Activation of Peripheral Cannabinoid Receptors Synergizes the Effect of Systemic Ibuprofen in a Pain Model in Rat

Abstract

Pharmacological synergism is a current strategy for the treatment of pain. However, few studies have been explored to provide evidence of the possible synergism between a non-steroidal anti-inflammatory drug (NSAID) and a cannabinoid agonist, in order to establish which combinations might be effective to manage pain. The aim of this study was to explore the synergism between ibuprofen (IBU) and the synthetic cannabinoid WIN 55,212-2 (WIN) to improve pain relief by analyzing the degree of participation of the CB1 and CB2 cannabinoid receptors in the possible antinociceptive synergism using an experimental model of pain in Wistar rats. First, the effective dose thirty (ED30) of IBU (10, 40, 80, and 160 mg/kg, subcutaneous) and WIN (3, 10, and 30 µg/p, intraplantar) were evaluated in the formalin test. Then, the constant ratio method was used to calculate the doses of IBU and WIN to be administered in combination (COMB) to determine the possible synergism using the isobolographic method. The participation of the CB1 and CB2 receptors was explored in the presence of the antagonists AM281 and AM630, respectively. The combination of these drugs produced a supra-additive response with an interaction index of 0.13. In addition, AM281 and AM630 antagonists reversed the synergistic effect in 45% and 76%, respectively, suggesting that both cannabinoid receptors are involved in this synergism, with peripheral receptors playing a relevant role. In conclusion, the combination of IBU + WIN synergism is mainly mediated by the participation of the CB2 receptor, which can be a good option for the better management of pain relief.

Cannabinoid Analgesia in Postoperative Pain Management: From Molecular Mechanisms to Clinical Reality

“…Preclinical research suggests that eCBs and synthetic cannabinoids exhibit synergistic antinociceptive effects when combined with common NSAIDs [ 372 , 373 , 374 , 375 , 376 ]. This finding holds promise for the development of novel pain management strategies.…”

Combination Drug Therapy for the Management of Chronic Neuropathic Pain

“…In another study, systemic administration of WIN 55,212-2, a potent non-selective cannabinoid receptor agonist, and ketorolac produced an additive analgesic effect in the acetic acid-induced writhing test (inflammatory visceral pain), but no effect or added benefit of ketorolac in addition to WIN 55,212-2 in the thermal tail flick test was observed [122]. Combination therapy with WIN 55,212-2 and ibuprofen also exhibited synergistic efficacy in the formalin-induced model of inflammatory pain in rats [123].…”