Citral exerts a more pronounced antinociceptive effect in obese adult male C57BL/6J mice mediated through the CB2 receptor

BACKGROUND: Obesity is a prevalent chronic disease strongly associated with pain, primarily due to low-grade systemic inflammation that sensitizes nociceptive neurons. OBJECTIVE: To evaluate the effects of citral, an acyclic monoterpene, present in essential oils such as Cymbopogon citratus (lemongrass), on nociception in obese mice and identify the mechanisms involved. METHODS: Adult male C57BL/6J mice (n=232) were fed a standard diet (SD) or a high-fat diet (HFD) for 12 weeks. Metabolic alterations were confirmed using an oral glucose tolerance test. Nociception was assessed using the formalin test to evaluate both neurogenic (phase I) and inflammatory (phase II) pain. Citral (100 or 300 mg/kg) was orally administered. Carrageenan-induced paw edema was utilized to investigate anti-inflammatory properties. Antagonists for 5-HT2A (ketanserin, 1 mg/kg, i.p.) and CB2 (AM630, 1 mg/kg, i.p.) receptors were used. The vehicle group received 1% Tween 80 (10 mL/kg, orally). Statistical significance was set at p < 0.05. RESULTS: HFD-fed mice developed obesity, hyperglycemia, and increased thermal sensitivity. Citral (300 mg/kg) significantly reduced nociception in both phases of the formalin test in SD and HFD mice, with a greater effect in the HFD group. CB2 receptor antagonism reversed the antinociceptive effects of citral in both phases of the formalin test, whereas 5-HT2A antagonism produced no change. LPS did not influence citral-induced antinociception only in obese mice, and citral showed no effect in the hot-plate test. CONCLUSION: Citral exerts antinociceptive effects in both eutrophic and obese mice, with enhanced efficacy in obese mice. Its action is mediated, at least in part, by CB2 receptor modulation, which reduces both neurogenic and inflammatory pain. These findings suggest that citral is a potential therapeutic candidate for pain management in obesity-related conditions.