Broad-spectrum analgesic efficacy of IBNtxA is mediated by exon 11-associated splice variants of the mu-opioid receptor gene

Most opioid analgesics used clinically, including morphine and fentanyl, as well as the recreational drug heroin, act primarily through the mu opioid receptor, a class A Rhodopsin-like G protein-coupled receptor (GPCR). The single-copy mu opioid receptor gene, OPRM1, undergoes extensive alternative splicing, creating multiple splice variants or isoforms via a variety of alternative splicing events. These OPRM1 splice variants can be categorized into three major types based on the receptor structure: (1) full-length 7 transmembrane (TM) C-terminal variants; (2) truncated 6TM; and (3) single TM variants. Increasing evidence suggests that these OPRM1 splice variants are pharmacologically important in mediating the distinct actions of various mu opioids. More importantly, the OPRM1 variants can be targeted for development of novel opioid analgesics that are potent against multiple types of pain, but devoid of many side-effects associated with traditional opiates. In this review, we provide an overview of OPRM1 alternative splicing and its functional relevance in opioid pharmacology.

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Correction to: Mu Opioids Induce Biased Signaling at the Full-Length Seven Transmembrane C-Terminal Splice Variants of the mu Opioid Receptor Gene, Oprm1

Cellular and Molecular Neurobiology ◽

10.1007/s10571-020-00990-4 ◽

2020 ◽

Author(s):

Ankita Narayan ◽

Amanda Hunkele ◽

Jin Xu ◽

Daniel L. Bassoni ◽

Gavril W. Pasternak ◽

...

Keyword(s):

Opioid Receptor ◽

Splice Variants ◽

Receptor Gene ◽

Mu Opioid Receptor ◽

Full Length ◽

Mu Opioid ◽

Biased Signaling ◽

Mu Opioids

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Identification and characterization of a novel promoter of the mouse mu opioid receptor gene (Oprm) that generates eight splice variants

Gene ◽

10.1016/s0378-1119(02)00825-9 ◽

2002 ◽

Vol 295 (1) ◽

pp. 97-108 ◽

Cited By ~ 37

Author(s):

Ying-Xian Pan

Keyword(s):

Opioid Receptor ◽

Splice Variants ◽

Receptor Gene ◽

Mu Opioid Receptor ◽

Mu Opioid ◽

Identification And Characterization

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Tetrapeptide Endomorphin Analogs Require Both Full Length and Truncated Splice Variants of the Mu Opioid Receptor Gene Oprm1 for Analgesia

ACS Chemical Neuroscience ◽

10.1021/acschemneuro.6b00240 ◽

2016 ◽

Vol 7 (12) ◽

pp. 1717-1727 ◽

Cited By ~ 5

Author(s):

Gina F. Marrone ◽

Zhigang Lu ◽

Grace Rossi ◽

Ankita Narayan ◽

Amanda Hunkele ◽

...

Keyword(s):

Opioid Receptor ◽

Splice Variants ◽

Receptor Gene ◽

Mu Opioid Receptor ◽

Full Length ◽

Mu Opioid

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Variation of the human mu-opioid receptor (OPRM1) gene predicts vulnerability to frustration

Scientific Reports ◽

10.1038/s41598-020-78783-4 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Alan M. Daniel ◽

Brenda G. Rushing ◽

Karla Y. Tapia Menchaca

Keyword(s):

Individual Differences ◽

Animal Models ◽

Opioid Receptor ◽

Receptor Gene ◽

Emotional Reaction ◽

Mu Opioid Receptor ◽

Reward Processing ◽

Physical Pain ◽

Mu Opioid ◽

Allelic Differences

AbstractUnderstanding the emotional reaction to loss, or frustration, is a critical problem for the field of mental health. Animal models of loss have pointed to the opioid system as a nexus of frustration, physical pain, and substance abuse. However, few attempts have been made to connect the results of animal models of loss to human behavior. Allelic differences in the human mu opioid receptor gene, notably the A118G single nucleotide polymorphism, have been linked to individual differences in pain sensitivity, depressive symptoms, and reward processing. The present study explored the relationship between A118G and behavior in two frustrating tasks in humans. Results showed that carriers of the mutant G-allele were slower to recover behavior following a reward downshift and abandoned a frustrating task earlier than those without the mutation. Additionally, G-carriers were more sensitive to physical pain. These results highlight the overlap between frustration and pain, and suggest that genetic variation in opioid tone may contribute to individual differences in vulnerability and resilience following emotional disturbances.

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A118G Single Nucleotide Polymorphism of Human μ-Opioid Receptor Gene Influences Pain Perception and Patient-controlled Intravenous Morphine Consumption after Intrathecal Morphine for Postcesarean Analgesia

Anesthesiology ◽

10.1097/aln.0b013e318182af21 ◽

2008 ◽

Vol 109 (3) ◽

pp. 520-526 ◽

Cited By ~ 197

Author(s):

Alex T. Sia ◽

Yvonne Lim ◽

Eileen C. P. Lim ◽

Rachelle W. C. Goh ◽

Hai Yang Law ◽

...

Keyword(s):

Opioid Receptor ◽

Pain Perception ◽

Intrathecal Morphine ◽

Receptor Gene ◽

Mu Opioid Receptor ◽

Morphine Consumption ◽

Mu Opioid ◽

Pain Scores ◽

Significant Difference ◽

Intravenous Morphine

Background Previous studies have shown that genetic variability at position 118 of the human mu-opioid receptor gene altered patients' response to intravenous morphine. The purpose of this study was to investigate whether this polymorphism contributes to the variability in response to morphine for postcesarean analgesia. Methods After investigators obtained informed consent, 588 healthy women received 0.1 mg intrathecal morphine for postcesarean analgesia. Their blood samples were genotyped for the A118G polymorphism-A118 homozygous (AA), heterozygous (AG), or homozygous for the G allele (GG). Pain scores, the severity of nausea and vomiting, the incidence of pruritus, and the total self-administered intravenous morphine were recorded for the first 24 postoperative hours. Results Two hundred seventy women (46%) were AA, 234 (40%) were AG, and 82 (14%) were GG. The 24-h self-administered intravenous morphine consumption was lowest in the AA group (P = 0.001; mean, 5.9; 95% confidence interval, 5.1-6.8) versus the AG (8.0; 6.9-9.1) and GG groups (9.4; 7.3-11.5). Pain scores were lowest in the AA group and highest in the GG group, with a statistically significant difference detected between AA, AG, and GG (P = 0.049). Total morphine consumption was also influenced by patients' age and paying status. AA group was associated with the highest incidence of nausea (26 of 272 [9.6%]; P = 0.02) versus the other two groups (13 of 234 [5.6%] and 1 of 82 [1.2%] for AG and GG, respectively). Conclusion Genetic variation at position 118 of the mu-opioid receptor is associated with interindividual differences in pain scores, self-administered intravenous morphine, and the incidence of nausea postoperatively.

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