μ-opioid receptor

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
Genetically Related Diseases
coronary artery disease[1]
Targeted by Drug
cebranopadol, eluxadoline, hydrocodone, hydromorphone, levorphanol, loperamide, methadone, nalbuphine, meperidine, tapentadol, codeine, DADLE, DAMGO, dihydromorphine, endomorphin-1, etonitazene, fentanyl, levomethadone, morphine, sufentanil, buprenorphine, butorphanol, (-)-pentazocine, alvimopan anhydrous, diprenorphine, levallorphan, methylnaltrexone, nalmefene, nalorphine, naloxone, naltrexone, naltriben, naltrindole, quadazocine[2]
Gene ontology Molecular function • voltage-gated calcium channel activity • morphine receptor activity • G-protein coupled receptor activity • protein domain specific binding • neuropeptide binding • signal transducer activity • G-protein beta-subunit binding • filamin binding • opioid receptor activity • protein C-terminus binding • protein binding • beta-endorphin receptor activity • G-protein alpha-subunit binding Cellular component • postsynapse • cytoplasm • integral component of membrane • perikaryon • Golgi apparatus • membrane • focal adhesion • plasma membrane • integral component of plasma membrane • dendrite membrane • dendrite • endoplasmic reticulum • neuron projection • membrane raft • sarcolemma • dendrite cytoplasm • cell Biological process • positive regulation of appetite • G-protein coupled receptor signaling pathway • 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 N-methyl-D-aspartate selective glutamate receptor activity • phospholipase C-activating G-protein coupled receptor signaling pathway • cellular response to stress • response to morphine • response to lipopolysaccharide • negative regulation of nitric oxide biosynthetic process • opioid receptor signaling pathway • calcium ion transmembrane transport • excitatory postsynaptic potential • positive regulation of ERK1 and ERK2 cascade • behavioral response to ethanol • negative regulation of cAMP biosynthetic process • response to food • sensory perception of pain • response to radiation • response to growth factor • response to ethanol • signal transduction • negative regulation of cell 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 Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
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_000905.3 NP_001008503.2 NP_001008504.2 NP_001008505.2 NP_001138751.1 NP_001138752.1 NP_001138753.1 NP_001138754.1 NP_001138755.1 NP_001138756.1 NP_001138757.1 NP_001138758.1 NP_001138759.1 NP_001272452.1 NP_001272453.1 NP_001272455.1 NP_001272456.1 NP_001272457.1	NP_001034741.1 NP_001289722.1 NP_001289723.1 NP_001289724.1 NP_001289725.1 NP_001291866.1 NP_001291867.1 NP_001291877.1 NP_001291879.1 NP_001291884.1
Location (UCSC)	Chr 6: 154.01 – 154.25 Mb	Chr 10: 6.76 – 7.04 Mb
PubMed search	[3]	[4]
Wikidata

View/Edit Human

View/Edit Mouse

Active and inactive μ-opioid receptors^[5]

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-opioid peptide (MOP) receptors. The prototypical μ-opioid receptor agonist is morphine, the primary psychoactive alkaloid in opium.

Types

Three variants of the μ-opioid receptor are well-characterized, though RT-PCR has identified up to 10 total splice variants in humans.^[6][7]

μ1	More is known about the μ1 opioid receptor than the other variants.
μ2	TRIMU 5 is a selective agonist of the μ2 receptor.[8]
μ3	The μ3 variant was first described in 2003.[9] It is responsive to opiate alkaloids but not opioid peptides.[10]

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.^[11]

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.^[12] 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.

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.^[13]

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.^[14] The most important regulatory proteins for the MOR are the β-arrestins arrestin beta 1 and arrestin beta 2,^[15][16][17] and the RGS proteins RGS4, RGS9-2, RGS14, and RGSZ2.^[18][19]

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.^[20][21][22] 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.^[23][24]

Tolerance and overdoses

Opioid overdoses kill through apnea and fatal hypoxia, often caused by combination with ethanol, benzodiazepines, or barbiturates. Substantial tolerance to respiratory depression develops quickly, and tolerant individuals can withstand larger doses. However, tolerance to respiratory depression is lost just as quickly during withdrawal. Many overdoses occur in people who misuse their medication after being in withdrawal long enough to lose the tolerance to respiratory depression. Less commonly, massive overdoses have been known to cause circulatory collapse.

Opioid overdoses can be rapidly reversed through the use of opioid antagonists, naloxone being the most widely used example.

