OPRM1

OPRM1
Identifikatori
Aliasi	OPRM1
Vanjski ID-jevi	OMIM: 600018 MGI: 97441 HomoloGene: 37368 GeneCards: OPRM1
Lokacija gena (čovjek)
Hrom.	Hromosom 6 (čovjek)
Kraj	154,246,867 bp
Lokacija gena (miš)
Hrom.	Hromosom 10 (miš)
Kraj	6,988,198 bp
Obrazac RNK ekspresije
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• 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; • GO:0001948, GO:0016582 vezivanje za proteine; • beta-endorphin receptor activity; • G-protein alpha-subunit binding; • protein C-terminus binding; • protein domain specific binding; • G-protein beta-subunit binding; • peptide binding;
Ćelijska komponenta	• postsynapse; • citoplazma; • integral component of membrane; • perikaryon; • Golđijev aparat; • membrana; • focal adhesion; • integral component of plasma membrane; • dendrite membrane; • Endoplazmatski retikulum; • neuron projection; • Lipidni splav; • Sarkolema; • dendrite cytoplasm; • ćelijska membrana; • dendrit; • endozom; • Akson; • projekcija ćelije; • spine apparatus; • integral component of postsynaptic membrane; • integral component of presynaptic membrane;
Biološki proces	• 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; • Zarastanje rana; • 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; • Nocicepcija; • response to radiation; • response to growth factor; • response to ethanol; • GO:0072468 Transdukcija signala; • 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; • GO:1904490 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;
	Izvori:Amigo / QuickGO
Ortolozi
	4988
	18390
	ENSG00000112038
	ENSMUSG00000000766
	P35372
	P42866
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
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
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

μ-Opioidni receptori (MOR) jesu protein koji je kod ljudi kodiran genom MOR. To je klasa opioidnih receptora sa visokim afinitetom za encefaline i beta-endorfine, ali niskim afinitetom za dinorfine. Također se nazivaju μ (mu)-opioidni peptidni (MOP) receptori. Prototipni μ-opioidni receptorski agonist je morfij, primarni psihoaktivni alkaloid u opijumu. To je inhibitorni receptor vezan za G-protein koji aktivira podjedinicu G_i alfa, inhibirajući aktivnost adenilat-ciklaza, snižavajući cAMP.

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 400 aminokiselina, а molekulska težina Da. 44 779^[6]

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

10	20	30	40	50
MDSSAAPTNA	SNCTDALAYS	SCSPAPSPGS	WVNLSHLDGN	LSDPCGPNRT
DLGGRDSLCP	PTGSPSMITA	ITIMALYSIV	CVVGLFGNFL	VMYVIVRYTK
MKTATNIYIF	NLALADALAT	STLPFQSVNY	LMGTWPFGTI	LCKIVISIDY
YNMFTSIFTL	CTMSVDRYIA	VCHPVKALDF	RTPRNAKIIN	VCNWILSSAI
GLPVMFMATT	KYRQGSIDCT	LTFSHPTWYW	ENLLKICVFI	FAFIMPVLII
TVCYGLMILR	LKSVRMLSGS	KEKDRNLRRI	TRMVLVVVAV	FIVCWTPIHI
YVIIKALVTI	PETTFQTVSW	HFCIALGYTN	SCLNPVLYAF	LDENFKRCFR
EFCIPTSSNI	EQQNSTRIRQ	NTRDHPSTAN	TVDRTNHQLE	NLEAETAPLP

Struktura

Krioelektronska mikroskopska struktura kompleksa μ-opioidnih receptora – Gi proteina objavljena je u 2018.^[7]

Varijante transkripta

Dobro su okarakterizirane tri varijante μ-opioidnog receptora, iako je lančana reakcija polimeraze reverzne transkripcije u realnom vremenu identificirala do 10 ukupnih varijanti prerade kod ljudi.^[8]^[9]^[10]

μ₁	Oμ₁ opioidnom receptoru zna se više nego o ostalim varijantama.
μ₂	TRIMU 5 je selektivni agonist receptora μ₂.^[11]
μ₃	Varijanta μ₃ prvi puta opisana je 2003.^[12] Reagira na opijatne alkaloide, ali ne i opioidne peptide.^[13]

Lokacija

Mogu postojati presinapsni ili postsinapsni, ovisno o tipu ćelije.

