Nociceptin/orphanin FQ exacerbates excitotoxic white-matter lesions in the murine neonatal brain
AUTOR(ES)
Laudenbach, Vincent
FONTE
American Society for Clinical Investigation
RESUMO
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.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=199242Documentos Relacionados
- Nociceptin/Orphanin FQ Receptor Activation Attenuates Antinociception Induced by Mixed Nociceptin/Orphanin FQ/μ-Opioid Receptor Agonists
- Nociceptin/orphanin FQ-induced nociceptive responses through substance P release from peripheral nerve endings in mice
- Orphanin FQ/nociceptin suppresses motor activity through an action along the mesoaccumbens axis in rats
- A synthetic agonist at the orphanin FQ/nociceptin receptor ORL1: Anxiolytic profile in the rat
- Targeted disruption of the orphanin FQ/nociceptin gene increases stress susceptibility and impairs stress adaptation in mice