Hypocretin/orexin and nociceptin/orphanin FQ coordinately regulate analgesia in a mouse model of stress-induced analgesia.
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.
Xie
Xinmin
X
Biosciences Division, SRI International, Menlo Park, California 94025, USA. simonxie@afasci.com
Wisor
Jonathan P
JP
Hara
Junko
J
Crowder
Tara L
TL
LeWinter
Robin
R
Khroyan
Taline V
TV
Yamanaka
Akihiro
A
Diano
Sabrina
S
Horvath
Tamas L
TL
Sakurai
Takeshi
T
Toll
Lawrence
L
Kilduff
Thomas S
TS
D000698:Analgesia; D000818:Animals; D000067699:Ataxin-3; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004594:Electrophysiology; D005260:Female; D007034:Hypothalamus, Posterior / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009292:Narcotic Antagonists; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics; D018847:Opioid Peptides / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000068797:Orexins; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D017729:Presynaptic Terminals / Q000502:physiology; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D011957:Receptors, Opioid; D013312:Stress, Physiological / Q000503:physiopathology*; D013779:Tetrodotoxin / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D000067699:Ataxin-3; D002118:Calcium; D047908:Intracellular Signaling Peptides and Proteins; D009292:Narcotic Antagonists; D009479:Neuropeptides; D009687:Nuclear Proteins; D018847:Opioid Peptides; D000068797:Orexins; D011957:Receptors, Opioid; D013779:Tetrodotoxin; D014157:Transcription Factors; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C511594:Atxn3 protein, mouse; C000722287:Oprl1 protein, mouse