HISTAMINE-INDUCED MODULATION OF NOCICEPTIVE RESPONSES

Because previous studies suggest an antinociceptive role for the neuro modulator histamine (HA) in the periaqueductal grey or the nearby dors al raphe (PAG/DR), a detailed pharmacological investigation of the eff ects of intracerebral HA on the hot-plate nociceptive test was perform ed in rats. Intracerebral microinjections of HA (1 mu g) into the PAG/ DR or into the median raphe evoked a mild, reversible antinociceptive response; injections into lateral or dorsal midbrain evoked either a d elayed response or no response, respectively. In the PAG/DR, the HA do se-response curve had an inverted U-shape, showing that HA can induce both antinociceptive (0.3-3 mu g) and pro-nociceptive (10-30 mu g) res ponses. Larger doses of HA (e.g., 100 mu g) produced irreversible and highly variable antinociceptive responses that were accompanied by beh avioral and histopathological changes; such effects, indicative of tox icity, were not observed after 0.3 mu g of HA, the peak antinociceptiv e dose. HA (0.3 mu g) antinociception was completely inhibited by intr acerebral co-administration of the opiate antagonist naloxone (1 ng), the H-1-receptor antagonist temelastine (20 pg), and the H-2-receptor antagonist tiotidine (1 ng); none of these drugs altered nociceptive s cores in the absence of HA. These results show that: (1) HA, a neurotr ansmitter in the FAG, can evoke antinociception in the absence of othe r behavioral or toxic effects; and (2) HA antinociception depends on t he activation of both opiate and HA receptors in the PAG/DR. Since pre vious studies have shown that: (1) systemic morphine increases the rel ease of HA in the PAG/DR, and (2) systemic morphine analgesia is inhib ited by PAG/DR injections of the H-2 antagonist tiotidine, the present results (showing antagonism of HA antinociception by intracerebral ti otidine treatment) strongly support the conclusion that histaminergic mechanisms in the PAG/DR mediate a portion of systemic morphine antino ciception.