Stefania Petrosino 1 , 2 , Marika Cordaro 3 , Roberta Verde 1 , Aniello Schiano Moriello 1 , 2 , Gabriele Marcolongo 2 , Carlo Schievano 4 , Rosalba Siracusa 3 , Fabiana Piscitelli 1 , Alessio F. Peritore 1 , Rosalia Crupi 3 , Daniela Impellizzeri 3 , Emanuela Esposito 3 , Salvatore Cuzzocrea 3 , Vincenzo Di Marzo 1
20 March 2018
Palmitoylethanolamide (PEA) is a pleiotropic lipid mediator with established anti-inflammatory and anti-hyperalgesic activity. Ultramicronized PEA (PEA-um) has superior oral efficacy compared to naïve (non-micronized) PEA. The aim of the present study was two-fold: (1) to evaluate whether oral PEA-um has greater absorbability compared to naïve PEA, and its ability to reach peripheral and central tissues under healthy and local inflammatory conditions (carrageenan paw edema); (2) to better characterize the molecular pathways involved in PEA-um action, particularly at the spinal level. Rats were dosed with 30 mg/kg of [ 13C] 4-PEA-um or naïve [ 13C] 4-PEA by oral gavage, and [ 13C] 4-PEA levels quantified, as a function of time, by liquid chromatography/atmospheric pressure chemical ionization/mass spectrometry. Overall plasma levels were higher in both healthy and carrageenan-injected rats administered [ 13C] 4-PEA-um as compared to those receiving naïve [ 13C] 4-PEA, indicating the greater absorbability of PEA-um. Furthermore, carrageenan injection markedly favored an increase in levels of [ 13C] 4-PEA in plasma, paw and spinal cord. Oral treatment of carrageenan-injected rats with PEA-um (10 mg/kg) confirmed beneficial peripheral effects on paw inflammation, thermal hyperalgesia and tissue damage. Notably, PEA-um down-regulated distinct spinal inflammatory and oxidative pathways. These last findings instruct on spinal mechanisms involved in the anti-hyperalgesic effect of PEA-um in inflammatory pain.