Dihydrokoumine, a dual-target analgesic with reduced side effects isolated from a traditional Chinese medicine.

Introduction: Opioids are the most common antinociceptive drugs, but long-term administration causes serious adverse side effects. Gelsemium elegans Benth. is traditionally used as an analgesic agent and mainly contains indole alkaloids with structures different from those in common opioids, indicating distinct pharmacological properties. This work aims to find a new analgesic from Gelsemium elegans Benth. and evaluate it in vitro and in vivo.

Methods: Dihydrokoumine was purified from Gelsemium elegans Benth. Binding to mu opioid receptor (MOR), M3 receptor (M3R) and other 15 G protein-coupled receptors were evaluated in vitro combined with molecular docking analysis. Analgesic efficacy and side effects were measured in vivo using hot-plate, formalin paw, and rotarod tests in mice. Cytotoxicity, acute toxicity in mice and pharmacokinetics were assessed.

Results: A MOR agonist, dihydrokoumine, was first identified from Gelsemium elegans Benth. Further investigations showed that dihydrokoumine exhibited selective partial agonist action on the MOR and antagonist action on the M3R among other 15 GPCRs. In in vivo mouse models, dihydrokoumine could relieve acute pain and chronic inflammatory pain without drug tolerance and sedative side effects. Additionally, we observed a good safety profile and favorable pharmacokinetic properties.

Conclusion: A MOR partial agonist/M3R antagonist analgesic with reduced side effects was isolated from a traditional Chinese medicine. This study bestows dihydrokoumine as a new dual-target analgesic and as a potential lead compound in long-term pain management.