The effects of compounds active at histamine H3-receptors on morphine-induced antinociception have been investigated in thermal and chemical tests in mice; tail-immersion (50 degrees C) and hot-plate (49 degrees and 55 degrees C) tests and acetic acid-induced writhing. Neither (R)alpha-methylhistamine, a specific agonist, (S)alpha-methylhistamine, a chemical control, nor thioperamide, an antagonist, had any antinociceptive action alone but thioperamide (3 mg kg-1) attenuated the effects of morphine in the tail-immersion test while (R)alpha-methylhistamine (1 mg kg-1), but not the (S) isomer, potentiated its effects in the hot-plate test at 55 degrees C. These results are consistent with the morphine potentiation seen with H1-antagonists and suggest that central histaminergic mechanisms can modulate opioid actions.
It appears that fenproporex and fenfluramine can interact with and inhibit the mechanism by which (+)-amphetamine but not tyramine releases noradrenaline. Our results lend support to the suggestion by Day (1967) that indirectly-acting sympathomimetic amines may produce their effects by at least two distinct mechanisms.We are not aware of any previous reports of a dose-dependent reduction in blood pressure to ascending doses of (+)-amphetamine ; this phenomenon occurs after pretreatment with either fenproporex or fenfluramine but the underlying mechanism has yet to be elucidated.In further work it will be interesting to observe if fenproporex and fenfluramine antagonize the stimulant action of (+)-amphetamine on the central nervous system. Jespersen & Bonaccorsi (1 969b) have shown fenfluramine to decrease the toxicity of (+)-amphetamine in grouped mice.We are grateful to Bottu Laboratories of Paris for supplying us with a sample of fenproporex for pharmacological studies.
Central histaminergic modulation of H1 rather than H2-receptors has been shown to modify epileptic activity. Compounds acting on the HIC- and H3-receptors were tested against chemically-induced seizures in mice. Compounds antagonising the microsomal and nuclear intracellular receptors (HIC) only modified seizures at doses where toxicity was observed. Antagonists of the histamine H3-receptor (thioperamide and burimamide) only potentiated the severity of clonic convulsions induced by picrotoxin, while impromidine (i.c.v.), an antagonist with H2-agonist activity, inhibited leptazol-induced seizures. The H3-agonist, (R)alpha-methylhistamine, potentiated chemically-induced seizures, but at lower doses there was slight inhibition.
Piperazine reduced the histamine content of Ascaris suum, yet it greatly increased the uptake of histamine from the surrounding medium, the neuromuscular structures of the nematode preferentially increasing in amount.
Bephenium reduced the histamine content of Ascaris and the uptake of histamine from the surrounding medium. However, the relative amount in the neuromuscular structures increased.
The flaccid paralysing action of piperazine may thus involve increased histamine absorption whereas the spastic paralysing action of bephenium may be independent of histamine.
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