Tonantzitlolone B Modulates the Endogenous Opioid System to Promote Antinociception in Mice.

ABSTRACT

Tonantzitlolone B (TZL-B) is a diterpene isolated from the roots of Stillingia loranthacea. Its antinociceptive effects were investigated in male Swiss mice using the following models of pain formalin test, inflammation induced by Complete Freund's Adjuvant (CFA), tail flick test, and cold plate test. The influence of TZL-B on the opioid system was assessed in vivo, using opioid antagonists; in silico, investigating the chemical similarity among TZL-B and opioid agonists; and ex vivo, measuring preproenkephalin (PENK) gene expression in the spinal cord by RT-qPCR. TZL-B (10-1000 µg/kg) promoted antinociception in the four experimental models without impairing mice's motor function. TZL-B did not alter paw edema during CFA-induced inflammation. The antinociceptive effects of TZL-B in the tail flick and cold plate tests were diminished by the opioid antagonists naloxone (5 mg/kg), NOR-BNI (0.5 mg/kg), naltrindole (3 mg/kg), and CTOP (1 mg/kg), indicating the involvement of κ-, δ-, and µ-opioid receptors. TZL-B showed no significant chemical similarity to opioid agonists, but the treatment with TZL-B (1000 µg/kg) increased PENK gene expression in the spinal cord of mice. These data suggest that TZL-B promotes antinociception by enhancing the transcription of PENK, hence modulating the endogenous opioid system.