Investigating the Anti-nociceptive Mechanism of Cinnamaldehyde in the Formalin Test in Mice

Background and objectives: Cinnamaldehyde has shown analgesic and anti-inflammatory effects. At present little is known about mechanism of its anti-nociceptive activity and the role of serotonin, adrenergic, muscarinic, dopamine and opioid receptors as well as the nitric oxide signaling pathway in its anti-nociceptive effect has not been studied yet. The present study aimed to find out the mechanism of anti-nociceptive effect of cinnamaldehyde in formalin test. Methods: This experimental study involved 108 male Swiss mice. Cinnamaldehyde was administered intraperitoneally at doses of 25, 50, and 100 mg/kg, and its anti-nociceptive effect was evaluated in the formalin test. Various antagonists and enzyme inhibitors were used to investigate the role of different receptors and pathways, including yohimbine, prazosin, propranolol, cyproheptadine, ondansetron, atropine, sulpiride, L-NAME, methylene blue, naloxone, and glibenclamide. All drugs were given intraperitoneally 30 minutes before formalin injection (20 μL of 2.5% solution, v/v). Results: A dose of 100 mg/kg of cinnamaldehyde demonstrated the highest anti-nociceptive effect in both acute and chronic phases. Pretreatment of mice with the adrenergic receptor antagonists did not alter the anti-nociceptive effect of cinnamaldehyde. In the chronic phase of pain, a significant difference was observed between the cinnamaldehyde/atropine group and the cinnamaldehyde group. Also, the cinnamaldehyde+naloxone group showed a significant difference in the chronic phase compared to the cinnamaldehyde alone. Pretreatment with sulpiride partially inhibited cinnamaldehyde anti-nociception. Conclusions: The findings suggest that a variety of receptors including opioid, muscarinic and dopamine D2 receptors are involved in the anti-nociceptive effect of cinnamaldehyde.