See also

• δ-opioid receptor
• K-opioid receptor

References

1. "Diseases that are genetically associated with OPRM1 view/edit references on wikidata".
2. "Drugs that physically interact with Mu-type opioid receptor view/edit references on wikidata".
3. "Human PubMed Reference:".
4. "Mouse PubMed Reference:".
5. Zhorov BS, Ananthanarayanan VS (March 2000). "Homology models of mu-opioid receptor with organic and inorganic cations at conserved aspartates in the second and third transmembrane domains". Arch. Biochem. Biophys. 375 (1): 31–49. doi:10.1006/abbi.1999.1529. PMID 10683246.
6. Dortch-Carnes J, Russell K (2007). "Morphine-stimulated nitric oxide release in rabbit aqueous humor". Exp. Eye Res. 84 (1): 185–90. doi:10.1016/j.exer.2006.09.014. PMC 1766947. PMID 17094965.
7. Pan L, Xu J, Yu R, Xu MM, Pan YX, Pasternak GW (2005). "Identification and characterization of six new alternatively spliced variants of the human mu opioid receptor gene, Oprm". Neuroscience. 133 (1): 209–20. doi:10.1016/j.neuroscience.2004.12.033. PMID 15893644.
8. Eisenberg RM (1994). "TRIMU-5, a μ₂-opioid receptor agonist, stimulates the hypothalamo-pituitary-adrenal axis". Pharmacol. Biochem. Behav. 47 (4): 943–6. doi:10.1016/0091-3057(94)90300-X. PMID 8029266.
9. Cadet P, Mantione KJ, Stefano GB (2003). "Molecular identification and functional expression of μ₃, a novel alternatively spliced variant of the human μ opiate receptor gene". J. Immunol. 170 (10): 5118–23. doi:10.4049/jimmunol.170.10.5118. PMID 12734358.
10. Stefano GB (2004). "Endogenous morphine: a role in wellness medicine". Med. Sci. Monit. 10 (6): ED5. PMID 15173675.
11. Chen, Wency (2012). "Opiate-induced constipation related to activation of small intestine opioid μ2-receptors". World Journal of Gastroenterology. 18 (12): 1391–6. doi:10.3748/wjg.v18.i12.1391. PMC 3319967. PMID 22493554.
12. Liao D, Lin H, Law PY, Loh HH (February 2005). "Mu-opioid receptors modulate the stability of dendritic spines". Proc. Natl. Acad. Sci. U.S.A. 102 (5): 1725–30. Bibcode:2005PNAS..102.1725L. doi:10.1073/pnas.0406797102. JSTOR 3374498. PMC 545084. PMID 15659552.
13. Liu XY, Liu ZC, Sun YG, Ross M, Kim S, Tsai FF, Li QF, Jeffry J, Kim JY, Loh HH, Chen ZF. "Unidirectional Cross-Activation of GRPR by MOR1D Uncouples Itch and Analgesia Induced by Opioids". Cell. 147 (2): 447–458. doi:10.1016/j.cell.2011.08.043. PMC 3197217. PMID 22000021. Lay summary – Washington University in St. Louis Press Release.
14. Martini L, Whistler JL (October 2007). "The role of mu opioid receptor desensitization and endocytosis in morphine tolerance and dependence". Current Opinion in Neurobiology. 17 (5): 556–64. doi:10.1016/j.conb.2007.10.004. PMID 18068348.
15. Zuo Z (September 2005). "The role of opioid receptor internalization and beta-arrestins in the development of opioid tolerance". Anesthesia and Analgesia. 101 (3): 728–34, table of contents. doi:10.1213/01.ANE.0000160588.32007.AD. PMID 16115983.
16. Marie N, Aguila B, Allouche S (November 2006). "Tracking the opioid receptors on the way of desensitization". Cellular Signalling. 18 (11): 1815–33. doi:10.1016/j.cellsig.2006.03.015. PMID 16750901.
17. DuPen A, Shen D, Ersek M (September 2007). "Mechanisms of opioid-induced tolerance and hyperalgesia". Pain Management Nursing. 8 (3): 113–21. doi:10.1016/j.pmn.2007.02.004. PMID 17723928.
18. Garzón J, Rodríguez-Muñoz M, Sánchez-Blázquez P (May 2005). "Morphine alters the selective association between mu-opioid receptors and specific RGS proteins in mouse periaqueductal gray matter". Neuropharmacology. 48 (6): 853–68. doi:10.1016/j.neuropharm.2005.01.004. PMID 15829256.
19. Hooks SB, Martemyanov K, Zachariou V (January 2008). "A role of RGS proteins in drug addiction". Biochemical Pharmacology. 75 (1): 76–84. doi:10.1016/j.bcp.2007.07.045. PMID 17880927.
20. Sirohi S, Dighe SV, Walker EA, Yoburn BC (November 2008). "The analgesic efficacy of fentanyl: relationship to tolerance and mu-opioid receptor regulation". Pharmacology, Biochemistry, and Behavior. 91 (1): 115–20. doi:10.1016/j.pbb.2008.06.019. PMC 2597555. PMID 18640146.
21. Lopez-Gimenez JF, Vilaró MT, Milligan G (November 2008). "Morphine desensitization, internalization, and down-regulation of the mu opioid receptor is facilitated by serotonin 5-hydroxytryptamine2A receptor coactivation". Molecular Pharmacology. 74 (5): 1278–91. doi:10.1124/mol.108.048272. PMID 18703670.
22. Kraus J (2009). "Regulation of mu-opioid receptors by cytokines". Frontiers in Bioscience (Scholar Edition). 1: 164–70. doi:10.2741/e16. PMID 19482692.
23. García-Fuster MJ, Ramos-Miguel A, Rivero G, La Harpe R, Meana JJ, García-Sevilla JA (November 2008). "Regulation of the extrinsic and intrinsic apoptotic pathways in the prefrontal cortex of short- and long-term human opiate abusers". Neuroscience. 157 (1): 105–19. doi:10.1016/j.neuroscience.2008.09.002. PMID 18834930.
24. Ueda H, Ueda M (2009). "Mechanisms underlying morphine analgesic tolerance and dependence". Frontiers in Bioscience. 14: 5260–72. doi:10.2741/3596. PMID 19482614.

External links

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