L-Malic acid from Cissus gongylodes induces cannabinoid-mediated antinociception in mice

Cissus gongylodes (Baker) Planch is a vine found in South America. Primarily used as food, its leaves and branches are consumed raw, cooked, roasted or flour by indigenous people (Kayapó, Kulina and Apinayé tribes) as muscle relaxant, to treat rheumatism, disinfection, gastritis, diabetes, kidney stones, joint pain and stomach ache.

This study provides scientific validation for the traditional use of C. gongylodes and opens new perspectives for L-malic acid as a potential analgesic for acute pain.

The extract was evaluated in a model of nociceptive and inflammatory pain (formalin test) in mice, and L-malic acid was assessed in a PGE₂-induced hyperalgesia model.

C. gongylodes extract significantly reduced licking time in both phases of the formalin test, without sedative effects. Pure L-malic acid (L-enantiomer) exhibited a potent peripheral antinociceptive effect, whereas the racemic form (DL-malic acid) was ineffective, highlighting the importance of chirality. The antinociception mediated by L-malic acid was partially antagonized by AM251, a selective CB₁ receptor antagonist, but not by AM630 (a CB₂ antagonist) or naloxone (an opioid antagonist). Furthermore, URB597, an inhibitor of FAAH (which degrades anandamide, AEA), potentiated the effect of L-malic acid, suggesting the involvement of AEA.

It provides scientific validation for the traditional use of C. gongylodes and identifies L-malic acid as a constituent with notable antinociceptive properties, suggesting its potential as a lead compound for the development of novel therapeutics that act via the endocannabinoid system.