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词条 Μ-opioid receptor
释义

  1. Structure

  2. Splice variants

  3. Location

  4. Activation

  5. Deactivation

  6. Tolerance and overdoses

  7. See also

  8. References

  9. External links

{{lowercase}}{{Infobox_gene}}

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. It is an inhibitory G-protein coupled receptor that activates the Gi alpha subunit, inhibiting adenylate cyclase activity, lowering cAMP levels.

Structure

A cryo-electron microscopy structure of the µ-opioid receptor–Gi protein complex was published in 2018.[2]

Splice variants

Three variants of the μ-opioid receptor are well characterized, though RT-PCR has identified up to 10 total splice variants in humans.[3][4][5]

μ1 More is known about the μ1 opioid receptor than the other variants.
μ2 TRIMU 5 is a selective agonist of the μ2 receptor.[6]
μ3 The μ3 variant was first described in 2003.[7] It is responsive to opiate alkaloids but not opioid peptides.[8]

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.[9]

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.[10] 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.[11]

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.[12] The most important regulatory proteins for the MOR are the β-arrestins arrestin beta 1 and arrestin beta 2,[13][14][15] and the RGS proteins RGS4, RGS9-2, RGS14, and RGSZ2.[16][17]

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.[18][19][20] 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.[21][22]

Tolerance and overdoses

Fatal opioid overdose typically occurs due to bradypnea, hypoxemia, and decreased cardiac output (hypotension occurs due to vasodilation, & bradycardia further contributes to decreased cardiac output).[23][24][25] A potentiation effect occurs when opioids are combined with ethanol, benzodiazepines, or barbiturates, which results in an increased risk for overdose to occur.[23][24] Substantial tolerance to respiratory depression develops quickly, and tolerant individuals can withstand larger doses.[26] However, tolerance to respiratory depression is lost just as quickly during withdrawal.[26] 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.[23]

