Postoperative
ileus (POI) is often exacerbated by
opioid analgesic use during and following surgery, since
mu opioid receptor activation results in a further delay of gastrointestinal (GI) transit. The effects of
alvimopan, a novel, selective, and peripherally acting
mu opioid receptor antagonist, and the reference compound
methylnaltrexone, upon POI were investigated in rats. Under
isoflurane anesthesia, POI was induced by
laparotomy with intestinal manipulation. Immediately after the surgery, the rats received (51)Cr by gavage. Three hours after the surgery, the rats were sacrificed and GI transit was estimated using the geometric center (GC) of (51)Cr.
Alvimopan (0.1-3 mg/kg) or
methylnaltrexone (100 mg/kg) were administered by gavage either before or after the surgery, with or without
morphine administration (1 mg/kg). GI transit was delayed by intestinal manipulation (GC = 2.92 +/- 0.17).
Alvimopan (1 and 3 mg/kg) significantly reversed this delayed GI transit when administered 45 min prior to surgery. However, the effects of
alvimopan were less pronounced when administered following surgery.
Morphine administration further delayed GI transit induced by intestinal manipulation (GC = 1.97 +/- 0.11). Under these conditions,
alvimopan (1 and 3 mg/kg) also significantly improved delayed GI transit when administered before surgery.
Methylnaltrexone was inactive under all experimental conditions. These data suggest that
mu opioid receptors play a role in the pathogenesis of POI, and that the clinical benefit reported to be afforded by
alvimopan may be in part mediated via inhibition of an endogenous
opioid release as well as blockade of the unwanted GI actions of
analgesic agents.