Ghaemi-Jandabi Masoumeh, Azizi Hossein, Semnanian Saeed
Department of Physiology, School of Medical Sciences, Tarbiat Modares University, PO Box 14115-331, Tehran, Iran.
Department of Physiology, School of Medical Sciences, Tarbiat Modares University, PO Box 14115-331, Tehran, Iran.
Brain Res. 2014 Aug 26;1578:14-22. doi: 10.1016/j.brainres.2014.06.033. Epub 2014 Jul 8.
Repetitive administration of opioid agonists is associated with the development of tolerance to the effects of these substances and limits their application. Orexin (also known as hypocretin) is involved in morphine tolerance and dependence. The lateral paragigantocellularis nucleus (LPGi) is a key brain region implicated in the tolerance and dependence to opiates. Orexin type 1 receptor (OXR1) has been detected in LPGi nucleus. In this study the effect of OXR1 blockade was investigated on neural activity of LPGi during the development of morphine tolerance in rats. Male Wistar rats weighing 250-300 g were used in this study. To incite tolerance, morphine sulfate was injected intraperitonealy (10 mg/kg, i.p.) once a day for 6 days. A selective OXR1 antagonist (SB-334867) was microinjected into the right cerebral ventricle (10 μg/10 μl, i.c.v.) immediately before each morphine injection. On day 7, the effect of morphine (10 mg/kg, i.p.) on neural activity of LPGi was investigated using in vivo extracellular single unit recording. In this study morphine injection during 6 days led to the development of morphine tolerance in LPGi neurons which was observed as a significant decrease in responsiveness of LPGi neurons to acute morphine injection. Administration of SB-334867 before each morphine injection could reverse the responses of LPGi neurons to acute morphine injection. This study showed that OXR1 blockade by SB-334867 prevents the development of tolerance to morphine in LPGi neurons. Further studies are required to determine molecular and anatomical mediators which are thought to be involved in this phenomenon.
反复给予阿片类激动剂会导致对这些物质的作用产生耐受性，并限制了它们的应用。食欲素（也称为下丘脑泌素）与吗啡耐受性和依赖性有关。外侧巨细胞旁核（LPGi）是与阿片类药物耐受性和依赖性相关的关键脑区。在LPGi核中已检测到食欲素1型受体（OXR1）。在本研究中，研究了OXR1阻断对大鼠吗啡耐受性形成过程中LPGi神经活动的影响。本研究使用体重250 - 300 g的雄性Wistar大鼠。为诱导耐受性，每天腹腔注射硫酸吗啡（10 mg/kg，腹腔注射），持续6天。在每次吗啡注射前，将选择性OXR1拮抗剂（SB - 334867）微量注射到右侧脑室（10 μg/10 μl，脑室内注射）。在第7天，使用体内细胞外单单位记录法研究吗啡（10 mg/kg，腹腔注射）对LPGi神经活动的影响。在本研究中，6天的吗啡注射导致LPGi神经元出现吗啡耐受性，表现为LPGi神经元对急性吗啡注射的反应性显著降低。每次吗啡注射前给予SB - 334867可逆转LPGi神经元对急性吗啡注射的反应。本研究表明，SB - 334867阻断OXR1可防止LPGi神经元对吗啡产生耐受性。需要进一步研究以确定被认为参与此现象的分子和解剖学介质。
