title: Delay of morphine tolerance by palmitoylethanolamide.
abstract: In spite of the potency and efficacy of morphine, its clinical application for chronic persistent pain is limited by the development of tolerance to the antinociceptive effect. The cellular and molecular mechanisms underlying morphine tolerance are complex and still unclear. Recently, the activation of glial cells and the release of glia-derived proinflammatory mediators have been suggested to play a role in the phenomenon. N-palmitoylethanolamine (PEA) is an endogenous compound with antinociceptive effects able to reduce the glial activation. On this basis, 30 mg kg(-1) PEA was subcutaneously daily administered in morphine treated rats (10 mg kg(-1) intraperitoneally, daily). PEA treatment significantly attenuated the development of tolerance doubling the number of days of morphine antinociceptive efficacy in comparison to the vehicle + morphine group. PEA prevented both microglia and astrocyte cell number increase induced by morphine in the dorsal horn; on the contrary, the morphine-dependent increase of spinal TNF-α levels was not modified by PEA. Nevertheless, the immunohistochemical analysis revealed significantly higher TNF-α immunoreactivity in astrocytes of PEA-protected rats suggesting a PEA-mediated decrease of cytokine release from astrocyte. PEA intervenes in the nervous alterations that lead to the lack of morphine antinociceptive effects; a possible application of this endogenous compound in opioid-based therapies is suggested.
authors: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino-Neurofarba-Sezione di Farmacologia e Tossicologia, Università di Firenze, Viale Pieraccini 6, 50139 Florence, Italy.
authors: Lorenzo
authors: L
authors: Di Cesare Mannelli
authors: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino-Neurofarba-Sezione di Farmacologia e Tossicologia, Università di Firenze, Viale Pieraccini 6, 50139 Florence, Italy.
authors: Francesca
authors: F
authors: Corti
authors: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino-Neurofarba-Sezione di Farmacologia e Tossicologia, Università di Firenze, Viale Pieraccini 6, 50139 Florence, Italy.
authors: Laura
authors: L
authors: Micheli
authors: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino-Neurofarba-Sezione di Farmacologia e Tossicologia, Università di Firenze, Viale Pieraccini 6, 50139 Florence, Italy.
authors: Matteo
authors: M
authors: Zanardelli
authors: Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino-Neurofarba-Sezione di Farmacologia e Tossicologia, Università di Firenze, Viale Pieraccini 6, 50139 Florence, Italy.
authors: Carla
authors: C
authors: Ghelardini
mesh_terms: D000577:Amides; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D059350:Chronic Pain / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004351:Drug Resistance / Q000187:drug effects*; D004983:Ethanolamines / Q000494:pharmacology*; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D010169:Palmitic Acids / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000577:Amides; D000700:Analgesics; D004983:Ethanolamines; D010169:Palmitic Acids; D014409:Tumor Necrosis Factor-alpha; C005958:palmidrol; D009020:Morphine