Narita Minoru, Nagumo Yasuyuki, Hashimoto Seiko, Narita Michiko, Khotib Junaidi, Miyatake Mayumi, Sakurai Takeshi, Yanagisawa Masashi, Nakamachi Tomoya, Shioda Seiji, Suzuki Tsutomu
Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo 142-8501, Japan.
J Neurosci. 2006 Jan 11;26(2):398-405. doi: 10.1523/JNEUROSCI.2761-05.2006.
In this study, we investigated the role of orexinergic systems in dopamine-related behaviors induced by the mu-opioid receptor agonist morphine in rodents. Extensive coexpression of tyrosine hydroxylase with orexin receptors was observed in the mouse ventral tegmental area (VTA). The levels of dopamine and its major metabolites in the nucleus accumbens were markedly increased by the microinjection of orexin A and orexin B into the VTA. The subcutaneous morphine-induced place preference and hyperlocomotion observed in wild-type mice were abolished in mice that lacked the prepro-orexin gene. An intra-VTA injection of a selective orexin receptor antagonist SB334867A [1-(2-methylbenzoxazol-6-yl)-3-[1.5]naphthyridin-4-yl urea] significantly suppressed the morphine-induced place preference in rats. Furthermore, the increased level of dialysate dopamine produced by morphine in the mouse brain was significantly decreased by deletion of the prepro-orexin gene. These findings provide new evidence that orexin-containing neurons in the VTA are directly implicated in the rewarding effect and hyperlocomotion induced by morphine through activation of the mesolimbic dopamine pathway in rodents.
在本研究中，我们调查了食欲素能系统在μ-阿片受体激动剂吗啡诱导的啮齿动物多巴胺相关行为中的作用。在小鼠腹侧被盖区（VTA）观察到酪氨酸羟化酶与食欲素受体广泛共表达。向VTA微量注射食欲素A和食欲素B可显著增加伏隔核中多巴胺及其主要代谢产物的水平。在缺乏前食欲素原基因的小鼠中，野生型小鼠皮下注射吗啡诱导的位置偏爱和运动亢进消失。向大鼠VTA内注射选择性食欲素受体拮抗剂SB334867A[1-(2-甲基苯并恶唑-6-基)-3-[1.5]萘啶-4-基脲]可显著抑制吗啡诱导的位置偏爱。此外，通过缺失前食欲素原基因，吗啡在小鼠脑中产生的透析液多巴胺水平升高显著降低。这些发现提供了新的证据，表明VTA中含食欲素的神经元通过激活啮齿动物的中脑边缘多巴胺通路，直接参与吗啡诱导的奖赏效应和运动亢进。
