to 60 mg/kg, we observed the effect on blood pressure and heart rate of normal rats.Results:No significant effect was observed in hot-plate and acetic acid writhing tests after oral administration of ZBH-ZP-21 (40 mg/kg), ZBH-ZP-42(40 mg/kg), and Ralfinamide (40 mg/kg). However, Ralfinamide (5-20 mg/kg, po), ZBH-ZP-21(1.25-10.00 mg/kg), ZBH-ZP-42 (0.1-10.0mg/kg) dose-dependently reduced mechanical allodynia in mouse SNI model and rat CCI model. Ralfinamide (5-20 mg/kg, po), ZBH-ZP-21 (1.25-10.00 mg/kg, po) dose-dependently reduced paclitaxel-evoked mechanical allodynia in mice. Similarly, Ralfinamide (5-20 mg/kg, po) reversed mechanical allodynia in oxaliplatin-evoked mechanical allodynia in mice. In CFA model, Ralfinamide (40 mg/kg, po), ZBH-ZP-21 (20 mg/kg, po), ZBH-ZP-42 (10 mg/kg, po) reduced mechanical allodynia in mice. No effects on blood pressure, heart rate were observed in rat at doses up to 60 mg/kg (Ralfinamide, ZBH-ZP-42) after oral administration. The compounds (Ralfinamide, ZBH-ZP-21, ZBH-ZP-42) orally administered (20 mg/kg) were well tolerated, without signs of neurological impairment (locomotor activity test in mice and rotarod test in mice).Conclusion:Our results demonstrated that Ralfinamide and its derivatives are effective in a broad range of pain models with limited side-effects. These data offer further support to the concept that sodium channel blockers may be beneficial in the treatment of neuropathic pain.