Shin Eun-Joo, Jang Choon-Gon, Bing Guoying, Park Dae Hun, Oh Chang-Hyun, Koo Kyo Hwan, Oh Ki Wan, Yamada Kiyofumi, Nabeshima Toshitaka, Kim Hyoung-Chun
Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, Republic of Korea.
Drug Alcohol Depend. 2009 Sep 1;104(1-2):175-84. doi: 10.1016/j.drugalcdep.2009.05.015. Epub 2009 Jun 25.
Dynorphin is the presumed endogenous ligand for the kappa-opioid receptor. The dynorphin gene may play a role in psychotropic agent-mediated behavioral changes via dopaminergic modulation. Therefore, in this study, possible involvement of the dynorphin gene in nalbuphine-mediated behavioral responses was examined using prodynorphin (Pdyn) gene knock-out (-/-) mice. Pdyn gene deficiency potentiates nalbuphine-induced behavioral sensitization of locomotor activity and accumbal c-Fos expression. Administration of nalbuphine induced a significant increase in the dialysate dopamine level in the nucleus accumbens. This increase was more pronounced in the Pdyn (-/-) mice than in the wild-type (WT) mice. In addition, Pdyn (-/-) mice were more vulnerable to the naloxone-precipitated withdrawal syndrome (i.e., teeth chattering, wet dog shakes, forepaw tremors, jumping, weight loss, and global withdrawal score) after repeated treatment with nalbuphine than the WT mice. Consistently, nor-binaltorphimine, a kappa-opioid receptor antagonist, significantly potentiated nalbuphine-induced behavioral effects in WT mice, whereas U-50488H, a kappa-opioid receptor agonist, significantly attenuated these changes in Pdyn (-/-) mice in a dose-dependent manner. Our data suggest that the kappa-opioid receptor/dynorphin system is specifically modulated in response to behavioral sensitization and withdrawal signs induced by nalbuphine.
强啡肽被认为是κ-阿片受体的内源性配体。强啡肽基因可能通过多巴胺能调节在精神药物介导的行为变化中发挥作用。因此，在本研究中，使用前强啡肽（Pdyn）基因敲除（-/-）小鼠来检测强啡肽基因在纳布啡介导的行为反应中可能的参与情况。Pdyn基因缺陷增强了纳布啡诱导的运动活动行为敏化和伏隔核c-Fos表达。给予纳布啡可使伏隔核透析液中的多巴胺水平显著升高。这种升高在Pdyn（-/-）小鼠中比野生型（WT）小鼠中更明显。此外，与WT小鼠相比，Pdyn（-/-）小鼠在反复用纳布啡治疗后更容易出现纳洛酮诱发的戒断综合征（即牙齿打颤、湿狗样抖动、前爪震颤、跳跃、体重减轻和整体戒断评分）。一致的是，κ-阿片受体拮抗剂nor-naltorphimine在WT小鼠中显著增强了纳布啡诱导的行为效应，而κ-阿片受体激动剂U-50488H以剂量依赖的方式显著减弱了Pdyn（-/-）小鼠中的这些变化。我们的数据表明，κ-阿片受体/强啡肽系统在对纳布啡诱导的行为敏化和戒断症状的反应中受到特异性调节。
