Molecular mechanism of central sensitization and suppression of morphine dependence under a neuropathic pain-like state

最近的临床研究表明，当吗啡用于控制疼痛时，心理依赖并不是一个主要问题。在这里，我证实了坐骨神经结扎抑制了吗啡诱导的啮齿类动物的奖赏效应，同时抑制了伏隔核多巴胺(DA)的释放。本研究旨在探讨坐骨神经结扎引起的神经病理性疼痛是否会改变腹侧被盖区(VTA)细胞外信号调节激酶(ERK)和p38的活性，从而直接影响吗啡奖赏效应的形成。我证明，神经损伤导致小鼠中脑下部胞浆部分的磷酸化ERK和p38蛋白水平持续显著下降。肌肉注射MEK选择性抑制剂抑制ERK活性可抑制吗啡的位置偏爱效应，而肌肉注射p38特异性抑制剂不影响吗啡的奖赏效应。免疫组织化学研究显示，坐骨神经结扎小鼠VTA内酪氨酸羟基酶阳性细胞内的磷酸化ERK免疫反应性显著降低。此外，增加的鸟苷-5‘-o-(3-[^&lt；35&gt；S]硫代)三磷酸([^&lt；35&gt；与假手术组大鼠相比，吗啡或选择性MOR激动剂诱导的大鼠VTA膜结合蛋白(GTPγS)显著减弱。这些结果直接证明，在神经病理性疼痛状态下，吗啡引起的下丘脑多巴胺释放减少与VTA内MOR功能降低有关，而VTA内DA能神经元ERK活性持续降低可能与抑制吗啡诱导的奖赏效应有关。

Recent clinical studies have demonstrated that when morphine is used to control pain, psychological dependence is not a major concern. Here, I confirmed that sciatic nerve ligation suppress the morphine-induced rewarding effect in rodents accompanied with the inhibition of dopamine(DA) release in the nucleus accumbens. The present study was then undertaken to investigate whether a neuropathic pain induced by sciatic nerve ligation could change the activities of the extracellular signal-regulated kinase(ERK) and p38 in the ventral tegmental area(VTA), and these changes could directly affect the development of the morphine-induced rewarding effect in mice. I demonstrated that nerve injury produced a sustained and significant reduction in protein levels of phosphorylated-ERK and -p38 in cytosolic fractions of the mouse lower midbrain. The inhibition of ERK activity by i.c.v.pretreatment with a selective inhibitor of MEK suppressed the morphine-induced place preference, whereas i.c.v.treatment with a specific inhibitor of p38 did not affect the morphine-induced rewarding effect. Immunohistochemical study showed a drastic reduction in phosphorylated-ERK immunoreactivity within tyrosine hydroxylase-positive cells of the VTA in sciatic nerve-ligated mice. In addition, the increased guanosine-5'-o-(3-[^<35>S]thio) triphosphate ([^<35>S]GTPγS) binding to membranes of the VTA induced by either morphine or a selective MOR agonist was significantly attenuated in nerve-ligated rats as compared to that observed in sham-operated rats.These findings provide direct evidence that the decrease in the morphine-induced DA release in the N.Acc with the reduction in MOR function in the VTA and the persistent decrease in ERK activity of DAnergic neurons in the VTA may contribute to the suppression of the morphine-induced rewarding effect under a neuropathic pain-like state.