Effects of IV and ICV hypocretin-1 (orexin A) in hypocretin receptor-2 gene mutated narcoleptic dogs and IV hypocretin-1 replacement therapy in a hypocretin-ligand-deficient narcoleptic dog

Sleep. 2003 Dec 15;26(8):953-9. doi: 10.1093/sleep/26.8.953.


Study objectives: Using two different canine models of narcolepsy, we evaluated the therapeutic effects of hypocretin-1 on cataplexy and sleep.

Measurements and results: Intracerebroventricular administration of hypocretin-1 (10 and 30 nmol per dog) but not intravenous administration (up to 6 microg/kg) induced significant wakefulness in control dogs. However, hypocretin-1 had no effect on cataplexy or wakefulness in hypocretin receptor-2 gene (Hcrtr2) mutated narcoleptic Dobermans. Only very high intravenously doses of hypocretin-1 (96-384 microg/kg) penetrated the brain, to produce a short-lasting anticataplectic effect in a hypocretin-ligand-deficient animal.

Conclusions: Hypocretin-1 administration, by central and systemic routes, does not improve narcoleptic symptoms in Hcrtr2 mutated Dobermans. Systemic hypocretin-1 hardly crosses the blood-brain barrier to produce therapeutic effects. The development of more centrally penetrable and longer lasting hypocretin analogs will be needed to further explore this therapeutic pathway in humans.

MeSH terms

  • Animals
  • Brain / metabolism
  • Carrier Proteins* / genetics
  • Carrier Proteins* / therapeutic use
  • Cataplexy / drug therapy
  • Cataplexy / genetics
  • Cataplexy / metabolism
  • Dogs
  • Electroencephalography
  • Electromyography
  • Electrooculography
  • Injections, Intravenous
  • Intracellular Signaling Peptides and Proteins*
  • Narcolepsy* / drug therapy
  • Narcolepsy* / genetics
  • Narcolepsy* / metabolism
  • Neuropeptides* / deficiency
  • Neuropeptides* / genetics
  • Neuropeptides* / metabolism
  • Neuropeptides* / therapeutic use
  • Orexin Receptors
  • Orexins
  • Point Mutation / genetics*
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide / genetics*
  • Receptors, Neuropeptide / metabolism*


  • Carrier Proteins
  • HCRT protein, human
  • Intracellular Signaling Peptides and Proteins
  • Neuropeptides
  • Orexin Receptors
  • Orexins
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide