Kolesnikov Y, Jain S, Pasternak G W
The Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Eur J Pharmacol. 1996 Jan 18;296(1):17-22. doi: 10.1016/0014-2999(95)00669-9.
Administered alone, agmatine at doses of 0.1 or 10 mg/kg is without effect in the mouse tailflick assay. However, agmatine enhances morphine analgesia in a dose-dependent manner, shifting morphine's ED50 over 5-fold. A far greater effect is observed when morphine is given intrathecally (9-fold shift) than after intracerebroventricular administration (2-fold). In contrast to the potentiation of morphine analgesia, agmatine (10 mg/kg) has no effect on morphine's inhibition of gastrointestinal transit. delta-Opioid receptor-mediated analgesia also is potentiated by agmatine, but kappa1-receptor-mediated (U50,488H; trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetemide) and kappa3-opioid receptor-mediated (naloxone benzoylhydrazone) analgesia is not significantly enhanced by any dose of agmatine tested in this acute model. In chronic studies, agmatine at a low dose (0.1 mg/kg) which does not affect morphine analgesia acutely prevents tolerance following chronic morphine dosing for 10 days. A higher agmatine dose (10 mg/kg) has a similar effect. Agmatine also blocks tolerance to the delta-opioid receptor ligand [D-Pen2,D-Pen5]enkephalin given intrathecally, but not to the kappa3-opioid receptor agonist naloxone benzoylhydrazone. Despite its inactivity on kappa1-opioid analgesia in the acute model, agmatine prevents kappa1-opioid receptor-mediated tolerance. These studies demonstrate the dramatic interactions between agmatine and opioid analgesia and tolerance.
单独给药时，剂量为0.1或10mg/kg的胍丁胺在小鼠甩尾试验中无效。然而，胍丁胺以剂量依赖的方式增强吗啡镇痛作用，使吗啡的半数有效剂量（ED50）变化超过5倍。鞘内注射吗啡（变化9倍）时观察到的效果远比脑室内给药（变化2倍）时显著。与增强吗啡镇痛作用相反，胍丁胺（10mg/kg）对吗啡抑制胃肠蠕动没有影响。δ阿片受体介导的镇痛作用也被胍丁胺增强，但在该急性模型中，任何测试剂量的胍丁胺均未显著增强κ1受体介导的（U50,488H；反式-3,4-二氯-N-甲基-N-[2-(1-吡咯烷基)环己基]苯乙酰胺）和κ3阿片受体介导的（纳洛酮苯甲酰腙）镇痛作用。在慢性研究中，低剂量（0.1mg/kg）的胍丁胺（急性时不影响吗啡镇痛）可防止慢性吗啡给药10天后产生耐受性。更高剂量的胍丁胺（10mg/kg）有类似效果。胍丁胺还可阻断对鞘内注射的δ阿片受体配体[D-青霉胺2，D-青霉胺5]脑啡肽的耐受性，但不阻断对κ3阿片受体激动剂纳洛酮苯甲酰腙的耐受性。尽管在急性模型中胍丁胺对κ1阿片镇痛无活性，但它可防止κ1阿片受体介导的耐受性。这些研究证明了胍丁胺与阿片类镇痛和耐受性之间的显著相互作用。
