title: Ellagic acid enhances morphine analgesia and attenuates the development of morphine tolerance and dependence in mice.
abstract: According to our previous study, ellagic acid has both dose-related central and peripheral antinociceptive effect through the opioidergic and l-arginine-NO-cGMP-ATP sensitive K(+) channel pathways. In the present study, the systemic antinociceptive effects of ellagic acid in animal models of pain, and functional interactions between ellagic acid and morphine in terms of analgesia, tolerance and dependence were investigated. Ellagic acid (1-30mg/kg; i.p.) showed significant and dose-dependent antinociceptive effects in the acetic acid-induced writhing test. Intraperitoneal ellagic acid acutely interacted with morphine analgesia in a synergistic manner in this assay. Ellagic acid (1-10mg/kg; i.p.) also exerted analgesic activity in the hot-plate test. Pre-treatment with naloxone (1mg/kg; i.p.) significantly reversed ellagic acid, morphine as well as ellagic acid-morphine combination-induced antinociceptin in these two tests. More importantly, when co-administered with morphine, ellagic acid (1-10mg/kg) effectively blocked the development of tolerance to morphine analgesia in the hot-plate test. Likewise, ellagic acid dose-dependently prevented naloxone-precipitated withdrawal signs including jumping and weight loss. Ellagic acid treatment (1-30mg/kg; i.p.) had no significant effect on the locomotion activity of animals using open-field task. Therefore, these results showed that ellagic acid has notable systemic antinociceptive activity for both tonic and phasic pain models. Altogether, ellagic acid might be used in pain relief alone or in combination with opioid drugs because of enhancing morphine analgesia and preventing morphine-induced tolerance to analgesia and dependence.
authors.affiliation: Department of Pharmacology, School of Medicine, Physiology and Atherosclerosis Research Centers, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. Electronic address: mansouri_smt@yahoo.com.
authors.forename: Mohammad Taghi
authors.initials: MT
authors.lastname: Mansouri
authors.affiliation: Department of Pharmacology, School of Medicine, Pain and Physiology Research Centers, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
authors.forename: Bahareh
authors.initials: B
authors.lastname: Naghizadeh
authors.affiliation: Department of Pharmacology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
authors.forename: Behnam
authors.initials: B
authors.lastname: Ghorbanzadeh
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004361:Drug Tolerance; D004610:Ellagic Acid / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage*; D009021:Morphine Dependence / Q000517:prevention & control* / Q000523:psychology; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods
chemical_list: D000701:Analgesics, Opioid; D004610:Ellagic Acid; D009020:Morphine
keywords: Antinociceptive; Dependence; Ellagic acid; Isobolography; Morphine; Tolerance