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Chronic restraint stress-induced mechanical/cold allodynia and enhanced inflammatory pain in rat: Effects of milnacipran, duloxetine and pregabalin. (POSTER)

Bardin L. Malfetes N, Newman-Tancredi A, Depoortère R.
Program No. 457.19, 2009 Neuroscience Meeting Planner. Chicago, IL: Society for Neuroscience, 2009. Online.

Whereas acute stress often results in analgesia, chronic stress can trigger hyperalgesia/allodynia. This influence on nociception may be relevant to numerous pain syndromes, particularly fibromyalgia (FM), a condition characterized by diffuse muscular pain and tenderness. Hence, there is a need for pre-clinical models integrating a chronic-stress dimension to the study of chronic pain. We assessed the effects of protracted intermittent stress produced by daily, 1 h restraint periods in cylinders, 4 days/week over 5 weeks, on models of hyperalgesia and allodynia in rats. In a separate cohort of rats, we assessed the effects of daily i.p. treatment with milnacipran, duloxetine and pregabalin (used clinically against painful pathologies, including FM) on stress-induced mechanical and cold allodynia, over a 3 week period.
After 5 weeks of chronic stress, chemical hyperalgesia induced by formalin was potentiated (160% and 76% increase of pain score above controls, during the early and late phases, respectively). Chronic stress also produced thermal allodynia in response to cold (paw acetone test: 2-fold increase of allodynia score during weeks 3 to 5) and heat (42°C tail immersion test: approximately 15% decrease of withdrawal threshold, at weeks 2 and 3). Finally, chronic stress resulted in mechanical allodynia in the von Frey filaments test (50% decrease in response threshold during weeks 2 to 5). However, chronic stress had no influence in the Randall-Selitto test of mechanical hyperalgesia, and in the tail immersion models of cold (4°C) or hot (48°C) thermal hyperalgesia, as well as cold (15°C) allodynia.
Milnacipran (10, 20 and 40 mg/kg/day) dose-dependently reversed mechanical allodynia, with complete reversion observed at 40 mg/kg from the first week. A tendency to reduce cold allodynia was observed at 20 and 40 mg/kg at week 2 and 3. Pregabalin reversed mechanical allodynia at 10 but not 20 mg/kg, and did not reverse acetone-induced allodynia. In contrast, duloxetine (10 and 20 mg/kg) did not attenuate either type of allodynia, and even tended to worsen (weeks 2 and 3) mechanical allodynia. In addition, rats treated with 20 mg/kg exhibited decreased (about 40g at week 3) body weight gain relative to control rats. This model of prolonged, intermittent restraint stress may be useful in investigating the mechanisms linking stress and pain, and in providing an assay to assess the potential therapeutic efficacy of drugs targeted against painful pathologies with a strong stress component. Milnacipran, pregabalin, and duloxetine, FDA-approved drugs for the management of FM, exhibited differential effects on mechanical and cold allodynia in this animal model.