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Nitric oxide has been proven to play an important role in nociception, accordingly, its promoters, phosphodiesterase inhibitors have been investigated as pain response modulators. Aiming to evaluate the central antinociceptive effect of tadalafil, a phosphodiesterase 5 inhibitor, and to determine its EC50, tail flick and hot plate tests were employed. On the other hand, tadalafil antinociceptive peripheral effect was assessed through acetic acid-induced writhing model. Formalin test was used to appraise both non-inflammatory and inflammatory pain responses. In order to elaborate the involvement of opioid receptors and nitric oxide/cyclic guanosine monophosphate/potassium-ATP pathway in tadalafil-induced analgesia, mice were pretreated with naloxone, L-nitro-arginine-methyl-ester (L-NAME), methylene blue, and glibenclamide.The results illustrated that tadalafil had a significant antinociceptive effect in the tail flick, hot plate, acetic acid-induced writhing and formalin tests indicating the involvement of peripheral and central analgesic mechanisms. Moreover, tadalafil mechanism of action involved several receptors and mediators, specifically NO/cGMP pathway and opioid receptors. In the formalin test, naloxone significantly blocked the effect of tadalafil in the first phase and partially in the second phase which is an inflammatory pain-dependent aspect. L-NAME, methylene blue and glibenclamide partially blocked the effect of tadalafil in the first phase and enhanced its effect in the second phase which is related to nitric oxide role in the inflammatory process.As a conclusion, tadalafil possesses a potential analgesic effect via the involvement of opioid and nitric oxide pathways.Tadalafil possesses a potential analgesic activity.In vivo pain models confirmed tadalafil antinociceptive effect.Tadalafil acts on both peripheral and central nociception levels.Tadalafil action is partially mediated through L-arginine/NO/cGMP pathway.Tadalafil mechanism also involves opioid receptors blockage.