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Hypocretin/orexin and nociceptin/orphanin FQ coordinately regulate analgesia in a mouse model of stress-induced analgesia
Xinmin Xie, … , Lawrence Toll, Thomas S. Kilduff
Xinmin Xie, … , Lawrence Toll, Thomas S. Kilduff
Published June 12, 2008
Citation Information: J Clin Invest. 2008;118(7):2471-2481. https://doi.org/10.1172/JCI35115.
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Research Article Neuroscience

Hypocretin/orexin and nociceptin/orphanin FQ coordinately regulate analgesia in a mouse model of stress-induced analgesia

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Abstract

Stress-induced analgesia (SIA) is a key component of the defensive behavioral “fight-or-flight” response. Although the neural substrates of SIA are incompletely understood, previous studies have implicated the hypocretin/orexin (Hcrt) and nociceptin/orphanin FQ (N/OFQ) peptidergic systems in the regulation of SIA. Using immunohistochemistry in brain tissue from wild-type mice, we identified N/OFQ-containing fibers forming synaptic contacts with Hcrt neurons at both the light and electron microscopic levels. Patch clamp recordings in GFP-tagged mouse Hcrt neurons revealed that N/OFQ hyperpolarized, decreased input resistance, and blocked the firing of action potentials in Hcrt neurons. N/OFQ postsynaptic effects were consistent with opening of a G protein–regulated inwardly rectifying K+ (GIRK) channel. N/OFQ also modulated presynaptic release of GABA and glutamate onto Hcrt neurons in mouse hypothalamic slices. Orexin/ataxin-3 mice, in which the Hcrt neurons degenerate, did not exhibit SIA, although analgesia was induced by i.c.v. administration of Hcrt-1. N/OFQ blocked SIA in wild-type mice, while coadministration of Hcrt-1 overcame N/OFQ inhibition of SIA. These results establish what is, to our knowledge, a novel interaction between the N/OFQ and Hcrt systems in which the corticotropin-releasing factor and N/OFQ systems coordinately modulate the Hcrt neurons to regulate SIA.

Authors

Xinmin Xie, Jonathan P. Wisor, Junko Hara, Tara L. Crowder, Robin LeWinter, Taline V. Khroyan, Akihiro Yamanaka, Sabrina Diano, Tamas L. Horvath, Takeshi Sakurai, Lawrence Toll, Thomas S. Kilduff

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Figure 2

N/OFQ directly hyperpolarizes Hcrt neurons in a dose-depenedent manner.

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N/OFQ directly hyperpolarizes Hcrt neurons in a dose-depenedent manner.
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(A) N/OFQ (1 μM) caused hyperpolarization and a decrease in input resistance in the presence of TTX (0.3 μM), which was used to block synaptic activity and action potentials in an Hcrt-containing cell. (B) In the same neuron, the NOP receptor antagonist SR14148 (10 μM) blocks the N/OFQ-induced hyperpolarization and input resistance decrease. The blockade was reversible after 20-minute washout of the antagonist (data not shown). (C) Since the N/OFQ-induced hyperpolarization apparently did not differ in the presence or absence of TTX, both data sets were pooled to construct a concentration-dependent response curve using the pharmacologic dose-response model-fitting function (OriginPro 7.5; OriginLab). The half-maximal effect of N/OFQ-induced hyperpolarization (EC50) was calculated at 0.329 μM with a Hill coefficient of 1.1. Error bars represent SEM.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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