Fukuda Hiroyuki, Suenaga Kiyotaka, Tsuchida Daisuke, Mantyh Christopher R, Pappas Theodore N, Hicks Gareth A, Dehaven-Hudkins Diane L, Takahashi Toku
Department of Surgery, Duke University Medical Center, Surgical Service 112, VA Medical Center, Durham, NC 27705, USA.
Brain Res. 2006 Aug 2;1102(1):63-70. doi: 10.1016/j.brainres.2006.02.092. Epub 2006 Jun 22.
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.
术后肠梗阻（POI）在手术期间及术后常因使用阿片类镇痛药而加重，因为μ阿片受体激活会导致胃肠（GI）转运进一步延迟。研究了新型、选择性、外周作用的μ阿片受体拮抗剂阿维莫潘和参比化合物甲基纳曲酮对大鼠POI的影响。在异氟烷麻醉下，通过剖腹术并进行肠操作诱导POI。手术后立即给大鼠灌胃给予（51）Cr。手术后3小时，处死大鼠，使用（51）Cr的几何中心（GC）评估胃肠转运。在手术前或手术后，通过灌胃给予阿维莫潘（0.1 - 3mg/kg）或甲基纳曲酮（100mg/kg），同时给予或不给予吗啡（1mg/kg）。肠操作导致胃肠转运延迟（GC = 2.92±0.17）。在手术前45分钟给予阿维莫潘（1和3mg/kg）可显著逆转这种延迟的胃肠转运。然而，在手术后给予阿维莫潘时，其效果不那么明显。给予吗啡会进一步延迟肠操作诱导的胃肠转运（GC = 1.97±0.11）。在这些条件下，在手术前给予阿维莫潘（1和3mg/kg）也可显著改善延迟的胃肠转运。甲基纳曲酮在所有实验条件下均无活性。这些数据表明，μ阿片受体在POI的发病机制中起作用，并且据报道阿维莫潘所带来的临床益处可能部分是通过抑制内源性阿片释放以及阻断镇痛药不必要的胃肠作用来介导的。
