D-limonene epoxidation generates (+)-limonene epoxide, an understudied compound in the pharmacologically point of view. Herein, we investigated the anti-inflammatory and antinociceptive potentialities of (+)-limonene epoxide and suggested a mechanism of action. The anti-inflammatory potential was analyzed using agents to induce paw edema, permeability, and myeloperoxidase (MPO) activity. Pro-inflammatory cytokines and cell migration of peritoneal cells were also assessed. Antinociceptive effects were evaluated by writhing test induced by acetic acid, formalin, and hot plate assays and contribution of opioid pathways. Pretreated animals with (+)-limonene epoxide showed reduced carrageenan-induced paw edema in all doses (25, 50, and 75 mg/kg) (P < 0.05). At 75 mg/kg, it suppressed edema provoked by compound 48/80, histamine, prostaglandin E2, and serotonin and reduced permeability determined by Evans blue and MPO activity. It also reduced leukocytes, neutrophils, and IL-1β levels in the peritoneal cavity in comparison with carrageenan group (P < 0.05). (+)-Limonene epoxide diminished abdominal contortions induced by acetic acid (78.9%) and paw licking times in both 1 (41.8%) and 2 (51.5%) phases and a pretreatment with naloxone (3 mg/kg) reverted the antinociceptive action in morphine- and (+)-limonene epoxide-treated groups (P < 0.05). Additionally, it enlarged response times to the thermal stimulus after 60 and 90 min. In conclusion, (+)-limonene epoxide inhibited release/activity of inflammatory mediators, vascular permeability, migration of neutrophils and displayed systemic and peripheral analgesic-dependent effects of the opioid system.
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We wish to thank the Federal Brazilian agency “Conselho Nacional de Desenvolvimento Científico e Tecnológico” (CNPq) for financial support in the form of grants (#473167/2012-3) and fellowships.
All procedures were approved by the Committee on Animal Research at the UFPI (Process no. 091/2014) and followed the Brazilian (Colégio Brasileiro de Experimentação Animal—COBEA) and International Standards on the care and use of experimental animals (Directive 2010/63/EU of the European Parliament and of the Council).
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The authors declare that there are no conflicts of interest.
Rivelilson Mendes de Freitas (In Memoriam)
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de Almeida, A.A.C., Silva, R.O., Nicolau, L.A.D. et al. Physio-pharmacological Investigations About the Anti-inflammatory and Antinociceptive Efficacy of (+)-Limonene Epoxide. Inflammation 40, 511–522 (2017). https://doi.org/10.1007/s10753-016-0496-y
- semisynthetic compound
- cell migration inhibition
- cytokine reduction
- opioid system involvement