Mechanisms That Underlie μ-Opioid Receptor Agonist–Induced Constipation: Differential Involvement of μ-Opioid Receptor Sites and Responsible Regions

Abstract

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 naloxonazinesensitive versus -insensitive sites or central-versus-peripheral m-opioid receptors? The present study was designed to investigate the mechanisms of m-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 fentanylinduced 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 m-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 m-opioid receptor agonist and improve the quality of life by reducing constipation in patients being treated for pain.

P2Y 12 Receptor Antagonists and Morphine

“…On the other hand, existing evidence suggests that there is a differential involvement of μ-opioid receptor sites and responsible regions for the different opioid agonists, which means that they may cause reduced gastrointestinal motility through different mechanisms, and the degree of induced dysmotility may vary. 35 In view of the above considerations, generalization of the observations regarding morphine to all opioids should be done with some reserve-at least until more evidence becomes available.…”

Oxycodone/Naloxone: Role in Chronic Pain Management, Opioid-Induced Constipation, and Abuse Deterrence

“…Unlike other side effects associated with opioids, constipation does not typically resolve with continued use [8, 13–24]. Although the interaction of opioids with the enteric nervous system is primarily responsible for OIC, there is evidence of a centrally mediated component as well [11, 25, 26]. Intraspinal administration of opioids has been shown to delay gastric emptying and prolong intestinal transit time, and research indicates possible differences in receptor mechanisms and sites (peripheral versus central) within the opioid class [26–30].…”

“…Although the interaction of opioids with the enteric nervous system is primarily responsible for OIC, there is evidence of a centrally mediated component as well [11, 25, 26]. Intraspinal administration of opioids has been shown to delay gastric emptying and prolong intestinal transit time, and research indicates possible differences in receptor mechanisms and sites (peripheral versus central) within the opioid class [26–30]. At this time, the full impact of centrally medicated OIC is unclear, as gastrointestinal function correlates more closely with opioid concentrations in the enteric nervous system than in the central nervous system (CNS) [11, 18].…”

Innovations in Pain Management: Morphine Combined with Omega-3 Fatty Acids

“…However, constipation is unlikely to improve over time, and therefore it should be monitored during treatment with morphine [49]. This persistent effect often requires a simultaneous additional treatment [41,42], with several studies having suggested that mu-opioid receptors play a key role in opioid-induced constipation [50]. Related to this, in the treatment of opioid-induced constipation, recent positive clinical efficacy data have been obtained with two peripherally acting antagonists, methylnaltrexone and alvimopan, of the mu-opioid receptor [51].…”