title: Complete knockout of the nociceptin/orphanin FQ receptor in the rat does not induce compensatory changes in mu, delta and kappa opioid receptors.
abstract: The nociceptin/orphanin FQ (N/OFQ) opioid peptide receptor (NOPr) is a new member of the opioid receptor family consisting of mu, delta and kappa 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 [(3)H]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 mu, delta and kappa opioid receptors using [(3)H]DAMGO, [(3)H]deltorphin and [(3)H]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 mu, delta and kappa opioid receptors. We anticipate that this mutant rat will have heuristic value to further understand the function of NOPr.
authors.affiliation: Hubrecht Institute and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands.
authors.forename: J R
authors.initials: JR
authors.lastname: Homberg
authors.forename: J D
authors.initials: JD
authors.lastname: Mul
authors.forename: E
authors.initials: E
authors.lastname: de Wit
authors.forename: E
authors.initials: E
authors.lastname: Cuppen
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000701:Analgesics, Opioid / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive / Q000235:genetics*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics; D018389:Codon, Nonsense / Q000235:genetics; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D018847:Opioid Peptides / Q000235:genetics*; D009924:Organ Culture Techniques; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000235:genetics*; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D014316:Tritium; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D000701:Analgesics, Opioid; D018389:Codon, Nonsense; D018847:Opioid Peptides; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D014316:Tritium; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C000722285:Oprl1 protein, rat