The inhibition of hindpaw (non-opiate) footshock-induced analgesia (HP-FSIA) by cimetidine, the histamine H2-receptor antagonist, was characterized in rats, and the drug's presence in brain was demonstrated. Cimetidine (100 mg/kg, IP) inhibited HP-FSIA when administered 30 min before testing, but was inactive when testing began sooner (15 min) or later (1-4 hr) than this time. Lower doses (20 mg/kg) were also ineffective when given 30 min before testing, whereas higher doses (200 mg/kg) effectively inhibited the response. Increasing the footshock current from 4 mA (which elicited cimetidine-sensitive analgesia) to higher currents (5 and 6 mA) yielded cimetidine-insensitive analgesia. Administration of isotopically labeled cimetidine (100 mg/kg, IP, 30 min) yielded whole brain cimetidine levels of 1.95 nmols/g, respectively, with a brain/blood ratio of 0.017. These findings confirm a limited penetration of brain by cimetidine, and show that large peripheral doses of cimetidine are required to block brain H2-receptors. The specific dose and time requirements for cimetidine to inhibit the HP-FSIA are probably attributable to the brain drug levels that can be achieved after peripheral administration.