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

• Published in: The Journal of clinical investigation 2008-07, Vol.118 (7), p.2471-2481
• Main Authors: Xie, Xinmin, Wisor, Jonathan P, Hara, Junko, Crowder, Tara L, LeWinter, Robin, Khroyan, Taline V, Yamanaka, Akihiro, Diano, Sabrina, Horvath, Tamas L, Sakurai, Takeshi, Toll, Lawrence, Kilduff, Thomas S
• Format: Article
• Language: English
• Subjects: Analgesia; Animals; Ataxin-3; Behavior, Animal - drug effects; Behavior, Animal - physiology; Biomedical research; Brain - cytology; Brain - drug effects; Brain - metabolism; Calcium - metabolism; Cytoplasm - metabolism; Electrophysiology; Female; Hypothalamus; Hypothalamus, Posterior - cytology; Hypothalamus, Posterior - metabolism; Hypothalamus, Posterior - ultrastructure; Immunohistochemistry; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Intracellular Signaling Peptides and Proteins - pharmacology; Light; Male; Membrane Potentials - drug effects; Membrane Potentials - physiology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Narcotic Antagonists; Neurons; Neurons - cytology; Neurons - drug effects; Neurons - physiology; Neuropeptides - genetics; Neuropeptides - metabolism; Neuropeptides - pharmacology; Nociceptin; Nociceptin Receptor; Nuclear Proteins - genetics; Opioid Peptides - genetics; Opioid Peptides - metabolism; Opioid Peptides - pharmacology; Orexins; Pain Threshold - drug effects; Pain Threshold - physiology; Peptides; Presynaptic Terminals - physiology; Reaction Time - drug effects; Reaction Time - physiology; Receptors, Opioid; Stress, Physiological - physiopathology; Tetrodotoxin - pharmacology; Transcription Factors - genetics
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci35115

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.