title: Co-activation of μ- and δ-opioid receptors elicits tolerance to morphine-induced ventilatory depression via generation of peroxynitrite.
abstract: We determined whether pretreatment with (1) the μ-/δ-opioid receptor (μ-/δ-OR) antagonist, naloxone, (2) the δ1,2-OR antagonist, naltrindole, or (3) the peroxynitrite scavenger, d-penicillamine, affects the development of tolerance to the ventilatory depressant effects of morphine in rats. The injection of morphine in vehicle-pretreated rats decreased minute ventilation predominantly via decreases in tidal volume. Pretreatment with naloxone blunted the responses to morphine whereas pretreatment with naltrindole or d-penicillamine did not. A second injection of morphine, given one day later, elicited markedly smaller responses in vehicle rats whereas it elicited pronounced ventilatory depression in rats that were pretreated with naloxone, naltrindole or d-penicillamine (prior to morphine) the day before. Moreover, the ventilatory responses elicited by subsequent exposure to a hypoxic-hypercapnic challenge were markedly depressed in naloxone- or d-penicillamine-pretreated rats compared to vehicle-pretreated rats. These findings suggest that activation of μ- and δ-ORs causes tolerance to the ventilatory depressant effects of morphine at least partly via the generation of peroxynitrite.
authors.affiliation: Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Alex P
authors.initials: AP
authors.lastname: Young
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Gruber
authors.forename: Joe F
authors.initials: JF
authors.lastname: Discala
authors.forename: Walter J
authors.initials: WJ
authors.lastname: May
authors.forename: Dylan
authors.initials: D
authors.lastname: McLaughlin
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Palmer
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lewis
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000931:Antidotes / Q000494:pharmacology; D004361:Drug Tolerance; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D010396:Penicillamine / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D012131:Respiratory Insufficiency / Q000139:chemically induced* / Q000378:metabolism; D013997:Time Factors
chemical_list: D000931:Antidotes; D009292:Narcotic Antagonists; D009294:Narcotics; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D030421:Peroxynitrous Acid; D009270:Naloxone; D009271:Naltrexone; D009020:Morphine; C055382:naltrindole; D010396:Penicillamine