Nicorandil repurposing in orofacial pain: preclinical findings in adult zebrafish

Abstract This study investigated the orofacial antinociceptive activity of nicorandil in adult zebrafish and explored the involvement of TRP channels in this effect. Nicorandil, a known antianginal drug, reduced nociceptive behaviors induced by capsaicin (TRPV1 agonist), cinnamaldehyde (TRPA1 agonist), and menthol (TRPM8 agonist) without altering the locomotor activity of the zebrafish. Pre-treatment with specific TRPA1 and TRPV1 antagonists prevented the antinociceptive effects of nicorandil, indicating its action on these channels. Molecular docking studies supported these findings, demonstrating high chemical affinity and specific binding of nicorandil to the TRPV1 and TRPA1 channels, leading to stabilization and reduced biological activity of these channels. In contrast, the antinociceptive effect of nicorandil on menthol-induced nociception was not affected by a TRPM8 antagonist, suggesting that TRPM8 modulation is not involved in nicorandil’s mechanism of action. The study highlights the potential of nicorandil as an analgesic through its interaction with TRPV1 and TRPA1 channels, providing a molecular basis for repositioning nicorandil as an effective analgesic drug.