Complete knockout of the nociceptin/orphanin FQ receptor in the rat does not induce compensatory changes in μ, δ and κ opioid receptors

The nociceptin/orphanin FQ (N/OFQ) opioid peptide receptor (NOPr) is a new member of the opioid receptor family consisting of μ, δ and κ opioid receptors. The anti-opioid properties of its endogenous ligand, N/OFQ provide the receptor interesting potentials in symptoms and processes related to drug addiction, learning and memory, anxiety and depression, and nociception. Using target-selected N-ethyl-N-nitrosourea (ENU)-driven mutagenesis we recently generated a rat model bearing a premature stop codon in the opioid-like receptor (oprl1) gene, and here we describe the primary characterization of this novel model. Data revealed that [³H]N/OFQ binding to brain slices was completely absent in rats homozygous for the premature stop codon (oprl1^-/-). Heterozygous rats displayed an intermediate level of NOPr binding. Oprl1 receptor transcript levels, as determined by Northern blot analysis, were reduced by approximately 50% in oprl1^-/- rats compared to wild-type controls (oprl1^+/+), and no alternative spliced transcripts were observed. Quantitative autoradiographic mapping of μ, δ and κ opioid receptors using [³H]DAMGO, [³H]deltorphin and [³H]CI-977, respectively, did not show any changes in opioid receptor binding. In conclusion, we present a novel mutant rat lacking NOPr without compensatory changes in μ, δ and κ opioid receptors. We anticipate that this mutant rat will have heuristic value to further understand the function of NOPr.