Incarvillateine produces antinociceptive and motor suppressive effects via adenosine receptor activation

• Published in: PloS one 2019-06, Vol.14 (6), p.e0218619-e0218619
• Main Authors: Kim, Jinwoo, Bogdan, Diane M, Elmes, Matthew W, Awwa, Monaf, Yan, Su, Che, Joyce, Lee, Garam, Deutsch, Dale G, Rizzo, Robert C, Kaczocha, Martin, Ojima, Iwao
• Format: Article
• Language: English
• Subjects: Adenosine; Adenosine A2 Receptor Agonists - pharmacology; Adenosine A2 Receptor Antagonists - pharmacology; Affinity; Alkaloids - pharmacology; Analgesia; Analgesics; Analgesics - pharmacology; Anesthesiology; Animal models; Animals; Backup software; Biochemistry; Biology; Biology and Life Sciences; Care and treatment; Chemistry; Chronic pain; Costs; Drug dosages; Economic aspects; Fatty acid-binding protein; Fatty Acid-Binding Proteins - metabolism; Fatty acids; Health care costs; Humans; Inhibition; Isoforms; Kim, Diane; Locomotion - drug effects; Locomotor activity; Male; Medical research; Medicine and Health Sciences; Metabolites; Mice; Monoterpenes - pharmacology; Narcotics; Natural products; Nociception - drug effects; Nonsteroidal anti-inflammatory drugs; Pain; Pain perception; Protein Binding; Proteins; R&D; Receptor mechanisms; Receptors, Adenosine A2 - metabolism; Research & development; Research and Analysis Methods; Theobromine - analogs & derivatives; Theobromine - pharmacology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0218619

(-)-Incarvillateine (INCA) is a natural product that has garnered attention due to its purported analgesic effects and historical use as a pain reliever in China. α-Truxillic acid monoesters (TAMEs) constitute a class of inhibitors targeting fatty acid binding protein 5 (FABP5), whose inhibition produces analgesia in animal models. The structural similarity between INCA and TAMEs motivated us to assess whether INCA exerts its antinociceptive effects via FABP inhibition. We found that, in contrast to TAMEs, INCA did not exhibit meaningful binding affinities toward four human FABP isoforms (FABP3, FABP4, FABP5 and FABP7) in vitro. INCA-TAME, a putative monoester metabolite of INCA that closely resembles TAMEs also lacked affinity for FABPs. Administration of INCA to mice produced potent antinociceptive effects while INCA-TAME was without effect. Surprisingly, INCA also potently suppressed locomotor activity at the same dose that produces antinociception. The motor suppressive effects of INCA were reversed by the adenosine A2 receptor antagonist 3,7-dimethyl-1-propargylxanthine. Collectively, our results indicate that INCA and INCA-TAME do not inhibit FABPs and that INCA exerts potent antinociceptive and motor suppressive effects at equivalent doses. Therefore, the observed antinociceptive effects of INCA should be interpreted with caution.