Mitsuo Murayama

Mechanism of analgesic action of mesaconitine. I. Relationship between analgesic effect and central monoamines or opiate receptors

The contribution of the central monoamines and the opiate receptor to mesaconitine (MA)-induced analgesia was investigated by means of pharmacological and neurochemical methods in which morphine (Mor) was used for comparison. The analgesic action of MA (i.c.) determined by the acetic acid-induced writhing method and the tail flick method was dose-dependent, indicating that its activity is elicited through the central nervous system. MA-induced analgesia was decreased by alpha-methyl-p-tyrosine (alpha-MT), 6-hydroxydopamine, diethyldithiocarbamate, disulfiram and reserpine, and increased by methamphetamine and norepinephrine (NE). The mode of action of MA was similar to that of Mor except for the results obtained upon combined administration with 1-dopa, dopamine, alpha-MT or chemicals related to 5-hydroxytryptamine. In addition, MA promoted the alpha-MT-induced decrease in NE levels in hippocampus, medulla oblongata plus pons and spinal cord. Levallorphan did not affect the analgesic activity of MA, showing that its activity is not mediated via the opiate receptors. Consequently, it is concluded that the analgesic activity mediated by MA is closely related to responses involving the central catecholaminergic system, in particular, the noradrenergic system.

Effect of cyclic AMP on mesaconitine-induced analgesia in mice☆

The effects of cyclic AMP, dibutyryl cyclic AMP, theophylline, isoproterenol and propranolol on mesaconitine (MA)-induced antinociception in mice were investigated employing the tail flick and acetic acid-induced writhing methods for the evaluation of antinociceptive activity. MA-induced antinociception was significantly potentiated by cyclic AMP and dibutyryl cyclic AMP. The phosphodiesterase inhibitor theophylline also significantly potentiated the MA-induced antinociception. Further, MA-induced antinociception was markedly increased by a beta-adrenoceptor agonist, isoproterenol, and reduced by a beta-adrenoceptor antagonist, propranolol. These results suggest that the antinociceptive action of MA is potentiated through cyclic AMP and stimulation of the central beta-adrenergic system.

Mechanism of the antinociceptive action of mesaconitine: participation of brain stem and lumbar enlargement

1 The antinociceptive action of mesaconitine (MA) microinjected into the nucleus reticularis gigantocellularis (NRGC), the nucleus reticularis paragigantocellularis (NRPG), the periaqueductal gray (PAG) or the lumbar enlargement was investigated in rats by use of the tail immersion test. In addition, the effects of β‐adrenoceptor antagonists and an α‐adrenoceptor antagonist administered intrathecally (i.t.) on the antinociceptive action of MA given into the NRPG were also examined by the tail immersion test. 2 MA (50, 100 ng per rat) microinjected into the NRGC, the NRPG, the PAG and the lumbar enlargement increased the response latency in rats in a dose‐dependent fashion. MA (50 ng per rat) microinjected into neighbouring sites, the nucleus reticularis parvocellularis, the nucleus originis nervi abducentis and the fasciculus longitudinalis medialis, elicited no significant effect. 3 Intrathecally administered propranolol (1 and 5 μg per rat), atenolol (1 and 5 μg per rat) and IPS‐339 (1 and 5 μg per rat) remarkably inhibited the increase of the response latency induced by MA (50 ng per rat) given into the NRPG. 4 Intrathecally administered phenoxybenzamine (1 and 5 μg per rat) inhibited the increase of the response latency induced by MA (50 ng per rat) injected into the NRPG but to a lesser extent than the β‐adrenoceptor antagonists. 5 It is concluded that the NRGC, the NRPG, the PAG and the lumbar enlargement are involved in the sites of the antinociceptive action of MA and that the antinociceptive effect of MA administered into NRPG is elicited by activation of the inhibitory noradrenergic neurones from the NRPG in particularly via β‐receptor‐mediated effects of noradrenaline.

Stimulating actions on ribonucleic acid biosynthesis of aconitines, diterpenic alkaloids of Aconitum roots.

Mesaconitine (MA) significantly stimulated the incorporation of 5-[3H]-orotic acid into liver nuclear RNA 16 h after its administration. MA exhibited the strongest activity among the aconitine alkaloids. This stimulatory effect of MA was inhibited by actinomycin D, but the incorporation ratio of 5-[3H]orotic acid in the combined treatment group with MA and actinomycin D was significantly higher than that in the single treatment group with actinomycin D. MA also increased the incorporation of 5-[3H]orotic acid into polysomal RNA in mouse liver. When MA was added to the RNA polymerase (EC 2.7.7.6) preparation obtained from rat liver, the increase of the enzyme activity was weak. While RNA polymerase preparation from the liver of rats, which were previously treated with MA, elicited increased incorporation of [3H]cytidine monophosphate into RNA as compared with that from the livers of normal rats. Accumulated data indicate that aconitine alkaloids, in particular MA, accelerate liver RNA synthesis mainly by the increase of RNA polymerase.