Reducing the side effects of
pain treatment is one of the most important strategies for improving the quality of life of
cancer patients. However, little is known about the mechanisms that underlie these side effects, especially
constipation induced by
opioid receptor agonists; i.e., do they involve
naloxonazine-sensitive versus -insensitive sites or central-versus-peripheral μ-
opioid receptors? The present study was designed to investigate the mechanisms of μ-
opioid receptor agonist-induced
constipation (i.e., the inhibition of gastrointestinal transit and colonic expulsion) that are antagonized by the peripherally restricted
opioid receptor antagonist naloxone methiodide and
naloxonazine in mice.
Naloxonazine attenuated the
fentanyl-induced inhibition of gastrointestinal transit more potently than the inhibition induced by
morphine or
oxycodone.
Naloxone methiodide suppressed the
oxycodone-induced inhibition of gastrointestinal transit more potently than the inhibition induced by
morphine, indicating that μ-
opioid receptor agonists induce the inhibition of gastrointestinal transit through different mechanisms. Furthermore, we found that the route of administration (intracerebroventricular, intrathecally, and/or intraperitoneally) of
naloxone methiodide differentially influenced the suppressive effect on the inhibition of colorectal transit induced by
morphine,
oxycodone, and
fentanyl. These results suggest that
morphine,
oxycodone, and
fentanyl induce
constipation through different mechanisms (
naloxonazine-sensitive versus
naloxonazine-insensitive sites and central versus peripheral
opioid receptors), and these findings may help us to understand the characteristics of the
constipation induced by each μ-
opioid receptor agonist and improve the quality of life by reducing
constipation in patients being treated for
pain.