Many neuropeptides involved in pain perception are generated by endoproteolytic cleavages of their precursor proteins by the proprotein convertases PC1 and PC2. To investigate the role of PC2 in nociception and analgesia, we tested wild-type and PC2-null mice for their responses to mechanical and thermal nociceptive stimuli, before and after a short swim in cold or warm water. Basal responses and responses after a cold swim were similar between the two groups. However, after a short forced swim in warm water, PC2-null mice were significantly less responsive to the stimuli than wild-type mice, an indication of increased opioid-mediated stress-induced analgesia. The enhanced analgesia in PC2-null mice may be caused by an accumulation of opioid precursor processing intermediates with potent analgesic effects, or by loss of anti-opioid peptides.