We investigated behavioral responses to noxious cold and heat stimuli in mice. Similar to the hot-plate test, mice showed licking or jumping responses on a cold-plate (0 degrees C). The sensitivity to noxious heat (55 degrees C) was not correlated to the sensitivity to noxious cold, indicating that nociceptive processing of cold and heat are different. Behavioral responses to noxious cold are inhibited by systemic morphine or intrathecal administration of morphine. Lesion of the medial frontal cortex, including the anterior cingulate cortex, or selective activation of two types of opioid receptors in the anterior cingulate cortex produces dose-dependent antinociceptive effects on behavioral responses to noxious cold stimuli. These results suggest that activation of opioid receptors in the anterior cingulate cortex can produce powerful antinociception.