OPRM1

Official Full Name

opioid receptor mu 1

Organism

Homo sapiens

GeneID

4988

Background

This gene encodes one of at least three opioid receptors in humans; the mu opioid receptor (MOR). The MOR is the principal target of endogenous opioid peptides and opioid analgesic agents such as beta-endorphin and enkephalins. The MOR also has an important role in dependence to other drugs of abuse, such as nicotine, cocaine, and alcohol via its modulation of the dopamine system. The NM_001008503.2:c.118A>G allele has been associated with opioid and alcohol addiction and variations in pain sensitivity but evidence for it having a causal role is conflicting. Multiple transcript variants encoding different isoforms have been found for this gene. Though the canonical MOR belongs to the superfamily of 7-transmembrane-spanning G-protein-coupled receptors some isoforms of this gene have only 6 transmembrane domains. [provided by RefSeq, Oct 2013]

Synonyms

MOP; MOR; LMOR; MOR1; OPRM; M-OR-1;

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Detailed Information

Opioid receptors are part of the Rhodopsin family of G-protein coupled receptors (GPCRs), which activate downstream signaling through interactions with heterotrimeric G proteins. The three most common types are the μ-opioid receptor (MOR), δ-opioid receptor (DOR), and κ-opioid receptor (KOR), encoded by the OPRM1, OPRD1, and OPRK1 genes, respectively. Each receptor type has seven transmembrane domains, three intracellular loops, three extracellular loops, an extracellular N-terminus, and an intracellular C-terminus. The three main receptor types are highly homologous within the transmembrane domains, which are arranged in a helical pattern, but have significantly less homology in the extracellular regions. Key residues within these domains create a ligand-binding pocket and binding of opioid agonists within the pocket results in activation of the opioid receptor and subsequent downstream signaling. Variation in the extracellular loops regulates ligand-receptor interaction and allows varying degrees of specificity between different endogenous peptides and opioid receptor types. MOR is activated by both endomorphins and β-endorphin, a cleavage product of the pro-opiomelanocortin precursor.

The μ-opioid Receptor

The μ-opioid receptor modulates a diverse range of physiological systems, including nociception and analgesia, reward and euphoria, immune function, stress responsivity, respiration and gut motility. The most well-characterized signaling pathways of the μ-opioid receptor proceed via activation of heterotrimeric G proteins or β-arrestin. The μ-opioid receptor can couple to a number of different G proteins, including Pertussis toxin-sensitive Gα_i/o subunits, the closely related Gα_z, and Gα₁₆. Canonical coupling of the μ-opioid receptor includes Gα_i/o inhibition of AC, Gβγ subunit activation of G protein-coupled, inwardly rectifying potassium channels and inhibition of voltage-gated Ca²⁺ channels (CaV), as well as activation of MAPK. Examples of G protein independent signaling of μ-opioid receptors include β-arrestin-mediated ERK1/2 activation, signal transducer and activator of transcription 5 phosphorylation and Src-mediated Ras/Raf-1 recruitment.

OPRM1 and Pain

Painful stimuli cause the release of endogenous opioids, activating MOR and causing analgesic responses. In this way, MOR is responsible for mitigating the sensation of pain in the absence of opioid medication. Various forms of painful stimuli result in different biochemical and physiological responses and it is, therefore, likely that there are differences in the effects of genetic variations on the thresholds and tolerance levels for different types of pain. Due to the involvement of MOR in analgesia, Fillingim et al. assessed the effects of the A118G polymorphism on pain from three different sources: pressure, heat, and ischemia. Individuals carrying the G allele were found to have higher thresholds for pressure pain, while no differences were observed in ischemic pain. For thermal pain, men with the G allele reported lower pain ratings, while women reported more pain. Another study found the minor allele of the intronic variant rs9479757 to also be associated with a higher pressure pain threshold. Although these experiments can provide valuable information about functional genetic variation, there is no guarantee that these effects are relevant to patient populations in less experimentally controlled settings. There is evidence, however, that OPRM1 variants do affect pain in some patients in a clinical setting. Women with the G allele of A118G report higher intensity pain from migraines, and have more pain and slower recovery from herniated disks. Fibromyalgia patients carrying the G allele also suffer from more pain, further suggesting that A118G is associated with pain sensitivity.

OPRM1-based Therapy

MOR naturally regulates the analgesic response to pain and also controls the rewarding effects of many drugs of abuse, including opioids, nicotine, and alcohol. Because of the opioid receptor's involvement, many analgesics are direct MOR agonists and treatments for addiction often act as either agonists, partial agonists, or antagonists of MOR. The connection between MOR and both addiction and pain makes OPRM1, the gene encoding MOR, an interesting target for pharmacogenetics studies. Genetic variants in OPRM1, particularly A118G, have been repeatedly associated with the efficacy of treatments for pain and alcohol dependence. In the two most well replicated findings, patients carrying the G allele had a reduced analgesic response to exogenous opioids and alcoholics with the G allele had reduced relapse rates when treated with naltrexone. Additional connections between OPRM1 and treatments for opioid and nicotine addiction are also promising, but require further study. Clear definitions of the phenotypes and ethnicities involved in these future analyses will be essential, as even minor variations in either factor could compromise the ability to replicate previous findings. By confirming the pharmacogenetics effects of OPRM1 polymorphisms and using those findings to guide treatment decisions, patients can be prescribed the therapeutic options with the best efficacy and the greatest tolerability.

References:

Knapman A, Connor M. Cellular signalling of non-synonymous single-nucleotide polymorphisms of the human μ-opioid receptor (OPRM1). British journal of pharmacology, 2015, 172(2): 349-363.
Crist R C, Berrettini W H. Pharmacogenetics of OPRM1. Pharmacology Biochemistry and Behavior, 2014, 123: 25-33.
Hastie B A, et al. Ethnicity interacts with the OPRM1 gene in experimental pain sensitivity. PAIN®, 2012, 153(8): 1610-1619.

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