Mu-opioid receptors modulate the stability of dendritic spines
Mu-opioid receptors modulate the stability of dendritic spines
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DOI：
10.1073/pnas.0406797102
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发表时间：
2005-02-01
影响因子：
11.1
通讯作者：
Loh, HH
中科院分区：
文献类型：
--
作者：
Liao, D;Lin, H;Loh, HH
阿片类药物通过抑制抑制性神经元的突触GABA释放来调节神经元的兴奋性。在这里，我们报告了阿片类药物在调节兴奋性突触传递中的作用。吗啡通过激活兴奋性突触中普遍聚集的mu-阿片受体（MOR），导致先前存在的树突棘塌陷和突触α -氨基-3-羟基-5-甲基-4-异恶唑烯丙酸受体减少。同时，阿片拮抗剂纳洛酮增加了脊髓密度。即使在钠通道阻滞剂河豚毒素存在的情况下，吗啡的慢性治疗也会降低树突棘的密度，这表明吗啡的作用不是通过抑制GABA释放而改变神经网络的活性引起的。在缺乏MORs的转基因小鼠中，吗啡对树突棘的影响不存在，并被一种mu受体拮抗剂CTOP （d - phe - cys - tyrr - d - trp - orn - thr - pen - thrnh(2)）阻断。这些数据和其他数据表明，内源性阿片类物质和/或MORs的组成活性参与维持脊柱的正常形态和功能，挑战了阿片类物质的经典模型。当阿片受体被外源性阿片过度激活时，可能出现药物成瘾时脊柱的异常改变。
Opioids classically regulate the excitability of neurons by suppressing synaptic GABA release from inhibitory neurons. Here, we report a role for opioids in modulating excitatory synaptic transmission. By activating ubiquitously clustered mu-opioid receptor (MOR) in excitatory synapses, morphine caused collapse of preexisting dendritic spines and decreased synaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Meanwhile, the opioid antagonist naloxone increased the density of spines. Chronic treatment with morphine decreased the density of dendritic spines even in the presence of Tetrodotoxin, a sodium channel blocker, indicating that the morphine's effect was not caused by altered activity in neural network through suppression of GABA release. The effect of morphine on dendritic spines was absent in transgenic mice lacking MORs and was blocked by CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-ThrNH(2)), a mu-receptor antagonist. These data together with others suggest that endogenous opioids and/or constitutive activity of MORs participate in maintaining normal morphology and function of spines, challenging the classical model of opioids. Abnormal alteration of spines may occur in drug addiction when opioid receptors are overactivated by exogenous opiates.