μ-opioid receptor

Opioid receptor, mu 1
Identifiers
Symbols OPRM1 ; LMOR; M-OR-1; MOP; MOR; MOR1; OPRM
External IDs OMIM: 600018 MGI: 97441 HomoloGene: 37368 IUPHAR: 319 ChEMBL: 233 GeneCards: OPRM1 Gene
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_001039652
RefSeq (protein) NP_000905 NP_001034741
Location (UCSC) Chr 6:
154.01 – 154.25 Mb		 Chr 10:
6.76 – 7.04 Mb
PubMed search
Active and inactive μ-opioid receptors[1]

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 reverse-transcriptase PCR has identified up to 10 total splice variants in humans.[2][3]

μ1 More is known about the μ1 opioid receptor than the other variants.
μ2 TRIMU 5 is a selective agonist of the μ2 receptor.[4]
μ3 The μ3 variant was first described in 2003.[5] It is responsive to opiate alkaloids but not opioid peptides.[6]

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.[7]

Activation

MOR can mediate acute changes in neuronal excitability via "disinhibition" 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.[8] 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, 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.[9]

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.[10] The most important regulatory proteins for the MOR are the β-arrestins arrestin beta 1 and arrestin beta 2,[11][12][13] and the RGS proteins RGS4, RGS9-2, RGS14, and RGSZ2.[14][15]

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.[16][17][18] 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.[19][20]

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.

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ Stefano GB (2004). "Endogenous morphine: a role in wellness medicine". Med. Sci. Monit. 10 (6): ED5. PMID 15173675.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ Liu X-Y, Liu Z-C, Sun Y-G, Ross M, K S, Tsai F-F, Li Q-F, Jeffry J, Kim J-Y, Loh HH, Chen Z-F. "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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ Kraus J (2009). "Regulation of mu-opioid receptors by cytokines". Frontiers in Bioscience (Scholar Edition) 1: 164–70. doi:10.2741/e16. PMID 19482692.
  19. ↑ 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.
  20. ↑ Ueda H, Ueda M (2009). "Mechanisms underlying morphine analgesic tolerance and dependence". Frontiers in Bioscience 14: 5260–72. doi:10.2741/3596. PMID 19482614.

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