Histamine-induced modulation of nociceptive responses

Because previous studies suggest an antinociceptive role for the neuromodulator histamine (HA) in the periaqueductal grey or the nearby dorsal raphe (PAG/DR), a detailed pharmacological investigation of the effects of intracerebral HA on the hot-plate nociceptive test was performed in rats. Intracerebral microinjections of HA (1 μg) into the PAG/DR or into the median raphe evoked a mild, reversible antinociceptive response; injections into lateral or dorsal midbrain evoked either a delayed response or no response, respectively. In the PAG/DR, the HA dose-response curve had an inverted U-shape, showing that HA can induce both antinociceptive (0.3–3 μg) and pro-nociceptive (10–30 μg) responses. Larger doses of HA (e.g., 100 μg) produced irreversible and highly variable antinociceptive responses that were accompanied by behavioral and histopathological changes; such effects, indicative of toxicity, were not observed after 0.3 μg of HA, the peak antinociceptive dose. HA (0.3 μg) antinociception was completely inhibited by intracerebral co-administration of the opiate antagonist naloxone (1 ng), the H1-receptor antagonist temelastine (20 pg), and the H2-receptor antagonist tiotidine (1 ng); none of these drugs altered nociceptive scores in the absence of HA. These results show that: (1) HA, a neurotransmitter in the PAG, can evoke antinociception in the absence of other behavioral or toxic effects; and (2) HA antinociception depends on the activation of both opiate and HA receptors in the PAG/DR. Since previous studies have shown that: (1) systemic morphine increases the release of HA in the PAG/DR, (2) systemic morphine analgesia is inhibited by PAG/DR injections of the H2 antagonist tiotidine, the present results (showing antagonism of HA antinociception by intracerebral tiotidine treatment) strongly support the conclusion that histaminergic mechanisms in the PAG/DR mediate a portion of systemic morphine antinociception.