In order to test directly the hypothesis that brain histamine and H2-receptors mediate the naloxone-resistant footshock-induced antinociception (FSIA) elicited by 3 min of 3.5 mA, the effect of i.c.v. H2-antagonists on this response was determined. Intracerebroventricular zolantidine dimaleate produced an inhibition of the response that was both time- and dose-dependent, with no effect on base-line responses. A dose of 20 micrograms produced maximal (93%) inhibition of FSIA when given 10 min before footshock, with a calculated ID50 of 7.18 nmol. Eight additional H2-antagonists with varying structures and brain-penetrating qualities also exhibited dose-dependent inhibition of the response with no effect on base-line nociception. The potencies of these compounds for inhibition of naloxone-resistant FSIA correlated significantly (r = 0.966, P less than .001; rho = 0.980, P less than .002) with their affinities at the H2-receptor, providing strong support for the hypothesis that brain histamine and H2-receptors are important components of naloxone-resistant FSIA.