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

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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Quantitative analysis of the modulatory effects of NC agonists and antag...
Quantitative analysis of the modulatory effects of NC agonists and antagonists on ibotenate-induced lesions. Bars represent mean length of the lesion along the sagittal fronto-occipital axis ± SEM. Numbers in parentheses are the numbers of animals used in each experimental group. (a and b) Effects of NC analogs and NC antagonists on excitotoxic white-matter (a) and cortical plate (b) lesions. Pups cotreated with NC and an NC antagonist received the highest dose of each peptide. Statistically significant differences between controls and experimental animals are shown (AP < 0.05, BP < 0.01 in ANOVA with Dunnett’s multiple comparison test). NC-NH2, NC(1–17)NH2; desPhe, [desPhe1]NC(1–17)NH2; F/G, [F/G]NC(1–13)NH2; Nphe, [Nphe1]NC(1–13)NH2; and Nalb, NalBzoH. (c) Mean length of the white-matter lesion at different times (indicated on the x axis) after ibotenate injection in pups cotreated with PBS (filled bars) or [Nphe1]NC(1–13)NH2 (open bars) injections. The two-way ANOVA showed a significant Treatment by Time interaction (P < 0.01). Contrast analyses revealed significant differences between controls and [Nphe1]NC(1–13)NH2-treated pups at 24 hours (P < 0.01), at 72 hours (P < 0.05), and at 120 hours (P < 0.01). (d) Effects of classical opioid agonists and antagonists on white-matter excitotoxic lesions. Pups cotreated with NC and naloxone received 25 mg/kg of each drug. Statistically significant differences between controls and experimental animals are shown (AP < 0.05, BP < 0.01 in ANOVA with Dunnett’s multiple comparison test). Endomorph I, endomorphin I. (e) Effects of fentanyl and sufentanil on cortical plate and white-matter excitotoxic lesion. Statistically significant differences from controls or pups treated with 10 μg/kg fentanyl are shown (AP < 0.05 or CP < 0.01 in ANOVA with Dunnett’s multiple comparison test, respectively). Fenta, fentanyl; Nalox, naloxone; Sufenta, sufentanil. When not indicated on the graph, the dose of fentanyl was 10 μg/kg, the dose of [Nphe1]NC(1–13)NH2 was 250 μg/kg and the dose of naloxone was 25 μg/kg. (f) Effects of pretreatment with precursor pro-NC mRNA antisense oligonucleotides (AON) or sense oligonucleotides (SON) on ibotenate-induced lesions. Statistically significant differences between controls and experimental animals are shown (BP < 0.01 in ANOVA with Dunnett’s multiple comparison test).