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

Area of Science:

• Neuroscience
• Developmental Neuroscience
• Toxicology

Background:

• Intracerebral ibotenate administration in newborn mice creates white-matter lesions similar to those in human preterm infants.
• Nociceptin (NC) is the endogenous ligand for the opioid receptor-like 1 (ORL1) receptor, distinct from classical opioid receptors.

Purpose of the Study:

• To investigate the role of Nociceptin (NC) and its receptor, ORL1, in excitotoxic white-matter lesions.
• To evaluate the potential of blocking NC/ORL1 signaling as a neuroprotective strategy for preterm infant brain injury.

Main Methods:

• Induction of white-matter lesions using intracerebral ibotenate in newborn mice.
• Administration of NC, NC antagonists, classical opioid receptor agonists/antagonists, and fentanyl.
• Treatment with antisense oligonucleotides targeting the NC precursor peptide mRNA.
• Assessment of lesion size and effects of pharmacological interventions.

Main Results:

• NC administration exacerbated ibotenate-induced white-matter lesions.
• Coadministration with NC antagonists reduced lesions by up to 64%.
• Classical opioid receptor modulators did not affect lesion size.
• Antisense oligonucleotides targeting NC precursor mRNA reduced white-matter damage.
• Fentanyl exacerbated lesions, with toxicity blocked by ORL1 inhibition.

Conclusions:

• Endogenous or exogenous stimulation of the ORL1 receptor is neurotoxic.
• Blocking NC/ORL1 signaling protects white matter from excitotoxic injury.
• Targeting NC/ORL1 signaling offers a potential neuroprotective approach for preterm infants.