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Beatriz de la Puente, Elizabeth Romero-Alejo, José Miguel Vela, Manuel Merlos, Daniel Zamanillo, Enrique Portillo-Salido Department of Pharmacology, Drug Discovery and Preclinical Development, ESTEVE, Barcelona, SpainAbstract: Reflex-based procedures are important measures in preclinical pain studies that evaluate stimulated behaviors. These procedures, however, are insufficient to capture the complexity of the pain experience, which is often associated with the depression of several innate behaviors. While recent studies have made efforts to evidence the suppression of some positively motivated behaviors in certain pain models, they are still far from being routinely used as readouts for analgesic screening. Here, we characterized and compared the effect of the analgesic ibuprofen (Ibu) and the stimulant, caffeine, in assays of acute pain-stimulated and pain-depressed behavior. Intraperitoneal injection of acetic acid (AA) served as a noxious stimulus to stimulate a writhing response or depress saccharin preference and locomotor activity (LMA) in mice. AA injection caused the maximum number of writhes between 5 and 20 minutes after administration, and writhing almost disappeared 1 hour later. AA-treated mice showed signs of depression-like behaviors after writhing resolution, as evidenced by reduced locomotion and saccharin preference for at least 4 and 6 hours, respectively. Depression-like behaviors resolved within 24 hours after AA administration. A dose of Ibu (40 mg/kg) – inactive to reduce AA-induced abdominal writhing – administered before or after AA injection significantly reverted pain-induced saccharin preference deficit. The same dose of Ibu also significantly reverted the AA-depressed LMA, but only when it was administered after AA injection. Caffeine restored locomotion – but not saccharin preference – in AA-treated mice, thus suggesting that the reduction in saccharin preference – but not in locomotion – was specifically sensitive to analgesics. In conclusion, AA-induced acute pain attenuated saccharin preference and LMA beyond the resolution of writhing behavior, and the changes in the expression of hedonic behavior, such as sweet taste preference, can be used as a more sensitive and translational model to evaluate analgesics. Keywords: saccharin preference, locomotor activity, pain, writhing, analgesia, ibuprofen, caffeine