The goal of the present study was to determine whether the serotonin (5-HT) system is involved in the effects of kappa opioids as measured with the squirrel monkey shock titration procedure. With this procedure, electric shock was delivered to the monkey's tail and scheduled to increase once every 15 sec from 0.01 to 2.0 mA in 30 steps. Monkeys responded under a fixed ratio 5 schedule to determine the level at which shock intensity was maintained. The intensity below which monkeys maintained shock 50% of the time, or the median shock level (MSL), and the rate of responding in the presence of shock (RR) were determined after the administration of saline and all drug combinations. The kappa opioids U50,488 and spiradoline increased MSL and decreased RR in a dose-dependent manner. The effects of U50,488 and spiradoline on both RR and MSL were enhanced in all three monkeys by the 5-HT2 antagonists ketanserin and pirenperone and in one monkey by another 5-HT2 antagonist, LY 53857. The effects of U50,488, but not spiradoline, were enhanced to a lesser degree by the 5-HT1A receptor agonist 8-OH-DPAT. The effects of U50,488 but not altered by the receptor agonist DOI, the 5-HT3 receptor antagonist MDL 72222 or the alpha-1 adrenergic receptor antagonist prazosin. These results suggest that the effects of kappa opioids in the shock titration procedure probably involve serotonergic mechanisms that are modulated via 5-HT2 and, perhaps, 5-HT1A receptors. Moreover, these interactions probably reflect nonspecific decreases in RR rather than alterations in the antinociceptive effects of kappa opioids.