title: mu-Opiate receptor agonist loperamide blocks bethanechol-induced gallbladder contraction, despite higher cholecystokinin plasma levels in man.
abstract: mu-Opiate receptor agonists, such as loperamide, influence biliary excretion and suppress cholecystokinin (CCK)-induced gallbladder contraction. Loperamide decreases cholinergic mechanisms, like pancreatic polypeptide (PP) release, while muscarinic agonist (bethanechol)-induced PP release remains unaffected. The effects of loperamide on gallbladder contraction and peptide release were performed to resolve this discrepancy.
  
  
  METHODS
  Six subjects (27.6 +/- 2.0 years) received bethanechol (12.5, 25 and 50 microg kg(-1) h(-1) continuously over 40 min) after oral 16 mg loperamide (vs placebo) in a crossover design. Gallbladder volume and plasma levels of CCK, PP, motilin, gastrin, neurotensin, cholylglycine were measured regularly.
  
  
  RESULTS
  Bethanechol significantly reduced gallbladder volume (26.7 +/- 1.9 to a nadir of 15.3 +/- 2.2 mL, P < or = 0.05), and this action was inhibited by loperamide. Basal CCK levels increased significantly after loperamide. Incremental integrated CCK release after bethanechol was higher under loperamide (P < or = 0.05), as placebo CCK release was significantly decreased under bethanechol (2.0 +/- 0.4-0.8 +/- 0.3 pmol L(-1)). In both settings, PP levels were significantly increased after bethanechol, while release of neurotensin, motilin, gastrin and cholylglycine was unaffected.
  
  
  CONCLUSIONS
  The mu-opiate receptor agonist loperamide inhibits bethanechol-induced gallbladder contraction. This effect is not mediated by inhibition of CCK release, as loperamide even enhances basal CCK plasma levels. As cholinergic mechanisms, like bethanechol-induced incremental PP release, were unaffected, mu-opiate agonists might influence gallbladder contraction via vagal-cholinergic pathways.
authors.affiliation: Department of Internal Medicine - Innenstadt, University Hospital, Munich, Germany. baerbel.otto@med.uni-muenchen.de
authors.forename: B
authors.initials: B
authors.lastname: Otto
authors.forename: G M
authors.initials: GM
authors.lastname: Mawe
authors.forename: R L
authors.initials: RL
authors.lastname: Riepl
mesh_terms: D000328:Adult; D018723:Bethanechol / Q000494:pharmacology*; D002766:Cholecystokinin / Q000097:blood*; D018592:Cross-Over Studies; D005704:Gallbladder / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008139:Loperamide / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010191:Pancreatic Polypeptide / Q000097:blood / Q000378:metabolism; D010919:Placebos; D017450:Receptors, Opioid, mu / Q000819:agonists*
chemical_list: D010919:Placebos; D017450:Receptors, Opioid, mu; D018723:Bethanechol; D010191:Pancreatic Polypeptide; D008139:Loperamide; D002766:Cholecystokinin