title: Ultramicronized palmitoylethanolamide reduces viscerovisceral hyperalgesia in a rat model of endometriosis plus ureteral calculosis: role of mast cells.
abstract: The effects of ultramicronized palmitoylethanolamide were evaluated on pain behaviours and markers of mast cell (MC) activity in a rat model of endometriosis plus ureteral calculosis (ENDO+STONE)-induced viscerovisceral hyperalgesia (VVH). Female Sprague-Dawley rats that underwent surgical induction of endometriosis were randomly assigned to receive active (ultramicronized palmitoylethanolamide 10 mg·kg(-1)·d(-1), orally) or placebo treatment for 25 days. At day 21, they underwent ureteral stone formation and were video-recorded till day 25 to evaluate ureteral and uterine pain behaviours. At autopsy (day 25), ureteral condition and number and diameter of endometrial cysts were evaluated. The following were then measured: number and percentage of degranulating MCs, number of vessels, chymase, nerve growth factor (NGF), vascular endothelial growth factor (VEGF), and Flk-1 (VEGF receptor) in cysts, and NGF in dorsal root ganglia (DRG). Ultramicronized palmitoylethanolamide-treated vs placebo-treated rats showed significantly lower number, duration and complexity of ureteral crises, shorter duration of uterine pain, and smaller cyst diameter (0.0001 < P < 0.004); a significantly higher percentage of expelled stones (P < 0.0001); significantly lower MC number (P < 0.01), vessel number (P < 0.01), chymase (P < 0.05), NGF (P < 0.05), VEGF (P < 0.01), and Flk-1 (P < 0.01) expression in cysts and NGF expression in DRG (P < 0.01). In all animals, the global duration of ureteral crises correlated linearly and directly with cyst diameter, MC number and chymase in cysts, and NGF in cysts and DRG (0.02 < P < 0.0002). Ultramicronized palmitoylethanolamide significantly reduces VVH from ENDO+STONE, probably by modulating MC expression/activity in cysts, thus reducing central sensitization due to noxious signals from endometriotic lesions. The results suggest potential utility of the compound for VVH in clinics.
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Naples, Italy Pathophysiology of Pain Laboratory, Ce.S.I., "G. D'Annunzio" University Foundation, and Geriatrics Clinic, Department of Medicine and Science of Aging, University of Chieti, Chieti, Italy Institute of Surgical Pathology, University of Chieti, Chieti, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Iuvone
authors.forename: Giannapia
authors.initials: G
authors.lastname: Affaitati
authors.forename: Daniele
authors.initials: D
authors.lastname: De Filippis
authors.forename: Mariangela
authors.initials: M
authors.lastname: Lopopolo
authors.forename: Gianluca
authors.initials: G
authors.lastname: Grassia
authors.forename: Domenico
authors.initials: D
authors.lastname: Lapenna
authors.forename: Luana
authors.initials: L
authors.lastname: Negro
authors.forename: Raffaele
authors.initials: R
authors.lastname: Costantini
authors.forename: Massimo
authors.initials: M
authors.lastname: Vaia
authors.forename: Francesco
authors.initials: F
authors.lastname: Cipollone
authors.forename: Armando
authors.initials: A
authors.lastname: Ialenti
authors.forename: Maria Adele
authors.initials: MA
authors.lastname: Giamberardino
mesh_terms: D000577:Amides; D000818:Animals; D053818:Chymases / Q000378:metabolism; D004195:Disease Models, Animal; D004715:Endometriosis / Q000150:complications* / Q000378:metabolism; D004983:Ethanolamines / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006930:Hyperalgesia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism; D010169:Palmitic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D014514:Ureteral Calculi / Q000150:complications* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000577:Amides; D004983:Ethanolamines; D010169:Palmitic Acids; D042461:Vascular Endothelial Growth Factor A; C005958:palmidrol; D020932:Nerve Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D053818:Chymases