Μ-opioidni receptori uglavnom postoje kao presinapsni saveznici u periakvaduktnoj sivoj regiji i u površinskom leđnom rogu kičmene moždine (posebno Rolandovoj substantia gelatinosa). Ostala područja na kojima su se nalazili uključuju vanjski pleksiformni sloj mirisnog režnje, nucleus accumbens, u nekoliko slojeva moždane kore i u nekim od amigdalnom jezgru, kao i jezgru usamljenog trakta.

Neki MOR također nalaze se u crijevnom traktu. Aktivacija ovih receptora inhibira djelovanje peristaltike, što koje uzrokuje zatvor, glavnu nuspojavu μ agonista.^[14]

Aktivacija

MOR može posredovati u akutnim promjenama neuronske ekscitabilnosti, suzbijanjem presinapsnog oslobađanja GABA. Aktivacija MOR-a dovodi do različitih učinaka na dendritske bodlje, ovisno o agonistima, a može biti primjer funkcionalne selektivnosti na μ-receptoru.^[15] Ostaje da se razjasne fiziološke i patološke uloge ova dva različita mehanizma. Možda bi oba mogla biti uključeni u ovisnost o opioidima i opioidom izazvane deficite u spoznaji.

Aktivacija μ-opioidnog receptora putem agonista kao što je morfij uzrokuje analgeziju, sedaciju, blago snižen krvni pritisak, svrbež, mučninu , euforiju, smanjeno disanje, miozu (sužene zjenica) i smanjenu pokretljivost crijeva koja često dovodi do konstipacija. Neki od ovih učinaka, poput analgezije, sedacije, euforije, svrbeža i smanjenog disanja, imaju tendenciju da se smanjuju uz nastavak upotrebe, kako se razvija tolerancija. Mioza i smanjena peristaltika crijeva nastoje opstati; na ove efekte razvija se mala tolerancija.

Kanonska izoforma MOR1 odgovorna je za analgeziju izazvanu morfijem, dok je alternativno prerađena izoforma MOR1D (putem heterodimerizacije sa peptidnim receptorom koji oslobađa gastrin) potrebna za svrab izazvan morfijom.^[16]

Deaktivacija

Kao i kod drugih G-protein spregnutih receptora, signalizacija pomoću μ-opioidnog receptora prekida se putem nekoliko različitih mehanizama, koji su pojačano regulirani hroničnom upotrebom, što dovodi do brze tahifilaksije.^[17] Najvažniji regulatorni proteini za MOR su β-arestin ареstin beta 1 i arestin beta 2,^[18]^[19]^[20] i proteini RGS RGS4, RGS9-2, RGS14 i RGSZ2.^[21]^[22]

Dugotrajna ili visoka doza opioida također može dovesti do uključivanja dodatnih mehanizama tolerancije. To uključuje smanjenu ekspresiju gena MOR, pa se broj receptora prisutnih na površini ćelije zapravo smanjuje, za razliku od kratkotrajne desenzibilizacije izazvane β-arestinima ili RGS proteinima.^[23]^[24]^[25] Druga dugotrajna prilagodba na upotrebu opijata može biti pojačana regulacija glutamatnih i drugih puteva u mozgu koji mogu imati opioidno suprotan učinak, pa smanjuje učinke opioidnih lijekova, mijenjanjem nizvodnih puteva, bez obzira na aktivaciju MOR-a.^[26]^[27]

Tolerancija i predoziranja

Smrtonosno predoziranje opioidima obično se javlja zbog bradipnea, hipoksemija i smanjenja srčanog volumena (hipotenzija se javlja zbog vazodilatacija, i bradikardija dodatno doprinoseči smanjenju minutnog volumena srca).^[28]^[29]^[30] Učinak potenciranja javlja se kada se opioidi kombiniraju s etanolom, benzodiazepinom ili barbituratima, što rezultira povećanim rizikom od predoziranja.^[28]^[29] Znatna tolerancija na respiratornu depresiju brzo se razvija i tolerantne osobe mogu izdržati veće doze.^[31] Međutim, tolerancija na respiratornu depresiju gubi se jednako brzo tokom odvikavanja.^[31] Mnoga predoziranja javljaju se kod ljudi koji zloupotrebljavaju svoje lijekove nakon što su dovoljno dugo bili u prekidu izgubli toleranciju na respiratornu depresiju. Manje često je poznato da masovna predoziranja uzrokuju cirkulatorni kolaps.

