μ‐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. 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. 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. 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.