title: 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 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.
authors.affiliation: Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan (T.M., Y.S., K.M., M.S., M.H., E.W., D.M., K.Y., T.S.); Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai International University, Chiba, Japan (K.M., S.H.); and Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan (K.Y.).
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Mori
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Shibasaki
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shibasaki
authors.forename: Minami
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Erika
authors.initials: E
authors.lastname: Wang
authors.forename: Daiki
authors.initials: D
authors.lastname: Masukawa
authors.forename: Kazumi
authors.initials: K
authors.lastname: Yoshizawa
authors.forename: Syunji
authors.initials: S
authors.lastname: Horie
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D003248:Constipation / Q000139:chemically induced / Q000378:metabolism*; D005772:Gastrointestinal Transit / Q000187:drug effects / Q000502:physiology*; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000378:metabolism; D009924:Organ Culture Techniques; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism / Q000502:physiology*
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu