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，心理依赖不是主要问题。在这里，我证实，坐骨神经结扎抑制吗啡诱导的奖励作用在啮齿动物伴随着抑制多巴胺（DA）释放的延髓核。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能改变腹侧被盖区（VTA）细胞外信号调节激酶（ERK）和p38的活性，这些变化是否能直接影响吗啡诱导的奖赏效应的形成。我证明，神经损伤产生了持续的和显着的蛋白水平的磷酸化ERK和p38在小鼠下中脑的胞质组分的减少。用MEK的选择性抑制剂预处理抑制ERK活性抑制吗啡诱导的位置偏爱，而用p38的特异性抑制剂预处理不影响吗啡诱导的奖励效应。免疫组织化学研究表明，在坐骨神经结扎小鼠腹侧被盖区酪氨酸羟化酶阳性细胞内磷酸化ERK免疫反应性急剧下降。此外，与假手术大鼠相比，吗啡或选择性莫尔激动剂诱导的与VTA膜结合的鸟苷-5 '-O-（3-[^<35>S]硫代）三磷酸（[^<35>S]GTPγS）的增加在神经结扎大鼠中显著减弱。VTA中莫尔功能的降低和VTA中DA能神经元ERK活性的持续降低可能有助于在神经性疼痛样状态下抑制吗啡诱导的奖励效应。

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.