title: Micronized/ultramicronized palmitoylethanolamide displays superior oral efficacy compared to nonmicronized palmitoylethanolamide in a rat model of inflammatory pain.
abstract: BACKGROUND
  The fatty acid amide palmitoylethanolamide (PEA) has been studied extensively for its anti-inflammatory and neuroprotective actions. The lipidic nature and large particle size of PEA in the native state may limit its solubility and bioavailability when given orally, however. Micronized formulations of a drug enhance its rate of dissolution and reduce variability of absorption when orally administered. The present study was thus designed to evaluate the oral anti-inflammatory efficacy of micronized/ultramicronized versus nonmicronized PEA formulations.
  
  
  METHODS
  Micronized/ultramicronized PEA was produced by the air-jet milling technique, and the various PEA preparations were subjected to physicochemical characterization to determine particle size distribution and purity. Each PEA formulation was then assessed for its anti-inflammatory effects when given orally in the carrageenan-induced rat paw model of inflammation, a well-established paradigm of edema formation and thermal hyperalgesia.
  
  
  RESULTS
  Intraplantar injection of carrageenan into the right hind paw led to a marked accumulation of infiltrating inflammatory cells and increased myeloperoxidase activity. Both parameters were significantly decreased by orally given micronized PEA (PEA-m; 10 mg/kg) or ultramicronized PEA (PEA-um; 10 mg/kg), but not nonmicronized PeaPure (10 mg/kg). Further, carrageenan-induced paw edema and thermal hyperalgesia were markedly and significantly reduced by oral treatment with micronized PEA-m and ultramicronized PEA-um at each time point compared to nonmicronized PeaPure. However, when given by the intraperitoneal route, all PEA formulations proved effective.
  
  
  CONCLUSIONS
  These findings illustrate the superior anti-inflammatory action exerted by orally administered, micronized PEA-m and ultramicronized PEA-um, versus that of nonmicronized PeaPure, in the rat paw carrageenan model of inflammatory pain.
authors.forename: Daniela
authors.initials: D
authors.lastname: Impellizzeri
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bruschetta
authors.forename: Marika
authors.initials: M
authors.lastname: Cordaro
authors.forename: Rosalia
authors.initials: R
authors.lastname: Crupi
authors.forename: Rosalba
authors.initials: R
authors.lastname: Siracusa
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.affiliation: Department of Biological and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, no 31, Messina 98166, Italy. salvator@unime.it.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
mesh_terms: D000284:Administration, Oral; D000577:Amides; D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D002351:Carrageenan / Q000633:toxicity; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004487:Edema / Q000139:chemically induced; D004983:Ethanolamines / Q000627:therapeutic use*; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D007249:Inflammation / Q000139:chemically induced / Q000150:complications*; D008297:Male; D008855:Microscopy, Electron, Scanning; D010146:Pain / Q000188:drug therapy* / Q000209:etiology*; D010169:Palmitic Acids / Q000627:therapeutic use*; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000577:Amides; D000700:Analgesics; D004983:Ethanolamines; D010169:Palmitic Acids; C005958:palmidrol; D002351:Carrageenan; D009195:Peroxidase