Co-activation of ¦Ì- and ¦Ä-opioid receptors elicits tolerance to morphine-induced ventilatory depression via generation of peroxynitrite

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• 作者：Alex P. Young^a ; Ryan B. Gruber^b ; Joe F. Discala^b ; Walter J. May^a ; Dylan McLaughlin^a ; Lisa A. Palmer^a ; Stephen J. Lewis^a ; ^{sjl3s@virginia.edu}
• 关键词：Morphine ; Ventilatory depression ; Tolerance ; Opiate receptors ; Peroxynitrite ; Rats
• 刊名：Respiratory Physiology & Neurobiology
• 出版年：2013
• 出版时间：1 May, 2013
• 年：2013
• 卷：186
• 期：3
• 页码：255-264
• 全文大小：2907 K

文摘

We determined whether pretreatment with (1) the ¦Ì-/¦Ä-opioid receptor (¦Ì-/¦Ä-OR) antagonist, naloxone, (2) the ¦Ä_1,2-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 ¦Ì- and ¦Ä-ORs causes tolerance to the ventilatory depressant effects of morphine at least partly via the generation of peroxynitrite.