title: Modification of morphine analgesia and tolerance by flumazenil in male and female rats.
abstract: This study assessed the effect of the central benzodiazepine receptor antagonist, 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester (flumazenil), on morphine-induced analgesia, locomotor effects, and development of tolerance in rats. The thermally evoked pain (tail flick) response was determined after acute and chronic intraperitoneal (i.p.) administration of morphine and flumazenil, alone and in combination. In acute studies, flumazenil induced weak analgesia unrelated to dose and sex, whereas morphine-induced analgesia was dependent on both dose and sex (male>female). Flumazenil dose-dependently enhanced the analgesic effect of morphine in female but not in male rats. Isobolographic analysis suggested synergism between flumazenil and morphine in female rats, but antagonism in male rats. Flumazenil-induced locomotor changes (alone and with morphine) were related to sex but not dose. Chronic coadministration of flumazenil with morphine enhanced analgesia and attenuated tolerance development in female rats. The findings suggest a possible role for flumazenil as an adjunct with opioids in acute and chronic pain therapy.
authors.affiliation: Department of Anesthesiology, University of Kentucky College of Medicine, Chandler Medical Center, 800 Rose Street, Lexington, KY 40536-0293, USA. jrjr@uky.edu
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Holtman
authors.forename: Jewell W
authors.initials: JW
authors.lastname: Sloan
authors.forename: Xin
authors.initials: X
authors.lastname: Jing
authors.forename: Elzbieta P
authors.initials: EP
authors.lastname: Wala
mesh_terms: D000698:Analgesia / Q000379:methods*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D004359:Drug Therapy, Combination; D004361:Drug Tolerance / Q000502:physiology*; D005260:Female; D005442:Flumazenil / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics
chemical_list: D005442:Flumazenil; D009020:Morphine