To determine the brain site of action of the H2 receptor antagonist tiotidine as an inhibitor of systemic morphine (MOR) antinociception, the effects of intracerebral microinjections of this drug were studied on this response in rats. As assessed on the hot plate test, microinjections of tiotidine (1 ng in 0.5 microliter) into the ventral lateral periaqueductal gray at the level of the dorsal raphe (PAG/DR) attenuated MOR-induced antinociceptive responses 10-15 min later, but potentiated these responses when tested 20-30 min after its administration. This treatment had neither effect in the absence of MOR. In contrast, intracerebral tiotidine had no effects on tail flick responses in the presence or absence of MOR. Intracerebral tiotidine reduced by about 50% the antinociception induced by systemic MOR (5.6 and 10 mg/kg), resulting in a parallel, rightward shift in the MOR dose-response curve. When testing occurred with a fixed dose of MOR at a fixed time interval, tiotidine dose-response curves were U-shaped, an effect postulated to result from the separate inhibitory and stimulatory mechanisms found at different times. Intracerebral mapping studies showed that the attenuation of MOR antinociception by tiotidine given into the PAG/DR was not reproduced by tiotidine injections into adjacent rostral, caudal, dorsal or ventral areas. Taken with previous studies showing that: (1) both MOR and histamine (HA) induce antinociception when given into the PAG/DR, and (2) systemic MOR releases HA in the PAG, the present results strongly suggest that systemic MOR attenuates supraspinally organized responses to phasic, thermal nociceptive stimuli by mechanisms that include PAG HA release and subsequent activation of PAG H2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)