Predoziranje opioidima može se brzo poništiti upotrebom opioidnih antagonista, a nalokson je najrašireniji primjer.^[28] Međutim, samo to obično nije dovoljno i obično je potrebna skrb podrške, kako bi se spriječile hipoksijske ozljede mozga praćenjem vitalnih znakova. Mogu biti potrebne i dodatne doze naloksona.

Takođerpogledajte

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000112038 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000000766 - Ensembl, maj 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Zhorov BS, Ananthanarayanan VS (mart 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.
^ "UniProt, P35372" (jezik: engleski). Pristupljeno 9. 10. 2021.
^ Koehl A, Hu H, Maeda S, et al. (2018). "Structure of the μ-opioid receptor-Gi protein complex". Nature. 558 (7711): 547–552. Bibcode:2018Natur.558..547K. doi:10.1038/s41586-018-0219-7. PMC 6317904. PMID 29899455.
^ 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.
^ 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. S2CID 22410194.
^ Xu J, Lu Z, Narayan A, et al. (2017). "Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine". J. Clin. Invest. 127 (4): 1561–1573. doi:10.1172/JCI88760. PMC 5373896. PMID 28319053.
^ 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. S2CID 54354971.
^ 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.
^ Stefano GB (2004). "Endogenous morphine: a role in wellness medicine". Med. Sci. Monit. 10 (6): ED5. PMID 15173675.
^ 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.
^ Liao D, Lin H, Law PY, Loh HH (februar 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.
^ Liu XY, Liu ZC, Sun YG, Ross M, Kim S, Tsai FF, Li QF, Jeffry J, Kim JY, Loh HH, Chen ZF (2011). "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. Sažetak – Washington University in St. Louis Press Release.
^ Martini L, Whistler JL (oktobar 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. S2CID 29491629.
^ Zuo Z (septembar 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.
^ Marie N, Aguila B, Allouche S (novembar 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.
^ DuPen A, Shen D, Ersek M (septembar 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.
^ Garzón J, Rodríguez-Muñoz M, Sánchez-Blázquez P (maj 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. S2CID 23797166.
^ Hooks SB, Martemyanov K, Zachariou V (januar 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.
^ Sirohi S, Dighe SV, Walker EA, Yoburn BC (novembar 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.
^ Lopez-Gimenez JF, Vilaró MT, Milligan G (novembar 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. S2CID 6310244.
^ Kraus J (2009). "Regulation of mu-opioid receptors by cytokines". Frontiers in Bioscience. 1: 164–70. doi:10.2741/e16. PMID 19482692.
^ García-Fuster MJ, Ramos-Miguel A, Rivero G, La Harpe R, Meana JJ, García-Sevilla JA (novembar 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. S2CID 9022097.
^ Ueda H, Ueda M (2009). "Mechanisms underlying morphine analgesic tolerance and dependence". Frontiers in Bioscience. 14: 5260–72. doi:10.2741/3596. PMID 19482614.
^ ^a ^b ^c Blok (2017). "Opioid toxicity" (PDF). Clinical Key. Elsevier.
^ ^a ^b Hughes CG, McGrane S, Pandharipande PP (2012). "Sedation in the intensive care setting". Clinical Pharmacology. 4 (53): 53–63. doi:10.2147/CPAA.S26582. PMC 3508653. PMID 23204873.
^ Passchier J, Goudswaard P, Orlebeke JF, Verhage F (2011). "Migraine and defense mechanisms: psychophysiological relationships in young females". Social Science & Medicine. 26 (3): 343–50. doi:10.1016/0277-9536(88)90399-1. PMC 3347855. PMID 22577457.
^ ^a ^b Zhilenko VN, Khoroshilova NV, Efremova VM (decembar 1989). "[Hygienic evaluation of atactic polypropylene]". Gigiena I Sanitariia. 10 (12): 86–7. PMID 2628209.