See also

  • δ-opioid receptor
  • κ-opioid receptor

References

1. ^{{cite journal | vauthors = Zhorov BS, Ananthanarayanan VS | title = Homology models of mu-opioid receptor with organic and inorganic cations at conserved aspartates in the second and third transmembrane domains | journal = Arch. Biochem. Biophys. | volume = 375 | issue = 1 | pages = 31–49 |date=March 2000 | pmid = 10683246 | doi = 10.1006/abbi.1999.1529 }}
2. ^{{cite journal |vauthors=Koehl A, Hu H, Maeda S, et al |title=Structure of the µ-opioid receptor-Gi protein complex |journal=Nature |volume=558 |issue=7711 |pages=547–552 |date=2018 |pmid=29899455 |doi=10.1038/s41586-018-0219-7 |url=}}
3. ^{{cite journal |vauthors=Dortch-Carnes J, Russell K |title=Morphine-stimulated nitric oxide release in rabbit aqueous humor |journal=Exp. Eye Res. |volume=84 |issue=1 |pages=185–90 |year=2007 |pmid=17094965 |doi=10.1016/j.exer.2006.09.014 |pmc=1766947}}
4. ^{{cite journal |vauthors=Pan L, Xu J, Yu R, Xu MM, Pan YX, Pasternak GW |title=Identification and characterization of six new alternatively spliced variants of the human mu opioid receptor gene, Oprm |journal=Neuroscience |volume=133 |issue=1 |pages=209–20 |year=2005 |pmid=15893644 |doi=10.1016/j.neuroscience.2004.12.033}}
5. ^{{cite journal |vauthors=Xu J, Lu Z, Narayan A, et al |title=Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine |journal=J. Clin. Invest. |volume=127 |issue=4 |pages=1561–1573 |date=2017 |pmid=28319053 |pmc=5373896 |doi=10.1172/JCI88760 |url=}}
6. ^{{cite journal |author=Eisenberg RM |title=TRIMU-5, a μ2-opioid receptor agonist, stimulates the hypothalamo-pituitary-adrenal axis |journal=Pharmacol. Biochem. Behav. |volume=47 |issue=4 |pages=943–6 |year=1994 |pmid=8029266 |doi=10.1016/0091-3057(94)90300-X}}
7. ^{{cite journal |vauthors=Cadet P, Mantione KJ, Stefano GB |title=Molecular identification and functional expression of μ3, a novel alternatively spliced variant of the human μ opiate receptor gene |journal=J. Immunol. |volume=170 |issue=10 |pages=5118–23 |year=2003 |pmid=12734358 |doi=10.4049/jimmunol.170.10.5118}}
8. ^{{cite journal |author=Stefano GB |title=Endogenous morphine: a role in wellness medicine |journal=Med. Sci. Monit. |volume=10 |issue=6 |pages=ED5 |year=2004 |pmid=15173675 |doi=}}
9. ^{{cite journal|last1=Chen|first1=Wency|title=Opiate-induced constipation related to activation of small intestine opioid μ2-receptors|journal=World Journal of Gastroenterology|date=2012|volume=18|issue=12|pages=1391–6|doi=10.3748/wjg.v18.i12.1391|pmc=3319967|pmid=22493554}}
10. ^{{cite journal | vauthors = Liao D, Lin H, Law PY, Loh HH|authorlink4=Harold Loh | title = Mu-opioid receptors modulate the stability of dendritic spines | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 102 | issue = 5 | pages = 1725–30 |date=February 2005 | pmid = 15659552 | pmc = 545084 | doi = 10.1073/pnas.0406797102 |jstor=3374498 |bibcode=2005PNAS..102.1725L}}
11. ^{{cite journal |vauthors=Liu XY, Liu ZC, Sun YG, Ross M, Kim S, Tsai FF, Li QF, Jeffry J, Kim JY, Loh HH, Chen ZF | title = Unidirectional Cross-Activation of GRPR by MOR1D Uncouples Itch and Analgesia Induced by Opioids | journal = Cell | date = | volume = 147 | issue = 2 | pages = 447–458 | doi = 10.1016/j.cell.2011.08.043 | laysummary = http://news.wustl.edu/news/Pages/22805.aspx | laysource = Washington University in St. Louis Press Release | pmid = 22000021 | pmc = 3197217 | year=2011}}
12. ^{{cite journal |vauthors=Martini L, Whistler JL |title=The role of mu opioid receptor desensitization and endocytosis in morphine tolerance and dependence |journal=Current Opinion in Neurobiology |volume=17 |issue=5 |pages=556–64 |date=October 2007 |pmid=18068348 |doi=10.1016/j.conb.2007.10.004 |url=}}
13. ^{{cite journal |author=Zuo Z |title=The role of opioid receptor internalization and beta-arrestins in the development of opioid tolerance |journal=Anesthesia and Analgesia |volume=101 |issue=3 |pages=728–34, table of contents |date=September 2005 |pmid=16115983 |doi=10.1213/01.ANE.0000160588.32007.AD |url=}}
