Μ-opioid receptor

The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(mu)-opioid peptide (MOP) receptors. The prototypical μ-opioid receptor agonist is morphine, the primary psychoactive alkaloid in opium and for which the receptor was named, with mu being the first letter of Morpheus, the compound's namesake in the original Greek. It is an inhibitory G-protein coupled receptor that activates the G_i alpha subunit, inhibiting adenylate cyclase activity, lowering cAMP levels.

OPRM1
Identifiers
Aliases	OPRM1, LMOR, M-OR-1, MOP, MOR, MOR1, OPRM, opioid receptor mu 1
External IDs	OMIM: 600018; MGI: 97441; HomoloGene: 37368; GeneCards: OPRM1; OMA:OPRM1 - orthologs
Gene location (Human) Chr. Chromosome 6 (human)[1] Band 6q25.2 Start 154,010,496 bp[1] End 154,246,867 bp[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)[2] Band 10 A1|10 1.85 cM Start 6,708,506 bp[2] End 6,988,198 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gonad testicle right hemisphere of cerebellum sperm left testis right testis prefrontal cortex Brodmann area 9 nucleus accumbens hypothalamus Top expressed in medial habenular nucleus autonomic nerve plexus myenteric plexus Subplate spinal ganglia embryo nucleus of trigeminal nuclear complex greater petrosal nerve superior frontal gyrus granulocyte More reference expression data BioGPS More reference expression data
Gene ontology Molecular function voltage-gated calcium channel activity morphine receptor activity G protein-coupled receptor activity neuropeptide binding signal transducer activity filamin binding G protein-coupled opioid receptor activity protein binding beta-endorphin receptor activity G-protein alpha-subunit binding protein C-terminus binding protein domain specific binding G-protein beta-subunit binding peptide binding Cellular component postsynapse cytoplasm integral component of membrane perikaryon Golgi apparatus membrane focal adhesion integral component of plasma membrane dendrite membrane endoplasmic reticulum neuron projection membrane raft sarcolemma dendrite cytoplasm plasma membrane dendrite endosome axon cell projection spine apparatus integral component of postsynaptic membrane integral component of presynaptic membrane Biological process positive regulation of appetite negative regulation of adenylate cyclase activity adenylate cyclase-activating dopamine receptor signaling pathway sensory perception negative regulation of cAMP-mediated signaling adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway regulation of sensory perception of pain eating behavior locomotory behavior estrous cycle positive regulation of cytosolic calcium ion concentration positive regulation of nitric oxide biosynthetic process G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger negative regulation of Wnt protein secretion wound healing acute inflammatory response to antigenic stimulus positive regulation of cAMP-mediated signaling positive regulation of neurogenesis regulation of NMDA receptor activity phospholipase C-activating G protein-coupled receptor signaling pathway response to morphine response to lipopolysaccharide negative regulation of nitric oxide biosynthetic process calcium ion transmembrane transport excitatory postsynaptic potential positive regulation of ERK1 and ERK2 cascade behavioral response to ethanol response to food sensory perception of pain response to radiation response to growth factor response to ethanol signal transduction negative regulation of cell population proliferation negative regulation of cytosolic calcium ion concentration adenylate cyclase-inhibiting opioid receptor signaling pathway response to cocaine cellular response to morphine chemical synaptic transmission neuropeptide signaling pathway G protein-coupled opioid receptor signaling pathway G protein-coupled receptor signaling pathway cytokine-mediated signaling pathway regulation of cellular response to stress negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4988 18390 Ensembl ENSG00000112038 ENSMUSG00000000766 UniProt P35372 P42866 RefSeq (mRNA) NM_000914 NM_001008503 NM_001008504 NM_001008505 NM_001145279 NM_001145280 NM_001145281 NM_001145282 NM_001145283 NM_001145284 NM_001145285 NM_001145286 NM_001145287 NM_001285522 NM_001285523 NM_001285524 NM_001285526 NM_001285527 NM_001285528 NM_001039652 NM_011013 NM_001302793 NM_001302794 NM_001302795 NM_001302796 NM_001304937 NM_001304938 NM_001304948 NM_001304950 NM_001304955 RefSeq (protein) NP_000905 NP_001008503 NP_001008504 NP_001008505 NP_001138751 NP_001138752 NP_001138753 NP_001138754 NP_001138755 NP_001138756 NP_001138757 NP_001138758 NP_001138759 NP_001272451 NP_001272452 NP_001272453 NP_001272455 NP_001272456 NP_001272457 NP_001034741 NP_001289722 NP_001289723 NP_001289724 NP_001289725 NP_001291866 NP_001291867 NP_001291877 NP_001291879 NP_001291884 Location (UCSC) Chr 6: 154.01 – 154.25 Mb Chr 10: 6.71 – 6.99 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Active and inactive μ-opioid receptors^[5]

