Mu opioid receptors mediate the pharmacological actions of morphine and morphine-like drugs, such as heroin. The mouse and human Oprm genes undergo splicing. In these present studies, we have identified and characterized three new MOR-1 splice variants from the rat Oprm gene. Using an RT-PCR approach, we isolated the new exons 7, 8 and 9 downstream of exon 3. The rat exons 7 and 9 were homologous to the mouse exons 7 and 9 while the rat exon 8 was not. Northern blot analysis with the new exon probes showed distinctive and abundant transcripts of the variants in the rat brain. Full-length cDNA clones containing the new exons, rMOR-1C1, rMOR-1C2 and rMOR-1D were obtained using an RT-PCR approach. Each contained the same exons 1, 2 and 3 as the original rMOR-1, followed by different combinations of the new exons in place of exon 4. In addition, we also isolated another new variant, rMOR-1A, which contains only exons 1, 2 and 3, and is homologous to the human variant MOR-1A previously identified. All the variants were highly mu-selective in binding studies with little difference in affinities for the mu ligands among the variants. However, functional evaluation of assessments of the variants using agonist stimulated [ ]enkephalin (DAMGO) and antagonists such as b-funaltrexamine also are highly selective for these receptors and have proven useful tools in exploring the pharmacology of these receptors. Evidence suggesting the existence of mu opioid receptor subtypes goes back several decades (Pasternak and Snyder 1975;Wolozin and Pasternak 1981), having initially been based upon detailed receptor binding approaches and the synthesis of antagonists highly selective for a subpopulation of mu opioid binding sites (Pasternak and Hahn 1980;Hahn et al. 1982). In vivo, these antagonists dissociated morphine analgesia from other actions, such as respiratory depression, the inhibition of gastrointestinal transit and even many of the components of dependence (Ling et al. 1984(Ling et al. , 1985(Ling et al. , 1986Heyman et al. 1988). In addition, differences among the mu opioids have also been noted. Clinicians have long appreciated the wide range of responses to different mu analgesics among their patients, leading to the recognition of the need to individualize therapy for patients. In addition to differences in the dose of drug needed to be effective among patients, the relative potencies of the drugs to each other also vary among patients. These observations can be observed in animal models as well. For
Stargardt disease‐3 (STGD3) is an autosomal dominant juvenile‐onset macular dystrophy characterized by progressive decreasing visual acuity, bilateral atrophic changes in the macula and absence of characteristic dark choroids. We identified a STGD3‐like macular dystrophy pedigree by clinical examination. To explore whether the STGD3‐like phenotype in the kindred is linked to ELOVL4 gene or associated with any other identified STGD gene, we extracted genomic DNA from leukocytes of peripheral blood from the available family members and 50 normal controls for mutation analysis. Then the exons of ELOVL4, RDS and the three exons of ABCR were amplified by polymerase chain reaction (PCR). All PCR products were screened for mutations by combination of denaturing high‐performance liquid chromatography (DHPLC) analysis and DNA sequencing. No mutation was found in the exons of three candidate genes, but we obtained three non‐pathogenic polymorphisms, IVS5–2533T A in ELOVL4, 558C T (Val106Val) and 1150G C (Glu304Gln) in RDS. And IVS5–2533T A is never shown in the previous references. These data suggested that there exist other unknown genes responsible for the STGD3‐like phenotype in the pedigree.
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