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 alpha(2)-delta(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: 22kHz 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: 2.5mg/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 160mg/kg for paw elevation (both phases) and paw licking (early phase). Milnacipran dose-dependently reduced USV (MED=10, near total inhibition at 20mg/kg); duloxetine was less potent (MED=20). Pregabalin (2.5-80mg/kg) was only significantly active at 40mg/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.
Bardin
L
L
Division of Neurobiology 2, Centre de Recherche Pierre Fabre, 17, Avenue Jean Moulin, 81106 Castres, France. laurent.bardin@pierre-fabre.com
Gregoire
S
S
Aliaga
M
M
Malfetes
N
N
Vitton
O
O
Ladure
P
P
Newman-Tancredi
A
A
Depoortère
R
R
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D003521:Cyclopropanes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000068736:Duloxetine Hydrochloride; D004597:Electroshock; D005557:Formaldehyde / Q000633:toxicity; D008297:Male; D000078764:Milnacipran; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects*; D000069583:Pregabalin; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000187:drug effects; D013876:Thiophenes / Q000494:pharmacology*; D014828:Vocalization, Animal / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
D018759:Adrenergic Uptake Inhibitors; D000700:Analgesics; D003521:Cyclopropanes; D013876:Thiophenes; D005557:Formaldehyde; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000068736:Duloxetine Hydrochloride; D000078764:Milnacipran