Effect of chronic pain on morphine-induced respiratory depression in mice.

Respiratory depression is the most well-known and dangerous side-effect of opioid analgesics. Clinical investigations have revealed that this opioid-induced respiratory depression is less severe in patients with chronic pain, but the mechanisms that underlie this phenomenon are unknown. Therefore, the present study was designed to examine the influence of chronic pain on morphine-induced respiratory depression. Respiration was detected by double-chamber, flow-through whole-body plethysmography. Respiratory frequency was dose-dependently and significantly decreased after morphine administration. This effect peaked at 30 min after administration and lasted 3 h. In contrast, tidal volume was increased. Minute volume was significantly decreased by morphine at a higher dose, but not a lower dose. In nerve-ligated mice, a morphine-induced decrease in respiratory frequency was observed, whereas the increase of tidal volume was more prominent. A decrease in minute volume was not observed in nerve-ligated mice. This attenuation of the morphine-induced decrease in minute volume in nerve-ligated mice was reversed by treatment with the serotonin (5-HT)4a receptor antagonist GR125487. Moreover, treatment with the 5-HT4 receptor agonist mosapride antagonized the morphine-induced decrease in minute volume, due to the enhancement of tidal volume. Finally, the expression of 5-HT4a receptor in the brainstem was enhanced in nerve-ligated mice compared to that in sham-operated mice. These results suggest that the decrease in morphine-induced respiratory depression under chronic pain is mediated by the enhancement of 5-HT4a receptor systems in the brainstem.