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Nociceptin/orphanin FQ exacerbates excitotoxic white-matter lesions in the murine neonatal brain
Vincent Laudenbach, … , Philippe Evrard, Pierre Gressens
Vincent Laudenbach, … , Philippe Evrard, Pierre Gressens
Published February 15, 2001
Citation Information: J Clin Invest. 2001;107(4):457-466. https://doi.org/10.1172/JCI9716.
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Article

Nociceptin/orphanin FQ exacerbates excitotoxic white-matter lesions in the murine neonatal brain

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Abstract

Intracerebral administration of the excitotoxin ibotenate to newborn mice induces white-matter lesions, mimicking brain lesions that occur in human preterm infants. Nociceptin (NC), also called orphanin FQ, is the endogenous ligand of the opioid receptor-like 1 (ORL1) receptor and does not bind classical high-affinity opioid receptors. In the present study, administration of NC exacerbated ibotenate-induced white-matter lesions while coadministration of ibotenate with either of two NC antagonists reduced excitotoxic white-matter lesions by up to 64%. Neither ibotenate plus endomorphin I (a selective μ receptor agonist), nor ibotenate plus naloxone (a classical opioid receptor antagonist) modulated the excitotoxic lesion. Pretreatment with antisense oligonucleotides targeting the NC precursor peptide mRNA significantly reduced ibotenate-induced white-matter damage. Finally, high doses of fentanyl, which stimulates both classical μ opioid receptors and ORL1, exacerbated excitotoxic white-matter lesion. This toxic effect was blocked by inhibiting ORL1 but not classical opioid receptors. Together, these findings show that endogenous or exogenous stimulation of the ORL1 receptor can be neurotoxic and that blocking NC signaling protects the white matter against excitotoxic challenge. These data point to potential new avenues for neuroprotection in human preterm infants at high risk of brain lesions.

Authors

Vincent Laudenbach, Girolamo Calo, Remo Guerrini, Géraldine Lamboley, Jean-François Benoist, Philippe Evrard, Pierre Gressens

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Figure 1

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NC exacerbates ibotenate-induced white-matter lesions and the blockade o...
NC exacerbates ibotenate-induced white-matter lesions and the blockade of endogenous NC neurotransmission is protective. Cresyl violet–stained sections showing brain lesions induced by ibotenate injected at P5 and studied at the age of P10. (a) Brain injected with ibotenate alone, showing typical neuronal loss in layers II–VI (arrow) and white-matter cystic lesion (arrowheads). (b and c) Brains cotreated with ibotenate and 25 μg/kg NC (b) or 250 μg/kg [Nphe1]NC(1–13)NH2 (c). (d) Brain pretreated with precursor pro-NC mRNA antisense oligonucleotide at P3 and P4, and injected with ibotenate at P5. Bar, 40 μm.

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

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