Experimental investigation of the diterpenoid alkaloid songorine regarding its antinociceptive activity and potential adverse effects

Introduction. Opioid and cannabinoid receptors are involved in the antinociceptive effects of songorine, a diterpene alkaloid isolated from the above-ground parts of Aconitum barbatum, as demonstrated in various models of chemical and thermal pain. The involvement of opioid receptors in songorine is antinociceptive mechanism necessitates studying its potential side effects, characteristic of narcotic analgesics. TRPA1 receptor involvement in songorine is analgesic mechanism is possible, requiring further investigation in models of mechanical hyperalgesia with formalin.

Aim: To study the antinociceptive activity of the diterpenoid alkaloid songorine at a dose of 25 μg/kg in the Randall-Selitto test against formalin-induced hyperalgesia and its potential opioid-like side effects.

Material and Methods. The study was performed on outbred male CDI and mice male CBA mice obtained from the Department of Experimental Biological Models at the E.D. Goldberg Research Institute of Pharmacology and Regenerative Medicine Tomsk NRMC. Songorine, a diterpene alkaloid of the atizine series, was administered orally to the animals at a previously established effective dose of 25 μg/kg. Tramadol (KRKA) at a dose of 20 mg/kg and ketorolac (Dr. Reddy´s Laboratories Ltd.) at a dose of 6 mg/kg were used as reference drugs. Antinociceptive activity was studied using the Randall-Selitto test with a Ugo Basile (Italy) analgesy-meter on a mechanical pain model, with and without formalin-induced hyperalgesia. To study the effect of songorine on the frequency of breathing in non-narcotized mice, the number of respiratory movements per minute was recorded after 5-fold administration of the alkaloid and the reference drug tramadol. The withdrawal syndrome was assessed using the non-selective opioid receptor antagonist naloxone (Sigma). The effect of the alkaloid on gastrointestinal smooth muscle was studied in the “charcoal meal” test.

Results. Songorine is antinociceptive effect in the Randall-Selitto test upon single administration is comparable to ketorolac and tramadol, but less prolonged than the latter. Songorine is pronounced analgesic activity in formalin-induced hyperalgesia suggests the possible involvement of TRPA1 receptors in its mechanism of action. The study of possible undesirable effects of the course per os administration of the diterpene alkaloid songorine at a dose of 25 μg/kg showed that it does not cause the development of respiratory depression, withdrawal syndrome and drug-induced obstipation.

Conclusion. In the Randall-Selitto test, TRPA1 receptor involvement in the antinociceptive activity of songorine was established against a background of formalin hyperalgesia. The diterpene alkaloid songorine at subchronic administration at a dose of 25 μg/kg does not show the side effects characteristic of morphine-like drugs.

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