Expansion of the human μ-opioid receptor gene architecture: novel functional variants

Abstract

The μ-opioid receptor (OPRM1) is the principal receptor target for both endogenous and exogenous opioid analgesics. There are substantial individual differences in human responses to painful stimuli and to opiate drugs that are attributed to genetic variations in OPRM1. In searching for new functional variants, we employed comparative genome analysis and obtained evidence for the existence of an expanded human OPRM1 gene locus with new promoters, alternative exons and regulatory elements. Examination of polymorphisms within the human OPRM1 gene locus identified strong association between single nucleotide polymorphism (SNP) rs563649 and individual variations in pain perception. SNP rs563649 is located within a structurally conserved internal ribosome entry site (IRES) in the 5′-UTR of a novel exon 13-containing OPRM1 isoforms (MOR-1K) and affects both mRNA levels and translation efficiency of these variants. Furthermore, rs563649 exhibits very strong linkage disequilibrium throughout the entire OPRM1 gene locus and thus affects the functional contribution of the corresponding haplotype that includes other functional OPRM1 SNPs. Our results provide evidence for an essential role for MOR-1K isoforms in nociceptive signaling and suggest that genetic variations in alternative OPRM1 isoforms may contribute to individual differences in opiate responses.

Prenatal exposure to cigarette smoke interacts with OPRM1 to modulate dietary preference for fat

“…[24][25][26] OPRM1 is a complex gene with multiple 5' and 3' alternative splice sites that can generate more than 20 alternative transcripts. 46,47 Further, genebody methylation may be involved in suppression of gene expression by, for example, inhibiting alternative promoters embedded in gene bodies 48 or by impeding RNA-polymerase transit and transcription elongation. 49,50 Whether the observed lower gene-body methylation of OPRM1 modulates its expression requires further experimental research.…”

Validation of a modified McGill Pain Questionnaire for orthodontic patients

“…Candidate genes linked to inflammation, tooth movement, and pain sensitivity include those of the interleukin-1 gene cluster, 20 catechol-O-methyltransferase, 12 prostaglandin-endoperoxide synthase 2, 21 and m-opioid recepter. 22 Combining these improvements in a study design with the validated MMPQ-SF11 should provide improved knowledge of the intensity as well as the quality of pain experienced by adolescents during orthodontic tooth movement. Future application of the MMPQ-SF11 to measure orthodontic pain more specifically could lead to appropriate management of this important facet of therapy.…”

Mu Opioids and Their Receptors: Evolution of a Concept

“…hMOR-1A was the first splice variant isolated (Bare et al, 1994), leading to the identification of its homolog in both mice and rats. This, in turn, led to the subsequent cloning of a range of human variants, most from human neuroblastoma cell lines (Cadet et al, 2003;Pan et al, 2003Pan et al, , 2005aChoi et al, 2006;Chou et al, 2006;Shabalina et al, 2009;Xu et al, 2009Xu et al, , 2011. As in rodents, most of the variants are generated through the exon 1 promoter and produce full-length G protein-coupled receptor variants in which exon 4 is replaced with a variety of alternative exons.…”

“…hMOR-1K contains an exon homologous to the mouse exon 13 (Shabalina et al, 2009). Located 3 kb upstream of exon 2, the human exon 13 has no predicted coding sequence.…”