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 δ 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 μ- and δ-ORs causes tolerance to the ventilatory depressant effects of morphine at least partly via the generation of peroxynitrite.