title: Nociceptin/orphanin FQ knockout mice display up-regulation of the opioid receptor-like 1 receptor and alterations in opioid receptor expression in the brain.
abstract: The opioid receptor-like 1 receptor is a novel member of the opioid receptor family and its endogenous peptide ligand has been termed nociceptin and orphanin FQ. Activation of the opioid receptor-like 1 receptor by nociceptin/orphanin FQ in vivo produces hyperalgesia when this peptide is given supraspinally but analgesia at the spinal level. Nociceptin/orphanin FQ also reverses stress-induced analgesia, suggesting that the peptide has anti-opioid properties. Nociceptin/orphanin FQ knockout mice show alterations in pain sensitivity and stress responses and display increased morphine dependence, suggesting an interaction of the nociceptin/orphanin FQ system with classical opioid receptor function. To determine if the behavioural phenotype of nociceptin/orphanin FQ knockout mice reflects changes in either opioid receptor-like 1 or classical opioid receptor expression, we have carried out quantitative autoradiography of the opioid receptor-like 1, mu-, delta- and kappa-opioid receptors in the brains of these animals. Receptor density was measured on coronal sections from wild-type, heterozygous and homozygous mice using [(3)H]nociceptin, [(3)H][D-Ala(2)-N-methyl-Phe(4)-Gly(5) ol] enkephalin, [(3)H]deltorphin-I, or [(3)H](-)-N-methyl-N-[7-(1-pyrrodinyl)-1-oxospiro[4,5]dec-8-yl]-4-benzofuranacetamide to label opioid receptor-like 1, mu-, delta- and kappa-receptors, respectively. A region-specific up-regulation of the opioid receptor-like 1 receptor (up to 135%) was seen in brains from homozygous mice. Mu-Receptors also showed significant differences between genotypes whilst changes in delta- and kappa- receptors were minor. In conclusion the region-specific up-regulation of the opioid receptor-like 1 receptor indicates a tonic role for nociceptin/orphanin FQ in some brain structures and may suggest the peptide regulates the receptor expression in these regions. The changes in the opioid receptor-like 1 receptor may relate to the anxiogenic phenotype of these animals but the observed change in mu-receptors does not correlate with altered morphine responses.
authors.affiliation: Pharmacology Group, School of Biomedical and Life Sciences, University of Surrey, Guildford, UK.
authors.forename: S
authors.initials: S
authors.lastname: Clarke
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: M-S
authors.initials: MS
authors.lastname: Hsu
authors.forename: R G
authors.initials: RG
authors.lastname: Hill
authors.forename: J E
authors.initials: JE
authors.lastname: Pintar
authors.forename: I
authors.initials: I
authors.lastname: Kitchen
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D011957:Receptors, Opioid / Q000032:analysis / Q000096:biosynthesis* / Q000172:deficiency* / Q000235:genetics; D015854:Up-Regulation / Q000502:physiology*; D000094942:Nociceptin Receptor
chemical_list: D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; C000722287:Oprl1 protein, mouse