The existence of neural opioid-mediated networks that are specific for the modulation of nociception is well established. Parallel non-opioid pathways exist, but their underlying physiology is little known. We now report that oxytocin administered intraperitoneally to rats, and intraperitoneally or intracisternally to mice has an anti-nociceptive effect, which is related to the activation of descending anti-nociceptive pathways. This anti-nociceptive effect can be reversed by an oxytocin antagonist but not by the opioid antagonist naloxone. The anti-nociceptive effect of oxytocin is not directly dependent on the activation of serotonergic pathways or to changes in temperature. Our data indicate that the oxytocinergic system has a modulatory function on nociception.