Effects of methylnaltrexone on guinea pig gastrointestinal motility

The purpose of the present study was to compare the effects of methylnaltrexone (MNTX), a peripherally acting μ opioid receptor (μOR) antagonist, on gastrointestinal (GI) motility in naïve vs. opiate chronically treated guinea pigs in vitro and in vivo. We have used the electrically stimulated muscle twitch contractions of longitudinal muscle-myenteric plexus (LMMP) preparations and total GI transit as measure of GI motility. In LMMP preparations of naïve guinea pigs, MNTX (1–30 μM) induced a significant, dose–response reduction of morphine-induced inhibition of electrically stimulated muscle twitch contractions, with an IC₅₀ of 9.4 10^?8M. By contrast, MNTX abolished the inhibitory effect of acute morphine at any concentrations tested (1–30 μM) in the guinea pigs chronically treated with opiates. In vivo, MNTX (10–50 mg s.c.) did not affect GI transit in naïve guinea pigs when administered acutely or for five consecutive days, but reversed the GI transit delay induced by chronic morphine treatment. These findings show that MNTX is effective in reversing opiate-induced inhibition of GI motility acting at peripheral μ opioid receptors, but does not exert a pharmacologic effect on GI transit in the absence of opiate stimulation.