Morphine is responsible for severe poisonings in chronically treated patients. We hypothesize that toxicity could be related to the development of weaker tolerance for morphine-induced deleterious respiratory effects in comparison to analgesic effects. Our objectives were to compare tolerance to both effects in mice and investigate possible mechanisms for such possible differences. Tolerance to morphine-induced analgesia and respiratory effects was assessed using hot plate response latencies and plethysmography, respectively. Mechanisms of tolerance were investigated using binding studies to mu-opioid receptors (MOR) and adenylate cyclase (AC) activity measurement in homogenates of cell membranes from the periaqueductal gray region (PAG) and brainstem. Morphine (2.5 mg/kg) was responsible for analgesia with significant increase in inspiratory time. Acute tolerance to analgesia (p<0.01) and effects on respiratory frequency (p<0.05) was observed in mice pre-treated with 100 mg/kg morphine in comparison to saline. Following repetitive administration (2.5 mg/kg/day during 10 days), we observed a 13-fold increase in the effective dose-50% (ED₅₀) of morphine-induced analgesia in comparison to a 2- or 4-fold increase in the ED₅₀ of its related increase in inspiratory time determined in air and 4% CO₂, respectively. No significant alteration in MOR expression was observed in either PAG or brainstem following repeated morphine administration. However, in PAG, in contrast to brainstem, superactivation of AC was observed in morphine-treated mice in comparison to controls (p<0.05). In conclusion, tolerance to morphine-induced respiratory effects is much more limited than tolerance to its analgesic effects in repeatedly morphine-treated mice. The difference in morphine-induced AC activation between the brainstem and the PAG contributes to the observed difference in tolerance between both morphine effects.
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