Structure

The structure of the inactive μ-opioid receptor has been determined with the antagonists β-FNA^[6] and alvimopan.^[7] Many structures of the active state are also available, with agonists including DAMGO,^[8] β-endorphin,^[9] fentanyl and morphine.^[10] The structure with the agonist BU72 has the highest resolution,^[11] but contains unexplained features that may be experimental artifacts.^[12][13] This large body of evidence has enabled structure-based design of a new class of opioids with functional selectivity.^[14]

Splice variants

Three variants of the μ-opioid receptor are well characterized, though reverse transcription polymerase chain reaction has identified up to 10 total splice variants in humans.^[15][16][17]

μ1	More is known about the μ1 opioid receptor than the other variants.
μ2	TRIMU 5 is a selective agonist of the μ2 receptor.[18]
μ3	The μ3 variant was first described in 2003.[19] It is responsive to opiate alkaloids but not opioid peptides.[20]

Location

They can exist either presynaptically or postsynaptically depending upon cell types.

The μ-opioid receptors exist mostly presynaptically in the periaqueductal gray region, and in the superficial dorsal horn of the spinal cord (specifically the substantia gelatinosa of Rolando). Other areas where they have been located include the external plexiform layer of the olfactory bulb, the nucleus accumbens, in several layers of the cerebral cortex, and in some of the nuclei of the amygdala, as well as the nucleus of the solitary tract.

Some MORs are also found in the intestinal tract. Activation of these receptors inhibits peristaltic action which causes constipation, a major side effect of μ agonists.^[21]

Activation

MOR can mediate acute changes in neuronal excitability via suppression of presynaptic release of GABA. Activation of the MOR leads to different effects on dendritic spines depending upon the agonist, and may be an example of functional selectivity at the μ-receptor.^[22] The physiological and pathological roles of these two distinct mechanisms remain to be clarified. Perhaps, both might be involved in opioid addiction and opioid-induced deficits in cognition.

Activation of the μ-opioid receptor by an agonist such as morphine causes analgesia, sedation, slightly reduced blood pressure, itching, nausea, euphoria, decreased respiration, miosis (constricted pupils), and decreased bowel motility often leading to constipation. Some of these effects, such as analgesia, sedation, euphoria, itching and decreased respiration, tend to lessen with continued use as tolerance develops. Miosis and reduced bowel motility tend to persist; little tolerance develops to these effects.^{[citation needed]}

The canonical MOR1 isoform is responsible for morphine-induced analgesia, whereas the alternatively spliced MOR1D isoform (through heterodimerization with the gastrin-releasing peptide receptor) is required for morphine-induced itching.^[23]

Deactivation

As with other G protein-coupled receptors, signalling by the μ-opioid receptor is terminated through several different mechanisms, which are upregulated with chronic use, leading to rapid tachyphylaxis.^[24] The most important regulatory proteins for the MOR are the β-arrestins arrestin beta 1 and arrestin beta 2,^[25][26][27] and the RGS proteins RGS4, RGS9-2, RGS14, and RGSZ2.^[28][29]

Long-term or high-dose use of opioids may also lead to additional mechanisms of tolerance becoming involved. This includes downregulation of MOR gene expression, so the number of receptors presented on the cell surface is actually reduced, as opposed to the more short-term desensitisation induced by β-arrestins or RGS proteins.^[30][31][32] Another long-term adaptation to opioid use can be upregulation of glutamate and other pathways in the brain which can exert an opioid-opposing effect, so reduce the effects of opioid drugs by altering downstream pathways, regardless of MOR activation.^[33][34]

Tolerance and overdoses

Fatal opioid overdose typically occurs due to bradypnea, hypoxemia, and decreased cardiac output (hypotension occurs due to vasodilation, and bradycardia further contributes to decreased cardiac output).^[35][36][37] A potentiation effect occurs when opioids are combined with ethanol, benzodiazepines, barbiturates, or other central depressants which can result in rapid loss of consciousness and an increased risk of fatal overdose.^[35][36]

Substantial tolerance to respiratory depression develops quickly, and tolerant individuals can withstand larger doses.^[38] However, tolerance to respiratory depression is quickly lost during withdrawal and may be completely reversed within a week. Many overdoses occur in people who return to their previous dose after having lost their tolerance following cessation of opioids. This puts addicts who receive medical treatment for opioid addiction at great risk of overdose when they are released, as they may be particularly vulnerable to relapse.