Vanjski linkovi

"Opioid Receptors: μ". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Arhivirano s originala, 3. 3. 2016. Pristupljeno 9. 10. 2021.
mu Opioid Receptor na US National Library of Medicine Medical Subject Headings (MeSH)
Lokacija ljudskog genoma OPRM1 i stranica sa detaljima o genu OPRM1 u UCSC Genome Browseru.

Šablon:Neuropeptidni receptori Šablon:Opioidergici

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000112038 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000000766 - Ensembl, maj 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid10683246-5] Zhorov BS, Ananthanarayanan VS (mart 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.

[UniProt-6] "UniProt, P35372" (jezik: engleski). Pristupljeno 9. 10. 2021.

[pmid29899455-7] Koehl A, Hu H, Maeda S, et al. (2018). "Structure of the μ-opioid receptor-Gi protein complex". Nature. 558 (7711): 547–552. Bibcode:2018Natur.558..547K. doi:10.1038/s41586-018-0219-7. PMC 6317904. PMID 29899455.

[pmid17094965-8] 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.

[pmid15893644-9] 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. S2CID 22410194.

[pmid28319053-10] Xu J, Lu Z, Narayan A, et al. (2017). "Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine". J. Clin. Invest. 127 (4): 1561–1573. doi:10.1172/JCI88760. PMC 5373896. PMID 28319053.

[pmid8029266-11] 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. S2CID 54354971.

[pmid12734358-12] 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.

[pmid15173675-13] Stefano GB (2004). "Endogenous morphine: a role in wellness medicine". Med. Sci. Monit. 10 (6): ED5. PMID 15173675.

[14] 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.

[pmid15659552-15] Liao D, Lin H, Law PY, Loh HH (februar 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.

[Liu_2011-16] Liu XY, Liu ZC, Sun YG, Ross M, Kim S, Tsai FF, Li QF, Jeffry J, Kim JY, Loh HH, Chen ZF (2011). "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. Sažetak – Washington University in St. Louis Press Release.

[pmid18068348-17] Martini L, Whistler JL (oktobar 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. S2CID 29491629.

[pmid16115983-18] Zuo Z (septembar 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.

[pmid16750901-19] Marie N, Aguila B, Allouche S (novembar 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.

[pmid17723928-20] DuPen A, Shen D, Ersek M (septembar 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.

[pmid15829256-21] Garzón J, Rodríguez-Muñoz M, Sánchez-Blázquez P (maj 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. S2CID 23797166.

[pmid17880927-22] Hooks SB, Martemyanov K, Zachariou V (januar 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.

[pmid18640146-23] Sirohi S, Dighe SV, Walker EA, Yoburn BC (novembar 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.

[pmid18703670-24] Lopez-Gimenez JF, Vilaró MT, Milligan G (novembar 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. S2CID 6310244.

[pmid19482692-25] Kraus J (2009). "Regulation of mu-opioid receptors by cytokines". Frontiers in Bioscience. 1: 164–70. doi:10.2741/e16. PMID 19482692.

[pmid18834930-26] García-Fuster MJ, Ramos-Miguel A, Rivero G, La Harpe R, Meana JJ, García-Sevilla JA (novembar 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. S2CID 9022097.

[pmid19482614-27] Ueda H, Ueda M (2009). "Mechanisms underlying morphine analgesic tolerance and dependence". Frontiers in Bioscience. 14: 5260–72. doi:10.2741/3596. PMID 19482614.

[Blok_2017-28] Blok (2017). "Opioid toxicity" (PDF). Clinical Key. Elsevier.

[Hughes_2012-29] Hughes CG, McGrane S, Pandharipande PP (2012). "Sedation in the intensive care setting". Clinical Pharmacology. 4 (53): 53–63. doi:10.2147/CPAA.S26582. PMC 3508653. PMID 23204873.

[30] Passchier J, Goudswaard P, Orlebeke JF, Verhage F (2011). "Migraine and defense mechanisms: psychophysiological relationships in young females". Social Science & Medicine. 26 (3): 343–50. doi:10.1016/0277-9536(88)90399-1. PMC 3347855. PMID 22577457.

[Zhilenko_1989-31] Zhilenko VN, Khoroshilova NV, Efremova VM (decembar 1989). "[Hygienic evaluation of atactic polypropylene]". Gigiena I Sanitariia. 10 (12): 86–7. PMID 2628209.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]