Euphol, a novel cannabinoid agonist, prevents inflammatory and neuropathic persistent pain in rodents

The cannabinoids have been considered a relevant target for pain management. Persistent pains, related to inflammatory and neuropathic states, are prevalent and debilitating diseases, which remain without safe and adequate treatments. Inflammatory and neuropathic pain was induced by carrageenan, CFA, PSNL, cancer/chemotherapeutic agent, PGE2 and PKCε agonist. Pro-inflammatory mediators were measured by immunohistochemistry, enzyme-linked immunosorbent assay (ELISA) and real time-PCR. Here, we reported that euphol exhibited pronounced and long-lasting oral analgesia in several rodent behaviour models of inflammatory and neuropathic persistent pain. These effects were markedly blocked by CB1 or CB2-selective antagonists and oligonucleotide antisense. Of note, cannabinoid receptor binding experiments showed that euphol directly bound with high affinity to both CB1 (Ki=71.090 nM) and CB2 (Ki=0.037 nM), being 1,880-fold more selective for CB2 receptors. Euphol at similar dose inhibited the levels/mRNA expression of pro-inflammatory mediators, as well the myeloperoxidase activity. Our data indicate that euphol activate transcription factors, such as PPAR-γ and inhibiting both NF-κB and CREB activation, associated with the inhibition of COX-2 and PKCε expression, either at the spinal cord or the dorsal root ganglia level. Of relevance, euphol did not display significant central nervous system alterations. Acute toxicological studies carried out in rodents showed that euphol is safe and well tolerate. Therefore, euphol represents a novel orally active and safe natural analgesic for the management of inflammatory and neuropathic pain states.

Keywords: Euphol, cannabinoid receptors, pain, inflammation

Acknowledgement: This work was supported by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), the Programa de Apoio aos Núcleos de Excelência (PRONEX), and the Fundação de Apoio a Pesquisa do Estado de Santa Catarina (FAPESC), all of Brazil. R.C.D., K.A.B.S.S., A.F.B., A.F.P. and R.M. are Ph.D. students in pharmacology receiving grants from CNPq.