Less commonly, massive overdoses have been known to cause circulatory collapse from vasodilation and bradycardia.^[39]

Opioid overdoses can be rapidly reversed through the use of opioid antagonists, naloxone being the most widely used example.^[35] Opioid antagonists work by binding competitively to μ-opioid receptors and displacing opioid agonists. Additional doses of naloxone may be necessary and supportive care should be given to prevent hypoxic brain injury by monitoring vital signs.

Tramadol and tapentadol carry additional risks associated with their dual effects as SNRIs and can cause serotonin syndrome and seizures. Despite these risks, there is evidence to suggest that these drugs have a lower risk of respiratory depression compared to morphine.^[40]

Ligands

See also: List of opioids

Agonists

Endogenous agonists

• Dynorphins (e.g., dynorphin A, dynorphin B)^[41]
• Endomorphins (endomorphin-1, endomorphin-2)^[41]
• Endorphins (e.g., β-endorphin)^[41]
• Enkephalins (leu-enkephalin, met-enkephalin, adrenorphin)^[41]

Full agonists

• Codeine^[42]
• Fentanyl^[42]
• Heroin^[43]
• Hydrocodone^[42]
• Hydromorphone^[42]
• Levorphanol^[42]
• Methadone^[42][44]
• Morphine^[42]
• Oxycodone^[42]
• Oxymorphone^[42]
• Pethidine (meperidine)^[45][46]
• Tianeptine^[47]

Partial agonists

• Buprenorphine^[42]
• Butorphanol^[44] (or antagonist)^[48]
• Dezocine^[49][50]
• Nalbuphine^[44] (or antagonist)^[48]
• Oliceridine^[42]
• Pentazocine^[42][44][46] (or antagonist)^[48]
• Tramadol^[43] (or partial agonist)^[42]

Biased agonists

• Oliceridine^[51]
• PZM21^[51]
• SHR9352^[52]
• SR-17018^[51]
• Tegileridine^[53]
• TRV734^[54]

Peripherally selective agonists

• Loperamide^[55][56]

Irreversible agonists

• Chloroxymorphamine^[57][58]
• Methoclocinnamox^[59]
• Oxymorphazone^[60][61]

Antagonists

Antagonists and inverse agonists

• Cyclazocine^[62]
• Cyprodime^[63]
• Diprenorphine^[64]
• Levallorphan^[65]
• Nalmefene^[66]
• Nalodeine^[67]
• Nalorphine^[65]
• Naloxone^[68]
• Naltrexone^[69]
• Samidorphan^[70]

Note that some of the above drugs may actually be very weak partial agonists rather than silent antagonists.

Peripherally selective antagonists

• 6β-Naltrexol^[71]
• Alvimopan^[72]
• Axelopran^[73]
• Bevenopran^[74]
• Methylnaltrexone^[75]
• Naldemedine^[76]
• Naloxegol^[77]

Gastrointestinally selective antagonists

• Naloxone (with oral administration)^[78]

Irreversible antagonists

• β-Chlornaltrexamine^[79][80]
• β-Funaltrexamine^[81]
• Clocinnamox^[82][83]
• Methocinnamox^[84][85]
• Naloxazone^[86]
• Naloxonazine^[87]

Allosteric modulators

Positive allosteric modulators

• BMS-986121^[88][89]
• BMS‐986122^{[88][90][89][91]}
• Comp5^[92][93]
• Hydroxynorketamine (HNK)^[94]
• Ignavine^[95]
• Ketamine^[94]
• MS1^[88][96]
• Norketamine^[94]
• Oxytocin^[97][98][99]

Negative allosteric modulators

• Δ⁹-Tetrahydrocannabinol (THC) (weak)^[88]
• Cannabidiol (weak)^[88][89]
• Salvinorin A (weak)^[88][89]

Silent allosteric modulators

• BMS-986124^[88]

Unsorted allosteric modulators

• SCH-202676 (highly non-selective)^[88][100]

See also

• δ-opioid receptor
• κ-opioid receptor

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External links

• "Opioid Receptors: μ". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
• mu+Opioid+Receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human OPRM1 genome location and OPRM1 gene details page in the UCSC Genome Browser.