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.