Behavioral pharmacology of the μ/δ opioid glycopeptide MMP2200 in rhesus monkeys
Behavioral pharmacology of the μ/δ opioid glycopeptide MMP2200 in rhesus monkeys
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DOI：
10.1124/jpet.108.138180
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发表时间：
2008-09-01
影响因子：
3.5
通讯作者：
Negus, S. Stevens
中科院分区：
文献类型：
--
作者：
Do Carmo, Gail Pereira;Polt, Robin;Negus, S. Stevens
H2 N-Tyr-D-Thr-Gly-Phe-Leu-Ser-（O-beta-D-lactose）-CONH 2（MMP 2200）是一种新型糖肽类阿片激动剂，对μ和δ受体具有相似的亲和力。在小鼠中，糖基化促进脑渗透和中枢介导的行为效应的产生;然而，尚不清楚在灵长类动物中全身给药后，增强的脑渗透的幅度是否足以允许药物效应的中枢介导和协同mu/delta抗伤害感受相互作用的产生。为了解决这个问题，本研究比较了MMP 2200和μ激动剂吗啡在恒河猴的四个行为程序中的作用。在热伤害感受的测定中，吗啡（1.0-5.6 mg/kg）产生剂量依赖性的抗伤害感受，而MMP 2200（10-56 mg/kg）无效。吗啡（0.01-1.0 mg/kg）和MMP 2200（0.032 - 3.2 mg/ kg）对辣椒素诱发的热异常性疼痛均有剂量依赖性的抗异常性疼痛作用。MMP 2200诱导的抗异常性疼痛被中度μ选择性拮抗剂纳曲酮（0.01 mg/kg）、δ选择性拮抗剂纳曲吲哚（1.0 mg/kg）和外周选择性阿片类拮抗剂季铵纳曲酮（0.32 mg/ kg）阻断。吗啡（0.01 - 1.0 mg/kg）和MMP 2200（10-56 mg/kg）均能降低大鼠的反应率。吗啡的作用可被纳曲酮（0.001-0.01 mg/ kg）拮抗，而MMP 2200的作用不被纳曲酮（0.01 mg/ kg）或纳曲吲哚（1.0 mg/kg）拮抗。吗啡（0.0032-0.32 mg/kg/注射）对吗啡依赖大鼠的自主给药有增强作用，而MMP 2200（0.032 - 0.32 mg/kg/注射）对吗啡依赖大鼠的自主给药无增强作用。这些结果表明，全身给药MMP 2200作为外周，μ/δ-阿片类激动剂与有限的分布到中枢神经系统的恒河猴。这些结果还表明糖肽类药物的药代动力学和脑渗透存在种属差异。
H2N-Tyr-D-Thr-Gly-Phe-Leu-Ser-(O-beta-D-lactose)-CONH2 (MMP2200) is a novel glycopeptide opioid agonist with similar affinities for mu and delta receptors. Glycosylation promoted brain penetration and production of centrally mediated behavioral effects in mice; however, it is unknown whether the magnitude of enhanced brain penetration is sufficient to permit central mediation of drug effects and production of synergistic mu/delta antinociceptive interactions after systemic administration in primates. To address this issue, the present study compared the effects of MMP2200 and the mu-agonist morphine in four behavioral procedures in rhesus monkeys. In an assay of thermal nociception, morphine (1.0-5.6 mg/kg) produced dose-dependent antinociception, whereas MMP2200 (10-56 mg/kg) was ineffective. In an assay of capsaicin-induced thermal allodynia, both morphine (0.01-1.0 mg/kg) and MMP2200 (0.032 -3.2 mg/ kg) produced dose-dependent antiallodynic effects. MMP2200-induced antiallodynia was blocked by the moderately mu-selective antagonist naltrexone (0.01 mg/kg), the delta-selective antagonist naltrindole (1.0 mg/kg), and the peripherally selective opioid antagonist quaternary naltrexone ( 0.32 mg/ kg). In an assay of schedulecontrolled behavior, both morphine (0.01 -1.0 mg/kg) and MMP2200 (10-56 mg/kg) decreased response rates. Morphine effects were antagonized by naltrexone (0.001-0.01 mg/ kg); however, the effects of MMP2200 were not antagonized by either naltrexone ( 0.01 mg/ kg) or naltrindole ( 1.0 mg/kg). In an assay of drug self-administration, morphine (0.0032-0.32 mg/kg/injection) produced reinforcing effects, whereas MMP2200 (0.032 -0.32 mg/kg/injection) did not. These results suggest that systemically administered MMP2200 acted as a peripheral, mu/delta-opioid agonist with limited distribution to the central nervous system in rhesus monkeys. These results also suggest the existence of species differences in the pharmacokinetics and brain penetration of glycopeptides.