title: Olea Europea-derived phenolic products attenuate antinociceptive morphine tolerance: an innovative strategic approach to treat cancer pain.
abstract: Morphine and related opioid drugs are currently the major drugs for severe pain. Their clinical utility is limited in the management of severe cancer pain due to the rapid development of tolerance. Restoring opioid efficacy is therefore of great clinical importance. A great body of evidence suggests the key role of free radicals and posttranslational modulation in the development of tolerance to the analgesic activity of morphine. Epidemiological studies have shown a relationship between the Mediterranean diet and a reduced incidence of pathologies such as coronary heart disease and cancer. A central hallmark of this diet is the high consumption of virgin olive oil as the main source of fat which contains antioxidant components in the non-saponifiable fraction, including phenolic compounds absent in seed oils. Here, we show that in a rodent model of opiate tolerance, removal of the free radicals with phenolic compounds of olive oil such as hydroxytyrosol and oleuropein reinstates the analgesic action of morphine. Chronic injection of morphine in mice led to the development of tolerance and this was associated with increased nitrotyrosin and malondialdehyde (MDA) formation together with nitration and deactivation of MnSOD in the spinal cord. Removal of free radicals by hydroxytyrosol and oleuropein blocked morphine tolerance by inhibiting nitration and MDA formation and replacing the MnSOD activity. The phenolic fraction of virgin olive oil exerts antioxidant activities in vivo and free radicals generation occurring during chronic morphine administration play a crucial role in the development of opioid tolerance. Our data suggest novel therapeutic approach in the management of chronic cancer pain, in particular for those patients who require long-term opioid treatment for pain relief without development of tolerance.
authors.affiliation: Department of Health Sciences, University Magna Graecia, Germaneto, Catanzaro, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Muscoli
authors.affiliation: Department of Health Sciences, University Magna Graecia, Germaneto, Catanzaro, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Lauro
authors.forename: C
authors.initials: C
authors.lastname: Dagostino
authors.affiliation: Department of Health Sciences, University Magna Graecia, Germaneto, Catanzaro, Italy.
authors.forename: C
authors.initials: C
authors.lastname: D'Agostino
authors.affiliation: Department of Health Sciences, University Magna Graecia, Germaneto, Catanzaro, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Ilari
authors.affiliation: Department of Health Sciences, University Magna Graecia, Germaneto, Catanzaro, Italy.
authors.forename: L A
authors.initials: LA
authors.lastname: Giancotti
authors.affiliation: Department of Health Sciences, University Magna Graecia, Germaneto, Catanzaro, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Gliozzi
authors.affiliation: Department of Health Sciences, University Magna Graecia, Germaneto, Catanzaro, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Costa
authors.affiliation: Department of Health Sciences, University Magna Graecia, Germaneto, Catanzaro, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Carresi
authors.affiliation: Department of Health Sciences, University Magna Graecia, Germaneto, Catanzaro, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Musolino
authors.affiliation: Department of Health Sciences, University Magna Graecia, Germaneto, Catanzaro, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Casale
authors.affiliation: Department of Health Sciences, University Magna Graecia, Germaneto, Catanzaro, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Ventrice
authors.forename: M
authors.initials: M
authors.lastname: Oliverio
authors.affiliation: Department of Health Sciences, University Magna Graecia, Germaneto, Catanzaro, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Oliverio
authors.affiliation: Department of Health Sciences, University Magna Graecia, Germaneto, Catanzaro, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Palma
authors.forename: S
authors.initials: S
authors.lastname: Nisticò
authors.affiliation: Department of Health Sciences, University Magna Graecia, Germaneto, Catanzaro, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Nistico'
authors.affiliation: Department of Health Sciences, University Magna Graecia, Germaneto, Catanzaro, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Procopio
authors.forename: M
authors.initials: M
authors.lastname: Rizzo
authors.affiliation: Department of Health Sciences, University Magna Graecia, Germaneto, Catanzaro, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Mollace
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D004361:Drug Tolerance; D057888:Iridoid Glucosides; D039823:Iridoids; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D009369:Neoplasms / Q000503:physiopathology*; D031658:Olea / Q000737:chemistry*; D018384:Oxidative Stress; D010148:Intractable Pain / Q000188:drug therapy*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011714:Pyrans / Q000627:therapeutic use*; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D000975:Antioxidants; D057888:Iridoid Glucosides; D039823:Iridoids; D011714:Pyrans; C005975:3,4-dihydroxyphenylethanol; C002769:oleuropein; D009020:Morphine; D013482:Superoxide Dismutase; D010626:Phenylethyl Alcohol