Evaluation of milnacipran, in comparison with amitriptyline, on cold and mechanical allodynia in a rat model of neuropathic pain

Milnacipran, a serotonin/norepinephrine reuptake inhibitor (SNRI), has shown efficacy against several chronic pain conditions, including fibromyalgia. Here, we evaluated, in rats, its anti-allodynic effects following acute or sub-chronic treatment in a model of neuropathic pain (chronic constriction injury, CCI, of the sciatic nerve). Amitriptyline, a tricyclic antidepressant active pre-clinically and clinically against neuropathic pains, was added as a comparison compound. Upon acute i.p. administration, milnacipran was potently efficacious in the CCI model. It significantly reduced thermal allodynia in the cold (4 °C) plate test (MED = 2.5 mg/kg), and attenuated mechanical allodynia in the von Frey filaments test (MED = 10 mg/kg). Given sub-chronically (7 day, b.i.d.), milnacipran was effective at 10 mg/kg i.p. in both tests. Acute amitriptyline (10 mg/kg i.p.) was efficacious against mechanical, but less so against cold allodynia; under sub-chronic conditions, it was only active against mechanical allodynia. These data show that milnacipran is as efficacious as the reference compound amitriptyline in a pre-clinical model of injury-induced neuropathy, and demonstrate for the first time that it is active acutely and sub-chronically against cold allodynia. They also suggest that milnacipran has the potential to alleviate allodynia associated with nerve compression-induced neuropathic pain in the clinic (for example following discal hernia, avulsion or cancer-induced tissue damage).