Vandergriff J, Rasmussen K
Lilly Research Laboratories, Eli Lilly and Co., Lilly Corporate Center, Indianapolis, IN, USA.
Neuropharmacology. 1999 Feb;38(2):217-22. doi: 10.1016/s0028-3908(98)00196-8.
Naltrexone-precipitated morphine withdrawal induces hyperactivity of locus coeruleus (LC) neurons, as well as a plethora of behavioral withdrawal signs. Previous research has demonstrated that an increased release of glutamate and activation of AMPA receptors, particularly in the LC, play an important role in opiate withdrawal. LY354740 is a novel Group II metabotropic glutamate mGlu2/3 receptor agonist that decreases the release of glutamate. Therefore, we investigated the effect of LY354740 on naltrexone-precipitated morphine-withdrawal-induced activation of LC neurons and behavioral signs of morphine withdrawal. In in vivo recordings from anesthetized rats, pretreatment with LY354740 (3-30 mg/kg, s.c.) dose-dependently attenuated the morphine-withdrawal-induced activation of LC neurons. In unanesthetized, morphine-dependent animals, pretreatment with LY354740 (3-30 mg/kg, s.c.) dose-dependently suppressed the severity and occurrence of many naltrexone-precipitated morphine-withdrawal signs. These results indicate mGlu2/3 receptor agonists: (1) can attenuate the morphine-withdrawal-induced activation of LC neurons and many behavioral signs of morphine withdrawal; and (2) may have therapeutic effects in man for the treatment of opiate withdrawal.
纳曲酮诱发的吗啡戒断会导致蓝斑（LC）神经元活动亢进，以及出现大量行为性戒断症状。先前的研究表明，谷氨酸释放增加和AMPA受体激活，尤其是在蓝斑中，在阿片类药物戒断中起重要作用。LY354740是一种新型的II型代谢型谷氨酸mGlu2/3受体激动剂，可减少谷氨酸的释放。因此，我们研究了LY354740对纳曲酮诱发的吗啡戒断所诱导的蓝斑神经元激活及吗啡戒断行为症状的影响。在对麻醉大鼠的体内记录中，LY354740（3 - 30 mg/kg，皮下注射）预处理剂量依赖性地减弱了吗啡戒断诱导的蓝斑神经元激活。在未麻醉的吗啡依赖动物中，LY354740（3 - 30 mg/kg，皮下注射）预处理剂量依赖性地抑制了许多纳曲酮诱发的吗啡戒断症状的严重程度和出现频率。这些结果表明，mGlu2/3受体激动剂：（1）可减弱吗啡戒断诱导的蓝斑神经元激活及吗啡戒断的许多行为症状；（2）可能对人类治疗阿片类药物戒断具有治疗作用。
