Differential expression and sensitivity of presynaptic and postsynaptic opioid receptors regulating hypothalamic proopiomelanocortin neurons.
Differential expression and sensitivity of presynaptic and postsynaptic opioid receptors regulating hypothalamic proopiomelanocortin neurons.
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DOI：
10.1523/jneurosci.4654-10.2011
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发表时间：
2011-01-05
期刊：
影响因子：
--
通讯作者：
Hentges ST
中科院分区：
文献类型：
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作者：
Pennock RL;Hentges ST
下丘脑原黑素皮质素（POMC）神经元释放内源性阿片样物质-内啡肽，POMC神经元的活性被阿片样物质抑制，从而提出β -内啡肽的反馈抑制作用。然而，内在特性和突触输入都有助于POMC神经元的调节，因此，将阿片的自调节作用归因于阿片受体必须考虑到阿片受体在突触前和突触后的定位和敏感性。在本研究中，我们对小鼠脑切片的POMC细胞进行全细胞记录，并使用选择性激动剂对mu， kappa和delta阿片受体进行突触前和突触后调节。激活mu，而不是kappa或delta受体，诱导直接突触后向外电流。每种受体的激动剂抑制自发抑制性突触后电流（IPSCs）的频率。Mu和kappa，而不是delta，激动剂降低了诱导多能干细胞的振幅，并且似乎在POMC神经元上的gaba能末端的很大一部分共定位。当测量突触后向外电流时，激动剂DAMGO引起的突触前抑制的EC50为80 nM，而EC50为350 nM。这种不同的敏感性增加了阿片依赖反馈调节的一个意想不到的组成部分，即低水平的阿片受体激活可能会解除对POMC神经元活动的抑制，而高浓度的阿片受体激活则会导致整体抑制。这一结果可能有助于解释为什么很难清楚地认识到阿片类药物在调节食物摄入和其他涉及POMC神经元的过程中所起的作用。
Hypothalamic proopiomelanocortin (POMC) neurons release the endogenous opioid beta-endorphin and POMC neuron activity is inhibited by opioids leading to the proposal that beta-endorphin acts to provide feedback inhibition. However, both intrinsic properties and synaptic inputs contribute to the regulation of POMC neurons such that attributing an auto-regulatory role to opioids must include consideration of opioid receptor localization and sensitivity at both pre- and postsynaptic sites. In the present study, whole cell recordings were made in POMC cells in mouse brain slices and the pre- and postsynaptic regulation of POMC neurons was examined using selective agonists for mu, kappa and delta opioid receptors. Activation of mu, but not kappa or delta receptors, induced a direct postsynaptic outward current. Agonists for each of the receptors inhibited the frequency of spontaneous inhibitory postsynaptic currents (IPSCs). Mu and kappa, but not delta, agonists reduced the amplitude of evoked IPSCs and appear to co-localize in a significant portion of GABAergic terminals onto POMC neurons. The presynaptic inhibition caused by the mu agonist DAMGO had an EC50 of 80 nM whereas the EC50 was 350 nM when measuring the postsynaptic outward current. This differential sensitivity adds an unexpected component of opioid dependent feedback regulation where low levels of opioid receptor activation would likely disinhibit POMC neuron activity whereas higher concentrations would result in an overall inhibition. The results may help explain why it has been difficult to clearly discern the role that opioids play in the regulation of food intake and other processes involving POMC neurons.