THE ANTINOCICEPTIVE EFFECTS OF THE TETRACYCLIC TRITERPENE EUPHOL IN INFLAMMATORY AND NEUROPATHIC PAIN MODELS: THE POTENTIAL ROLE OF PKC epsilon

摘要

Evidences suggest protein kinase C epsilon (PKC epsilon) activation is involved in both inflammatory and neuropathic pains. We have previously shown that tetracyclic triterpene euphol produces antinociception in different models of persistent pain, an action associated with its anti-inflammatory properties. Among these properties are the cannabinoid system activation and different PKC isozymes modulation. Herein, we sought to explore the potential role of PKC epsilon modulation on euphol antinociceptive effect, in inflammatory and neuropathic pain models, in rodents. Also, we investigated further mechanisms associated with euphol effects. Oral treatment with euphol (30 mg/kg) prevented the putative effect of PGE(2)-induced acute and persistent mechanical hypersensitivity in mice and rats, respectively. In the PGE(2)-induced acute mechanical hypersensitivity euphol promoted an inhibitory effect similar to a PKC epsilon inhibitor peptide. Likewise, in rats it prevented the mechanical hypersensitivity induced by a PKC epsilon activator. Conversely, euphol effectiveness was not observed in a cAMP/PKA-induced mechanical hypersensitivity in mice. Single (1 h prior) or repeated (twice daily during 3 or 13 days) treatments with euphol ameliorated painful peripheral neuropathy induced by paclitaxel and also the mechanical hypersensitivity induced by B16F10 melanoma cells injection, in mice. Additionally, in both inflammatory and neuropathic pain models, euphol consistently prevented PKC epsilon up-regulation, as well as, inhibited the up-regulation of PKC epsilon-activated intracellular pathways; namely nuclear factor-kappa B (NF-kappa B), cyclic AMP response element binding protein (CREB) and cyclooxygenase- 2 (COX-2). The present results suggest the antinociceptive effect on persistent pain caused by euphol is likely dependent on the inhibition of pro-inflammatory mediators modulated by PKC epsilon. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.