title: Circular muscle contraction in the mice rectum plays a key role in morphine-induced constipation.
abstract: BACKGROUND
  Although opioids induce intestinal muscle contraction and provoke constipation, the intestinal region(s) that contribute to the constipation have remained unclear. We report here a region-specific response of intestinal muscle contraction to morphine and its correlation with in vivo constipation.
  
  
  METHODS
  Regions of mice small and large intestines were dissected histologically and circular muscle contractile responses were measured using isometric transducers. Bead expulsion assays were performed to assess in vivo constipation.
  
  
  RESULTS
  The strongest contraction in response to morphine was detected in the rectum. The distal and transverse colon also showed strong contractions, whereas weak responses were detected in the proximal colon, jejunum, and ileum. Regarding the sustainability of muscle contractions during morphine exposure, prolonged waves were detected only in the rectum, while the waves diminished gradually in other regions. To identify the mechanism(s) underlying this difference, we focused on nitric oxide synthase (NOS). In the distal colon, decreased contraction during morphine exposure was recovered by application of a NOS inhibitor (L-NAME), while a NOS substrate (L-arginine) enhanced contractile degradation. In contrast L-NAME and L-arginine modestly affected the sustained contraction in the rectum. To confirm the correlation with constipation, beads were inserted into the transverse colon, distal colon, or rectum after morphine administration and expulsion times were examined. Beads tended to stop at the rectum even when inserted in the deeper colonic regions.
  
  
  CONCLUSIONS
  The rectum showed the greatest response to morphine in both in vitro and in vivo analyses, therefore it may play a key role for opioid-induced constipation.
authors.affiliation: Pain & Neurology, Medicinal Research Laboratories, Shionogi and Co., Ltd., Toyonaka, Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Ono
authors.forename: A
authors.initials: A
authors.lastname: Nakamura
authors.forename: K
authors.initials: K
authors.lastname: Matsumoto
authors.forename: S
authors.initials: S
authors.lastname: Horie
authors.forename: G
authors.initials: G
authors.lastname: Sakaguchi
authors.forename: T
authors.initials: T
authors.lastname: Kanemasa
mesh_terms: D000818:Animals; D003248:Constipation / Q000139:chemically induced / Q000503:physiopathology*; D007420:Intestine, Large / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D009020:Morphine / Q000633:toxicity*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D012007:Rectum / Q000187:drug effects* / Q000503:physiopathology
chemical_list: D017450:Receptors, Opioid, mu; D009569:Nitric Oxide; D009020:Morphine
keywords: constipation; morphine; nitric oxide (NO); rectum; μ-opioid receptor (MOR)