The selective mu opioid receptor antagonist, alvimopan, improves delayed GI transit of postoperative ileus in rats.
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.
Fukuda
Hiroyuki
H
Department of Surgery, Duke University Medical Center, Surgical Service 112, VA Medical Center, Durham, NC 27705, USA.
Suenaga
Kiyotaka
K
Tsuchida
Daisuke
D
Mantyh
Christopher R
CR
Pappas
Theodore N
TN
Hicks
Gareth A
GA
Dehaven-Hudkins
Diane L
DL
Takahashi
Toku
T
D000701:Analgesics, Opioid / Q000009:adverse effects; D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005772:Gastrointestinal Transit / Q000187:drug effects*; D045823:Ileus / Q000188:drug therapy* / Q000209:etiology; D007813:Laparotomy / Q000009:adverse effects; D008297:Male; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives; D009292:Narcotic Antagonists / Q000627:therapeutic use*; D010880:Piperidines / Q000627:therapeutic use*; D011183:Postoperative Complications / Q000188:drug therapy*; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D010880:Piperidines; D000644:Quaternary Ammonium Compounds; C032257:methylnaltrexone; D009271:Naltrexone; C419502:alvimopan