(667): Bicifadine is an efficacious analgesic in animal models of neuropathic pain

Abstract

Bicifadine (DOV 220,075), a balanced inhibitor of norepinephrine and serotonin uptake, was evaluated in two models of neuropathic pain: streptozotocin-induced diabetic neuropathy, and the spinal nerve ligation (SNL) model (Kim and Chung, 1992). In the diabetic neuropathy model, the effect of bicifadine on the paw pressure withdrawal threshold was determined using the Randall-Selitto test. Bicifadine’s efficacy in reducing mechanical allodynia in the SNL model was measured using Semmes-Weinstein filaments and its effects on mechanical and thermal hyperalgesia were evaluated with the Randall-Selitto test and a focused beam of infrared radiation, respectively. Bicifadine dose-dependently reduced the nociceptive threshold for paw withdrawal in diabetic rats (ED50= 5 mg/kg PO). Similarly, bicifadine reduced mechanical allodynia in the SNL model, with a maximum anti-allodynic action observed at 40mg/kg PO, an effect comparable in magnitude to 300 mg/kg PO of gabapentin. In addition, bicifadine induced anti-mechanical (ED50= 12 mg/kg PO) and thermal (MED 12.5 mg/kg PO) hyperalgesic effects. The effect of bicifadine in blocking mechanical hyperalgesia in the SNL model reached a maximum at 60 minutes and remained significant up to 120 minutes after administration. Its effects in blocking thermal hyperalgesia reached a maximum at 30 minutes and lasted up to 240 minutes after administration. Chronic administration (50mg/kg/day, 5 days, PO) of bicifadine did not result in the development of analgesic tolerance, with efficacy in reducing mechanical hyperalgesia in SNL rats similar to acute bicifadine (50mg/kg). In contrast, repeated administration of morphine (128 mg/kg/D, 5 days, PO) resulted in a significant reduction in efficacy. In conclusion, bicifadine is a potent and efficacious analgesic in two well-described models of neuropathic pain, and exhibits no abuse potential.