Culpepper-Morgan J A, Holt P R, LaRoche D, Kreek M J
Rockefeller University, New York, N.Y. 10021, USA.
Life Sci. 1995;56(14):1187-92. doi: 10.1016/0024-3205(95)00057-d.
Kappa(kappa) opioid agonists slow gastrointestinal transit in the guinea pig and the mouse but not the rat. Opioid antagonists naloxone and naltrexone are mu (mu) preferring, while the antagonist nalmefene has more kappa binding activity. When administered orally, the specific opioid antagonists naloxone, naltrexone, and nalmefene are able to reverse the gastrointestinal transit delay caused by orally administered mu and kappa opioid agonists (morphine and U-50, 488H) in a dose dependent fashion as measured by the leading edge of charcoal meal in the guinea pig. Oral naltrexone and nalmefene have significantly more central nervous system (CNS) bioavailability than oral naloxone. However, orally administered naloxone was as effective as either naltrexone or nalmefene in reversing mu opioid agonist induced orocecal transit delays (single agonist dose apparent ED50s = 12.3 +/- 4, 7.3 +/- 4, and 13.5 +/- 6 mg/kg respectively). Nalmefene was more active than either naltrexone or naloxone in its ability to reverse the kappa agonist U-50,488H (single agonist dose apparent ED50s = 18.3 +/- 12*, 37.5 +/- 5, and 61.9 +/- 5 mg/kg respectively; * = p < 0.05). These data confirm the enteric action of orally administered opioids and further supports our earlier findings of the presence of kappa opioid activity in the guinea pig enteric nervous system.
κ阿片受体激动剂可减缓豚鼠和小鼠的胃肠蠕动，但对大鼠无效。阿片受体拮抗剂纳洛酮和纳曲酮对μ阿片受体具有更高的亲和力，而拮抗剂纳美芬则具有更强的κ阿片受体结合活性。口服给药时，特异性阿片受体拮抗剂纳洛酮、纳曲酮和纳美芬能够以剂量依赖的方式逆转口服μ和κ阿片受体激动剂（吗啡和U-50,488H）所引起的胃肠蠕动延迟，这一延迟通过豚鼠中炭末推进前沿来衡量。口服纳曲酮和纳美芬的中枢神经系统（CNS）生物利用度显著高于口服纳洛酮。然而，口服纳洛酮在逆转μ阿片受体激动剂诱导的口腔至盲肠转运延迟方面与纳曲酮或纳美芬效果相当（单一激动剂剂量的表观ED50分别为12.3±4、7.3±4和13.5±6mg/kg）。在逆转κ阿片受体激动剂U-50,488H方面，纳美芬比纳曲酮或纳洛酮更具活性（单一激动剂剂量的表观ED50分别为18.3±12*、37.5±5和61.9±5mg/kg；* = p < 0.05）。这些数据证实了口服阿片类药物的肠道作用，并进一步支持了我们早期关于豚鼠肠神经系统中存在κ阿片受体活性的发现。