14. ^{{cite journal |vauthors=Marie N, Aguila B, Allouche S |title=Tracking the opioid receptors on the way of desensitization |journal=Cellular Signalling |volume=18 |issue=11 |pages=1815–33 |date=November 2006 |pmid=16750901 |doi=10.1016/j.cellsig.2006.03.015 |url=}}
15. ^{{cite journal |vauthors=DuPen A, Shen D, Ersek M |title=Mechanisms of opioid-induced tolerance and hyperalgesia |journal=Pain Management Nursing |volume=8 |issue=3 |pages=113–21 |date=September 2007 |pmid=17723928 |doi=10.1016/j.pmn.2007.02.004 |url=}}
16. ^{{cite journal |vauthors=Garzón J, Rodríguez-Muñoz M, Sánchez-Blázquez P |title=Morphine alters the selective association between mu-opioid receptors and specific RGS proteins in mouse periaqueductal gray matter |journal=Neuropharmacology |volume=48 |issue=6 |pages=853–68 |date=May 2005 |pmid=15829256 |doi=10.1016/j.neuropharm.2005.01.004 |url=}}
17. ^{{cite journal |vauthors=Hooks SB, Martemyanov K, Zachariou V |title=A role of RGS proteins in drug addiction |journal=Biochemical Pharmacology |volume=75 |issue=1 |pages=76–84 |date=January 2008 |pmid=17880927 |doi=10.1016/j.bcp.2007.07.045 |url=}}
18. ^{{cite journal |vauthors=Sirohi S, Dighe SV, Walker EA, Yoburn BC |title=The analgesic efficacy of fentanyl: relationship to tolerance and mu-opioid receptor regulation |journal=Pharmacology Biochemistry and Behavior |volume=91 |issue=1 |pages=115–20 |date=November 2008 |pmid=18640146 |doi=10.1016/j.pbb.2008.06.019 |url= |pmc=2597555}}
19. ^{{cite journal |vauthors=Lopez-Gimenez JF, Vilaró MT, Milligan G |title=Morphine desensitization, internalization, and down-regulation of the mu opioid receptor is facilitated by serotonin 5-hydroxytryptamine2A receptor coactivation |journal=Molecular Pharmacology |volume=74 |issue=5 |pages=1278–91 |date=November 2008 |pmid=18703670 |doi=10.1124/mol.108.048272 |url=}}
20. ^{{cite journal |author=Kraus J |title=Regulation of mu-opioid receptors by cytokines |journal=Frontiers in Bioscience |volume=1 |issue= |pages=164–70 |year=2009 |pmid=19482692 |doi= 10.2741/e16|url=}}
21. ^{{cite journal |vauthors=García-Fuster MJ, Ramos-Miguel A, Rivero G, La Harpe R, Meana JJ, García-Sevilla JA |title=Regulation of the extrinsic and intrinsic apoptotic pathways in the prefrontal cortex of short- and long-term human opiate abusers |journal=Neuroscience |volume=157 |issue=1 |pages=105–19 |date=November 2008 |pmid=18834930 |doi=10.1016/j.neuroscience.2008.09.002 |url=}}
22. ^{{cite journal |vauthors=Ueda H, Ueda M |title=Mechanisms underlying morphine analgesic tolerance and dependence |journal=Frontiers in Bioscience |volume=14 |issue= |pages=5260–72 |year=2009 |pmid=19482614 |doi= 10.2741/3596|url=}}
23. ^1 2 {{cite journal | last = Blok | first = | date = 2017 | title = Opioid toxicity | url = https://www.elsevier.com/__data/assets/pdf_file/0010/545824/Opioid-toxicity-ClinicalKey.pdf | journal = Clinical Key | publisher = Elsevier}}
24. ^1 {{cite journal | vauthors = Hughes CG, McGrane S, Pandharipande PP | title = Sedation in the intensive care setting | journal = Clinical Pharmacology | volume = 4 | issue = 53 | pages = 53–63 | date = 2012 | pmid = 23204873 | pmc = 3508653 | doi = 10.2147/CPAA.S26582 }}
25. ^{{cite journal | vauthors = Passchier J, Goudswaard P, Orlebeke JF, Verhage F | title = Migraine and defense mechanisms: psychophysiological relationships in young females | journal = Social Science & Medicine | volume = 26 | issue = 3 | pages = 343–50 | date = 2011 | pmc = 3347855 | pmid=22577457 | doi=10.1016/0277-9536(88)90399-1}}
26. ^1 {{cite journal | vauthors = Zhilenko VN, Khoroshilova NV, Efremova VM | title = [Hygienic evaluation of atactic polypropylene] | journal = Gigiena I Sanitariia | volume = 10 | issue = 12 | pages = 86–7 | date = December 1989 | pmc = 2628209 | pmid=18989788 | doi=10.1208/s12248-008-9056-1}}

External links

  • {{cite web | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2405 | title = Opioid Receptors: μ | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology }}
  • {{MeshName|mu+Opioid+Receptor}}
  • {{UCSC gene info|OPRM1}}
{{G protein-coupled receptors}}{{Neuropeptide receptors}}{{Opioidergics}}{{DEFAULTSORT:Mu Opioid Receptor}}

2 : Opioid receptors|Human proteins
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