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

J Clin Invest. 2008 Jul;118(7):2471-81. doi: 10.1172/JCI35115.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesia*
  • Animals
  • Ataxin-3
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology
  • Brain / cytology
  • Brain / drug effects
  • Brain / metabolism
  • Calcium / metabolism
  • Cytoplasm / metabolism
  • Electrophysiology
  • Female
  • 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
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Narcotic Antagonists
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / physiology
  • Neuropeptides / genetics
  • Neuropeptides / metabolism*
  • Neuropeptides / pharmacology
  • Nuclear Proteins / genetics
  • Opioid Peptides / genetics
  • Opioid Peptides / metabolism*
  • Opioid Peptides / pharmacology
  • Orexins
  • Pain Threshold / drug effects
  • Pain Threshold / physiology
  • Presynaptic Terminals / physiology
  • Reaction Time / drug effects
  • Reaction Time / physiology
  • Receptors, Opioid
  • Stress, Physiological / physiopathology*
  • Tetrodotoxin / pharmacology
  • Transcription Factors / genetics

Substances

  • Intracellular Signaling Peptides and Proteins
  • Narcotic Antagonists
  • Neuropeptides
  • Nuclear Proteins
  • Opioid Peptides
  • Orexins
  • Receptors, Opioid
  • Transcription Factors
  • Tetrodotoxin
  • nociceptin
  • nociceptin receptor
  • Ataxin-3
  • Atxn3 protein, mouse
  • Calcium