Direct inhibition of hypothalamic proopiomelanocortin neurons by dynorphin A is mediated by the μ-opioid receptor.
Direct inhibition of hypothalamic proopiomelanocortin neurons by dynorphin A is mediated by the μ-opioid receptor.
复制标题
强啡肽 A 对下丘脑原阿片黑皮素神经元的直接抑制是由 μ-阿片受体介导的。
DOI：
10.1113/jphysiol.2014.275339
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Hentges,ShaneT
中科院分区：
文献类型：
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作者：
Pennock,ReaganL;Hentges,ShaneT
尽管强啡肽A被认为对κ阿片受体有选择性，但目前的数据表明，强啡肽A诱导的钾电导被μ阿片受体选择性拮抗剂逆转，在缺乏功能性μ阿片受体的小鼠中不存在。因此，μ阿片受体介导了强啡肽A引起的阿片皮质素原神经元的抑制，这与其他研究表明，当κ阿片受体选择性激动剂和拮抗剂充分使用时，μ阿片受体选择性激动剂和拮抗剂可以作用于μ阿片受体的摄取。结果表明，如果强啡肽A抑制阿片皮质素神经元增加食物，最近的研究表明，强啡肽A是μ阿片受体的内源性激动剂，通过激活G蛋白偶联的内向整流钾通道(GIRKs)直接抑制下丘脑中的κ阿片皮质素原神经元。这种作用被认为是由κ-2阿片受体(KOR-2)介导的，并被认为是KOR激动剂促食欲作用的可能机制。本研究采用全细胞电压钳记录脑片制备方法，证明Dyn-A(1或5μm)可在前角运动神经元产生外向电流，该电流可被高选择性μ-阿片受体(MOR)拮抗剂CTAP逆转，且在缺乏MORS的小鼠中不存在。此外，KOR-2选择性激动剂GR89696可与POMC神经元上的MORs结合，但不能诱发外向电流。与Dyn-A类似，KOR选择性拮抗剂Nor-BNI在足够高的浓度下使用时缺乏特异性。最大浓度的吗啡选择性激动剂DAMGO在POMC神经元上诱发外向电流，而较高浓度的Nor-BNI可完全逆转该电流。使用一半最大浓度的DAMGO的实验表明，Nor-BNI必须在浓度为100nm时使用，以避免位于POMC神经元上的MORS拮抗剂的非特异性作用。这些数据表明，Dyn-A对POMC神经元的直接抑制是通过MOR而不是KOR-2介导的，这与先前的研究表明，Dyn-A在高浓度存在时可以作用于μ-阿片受体(MOR)。
Key pointsDynorphin A inhibits anorexigenic hypothalamic proopiomelanocortin neurons by activating a potassium conductance.Although dynorphin A is considered selective for κ‐opioid receptors, the present data show that the dynorphin A‐induced potassium conductance is reversed by a μ‐opioid receptor‐selective antagonist and is absent in mice lacking functional μ‐opioid receptors.Thus, μ‐opioid receptors mediate the inhibition of proopiomelanocortin neurons caused by dynorphin A, consistent with other studies showing that κ‐opioid receptor‐selective agonists and antagonists can act at the μ‐opioid receptor when used at sufficiently high concentrations.The results indicate that if dynorphin A inhibits proopiomelanocortin neurons to increase food intake, it does so either by activating μ‐opioid receptors on these neurons or by inhibiting κ‐opioid receptors located in the presynaptic compartment of proopiomelanocortin neurons.AbstractIt has recently been shown that dynorphin A (Dyn A), an endogenous agonist of the κ‐opioid receptor (KOR), directly inhibits proopiomelanocortin (POMC) neurons in the hypothalamus through activation of G‐protein‐coupled inwardly rectifying K+channels (GIRKs). This effect has been proposed to be mediated by the putative κ2‐opioid receptor (KOR‐2), and has been suggested as a possible mechanism for the orexigenic actions of KOR agonists. Using whole‐cell voltage clamp recordings in brain slice preparations, the present study demonstrates that Dyn A (1 or 5 μm) induces an outward current in POMC neurons that is reversed by the highly selective μ‐opioid receptor (MOR) antagonist CTAP and is absent in mice lacking MORs. Additionally, the KOR‐2‐selective agonist GR89696 binds MORs on POMC neurons but fails to induce an outward current. Similar to Dyn A, the KOR‐selective antagonistnor‐binaltorphimine (nor‐BNI) lacked specificity when used at sufficiently high concentrations. Maximal concentrations of the MOR‐selective agonist DAMGO induced outward currents in POMC neurons that were completely reversed by a relatively high concentration of nor‐BNI. Experiments using a half‐maximal concentration of DAMGO demonstrate that nor‐BNI must be used at concentrations <100 nmto avoid non‐specific actions of the antagonist at MORs located on POMC neurons. These data suggest that direct inhibition of POMC neurons by Dyn A is mediated through the MOR, not the KOR‐2, which is consistent with previous studies demonstrating that Dyn A can act at the μ‐opioid receptor (MOR) when present in high concentrations.