Comparison of milnacipran, duloxetine and pregabalin in the formalin pain test and in a model of stress-induced ultrasonic vocalizations in rats

Milnacipran and duloxetine, serotonin/noradrenalin reuptake inhibitors, and pregabalin, a α 2-δ 1 Ca 2+ channel blocker, are efficacious against fibromyalgia, a condition characterized by diffuse chronic pain and associated with stress. We compared these compounds (i.p. route), in rat models of acute/inflammatory pain (2.5% intraplantar formalin) and stress-induced ultrasonic vocalization (USV: 22 kHz calls following presentation of a conditioned stimulus previously associated with foot-shocks). In the formalin test, milnacipran dose-dependently attenuated paw elevation and licking (minimal effective dose, MED: 2.5 mg/kg for licking/late phase). Duloxetine was slightly more potent (MED = 0.63). Pregabalin also reduced paw licking/late phase (MED = 0.63), but was inactive up to 160 mg/kg for paw elevation (both phases) and paw licking (early phase). Milnacipran dose-dependently reduced USV (MED = 10, near total inhibition at 20 mg/kg); duloxetine was less potent (MED = 20). Pregabalin (2.5–80 mg/kg) was only significantly active at 40 mg/kg. Milnacipran, duloxetine and pregabalin possess analgesic activity in the formalin test on paw licking/late phase (corresponding to inflammatory pain with a central sensitization component). In the stress-induced USV model, milnacipran was the most potent and efficacious compound. To summarize, reduction of formalin-induced paw licking/late phase might constitute a useful indicator of potential activity against inflammatory/centrally sensitized pain, as might be expressed in fibromyalgia.