μ-opioid receptor#Splice variants

The structure of the inactive μ-opioid receptor has been determined with the antagonists β-FNA{{cite journal | vauthors = Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, Pardo L, Weis WI, Kobilka BK, Granier S | title = Crystal structure of the μ-opioid receptor bound to a morphinan antagonist | journal = Nature | volume = 485 | issue = 7398 | pages = 321–326 | date = March 2012 | pmid = 22437502 | pmc = 3523197 | doi = 10.1038/nature10954 | bibcode = 2012Natur.485..321M }} and alvimopan.{{cite journal | vauthors = Robertson MJ, Papasergi-Scott MM, He F, Seven AB, Meyerowitz JG, Panova O, Peroto MC, Che T, Skiniotis G | title = Structure determination of inactive-state GPCRs with a universal nanobody | journal = Nature Structural & Molecular Biology | volume = 29 | issue = 12 | pages = 1188–1195 | date = December 2022 | pmid = 36396979 | doi = 10.1038/s41594-022-00859-8 | pmc = 12014012 }} Many structures of the active state are also available, with agonists including DAMGO,{{cite journal | vauthors = Koehl A, Hu H, Maeda S, Zhang Y, Qu Q, Paggi JM, Latorraca NR, Hilger D, Dawson R, Matile H, Schertler GF, Granier S, Weis WI, Dror RO, Manglik A, Skiniotis G, Kobilka BK | title = Structure of the μ-opioid receptor-G_i protein complex | journal = Nature | volume = 558 | issue = 7711 | pages = 547–552 | date = June 2018 | pmid = 29899455 | pmc = 6317904 | doi = 10.1038/s41586-018-0219-7 | bibcode = 2018Natur.558..547K }} β-endorphin,{{cite journal | vauthors = Wang Y, Zhuang Y, DiBerto JF, Zhou XE, Schmitz GP, Yuan Q, Jain MK, Liu W, Melcher K, Jiang Y, Roth BL, Xu HE | title = Structures of the entire human opioid receptor family | journal = Cell | volume = 186 | issue = 2 | pages = 413–427.e17 | date = January 2023 | pmid = 36638794 | doi = 10.1016/j.cell.2022.12.026 | s2cid = 255750597 | doi-access = free }} fentanyl and morphine.{{cite journal | vauthors = Zhuang Y, Wang Y, He B, He X, Zhou XE, Guo S, Rao Q, Yang J, Liu J, Zhou Q, Wang X, Liu M, Liu W, Jiang X, Yang D, Jiang H, Shen J, Melcher K, Chen H, Jiang Y, Cheng X, Wang MW, Xie X, Xu HE | title = Molecular recognition of morphine and fentanyl by the human μ-opioid receptor | journal = Cell | volume = 185 | issue = 23 | pages = 4361–4375.e19 | date = November 2022 | pmid = 36368306 | doi = 10.1016/j.cell.2022.09.041 | s2cid = 253426623 | doi-access = free }} The structure with the agonist BU72 has the highest resolution,{{cite journal | vauthors = Huang W, Manglik A, Venkatakrishnan AJ, Laeremans T, Feinberg EN, Sanborn AL, Kato HE, Livingston KE, Thorsen TS, Kling RC, Granier S, Gmeiner P, Husbands SM, Traynor JR, Weis WI, Steyaert J, Dror RO, Kobilka BK | title = Structural insights into μ-opioid receptor activation | journal = Nature | volume = 524 | issue = 7565 | pages = 315–321 | date = August 2015 | pmid = 26245379 | pmc = 4639397 | doi = 10.1038/nature14886 | bibcode = 2015Natur.524..315H }} but contains unexplained features that may be experimental artifacts.{{Cite journal | vauthors = Zou R, Wang X, Li S, Chan HS, Vogel H, Yuan S |date=2022 |title=The role of metal ions in G protein-coupled receptor signalling and drug discovery |journal=WIREs Computational Molecular Science |language=en |volume=12 |issue=2 |pages=e1565 |doi=10.1002/wcms.1565 |s2cid=237649760 |issn=1759-0876}}{{cite journal | vauthors = Munro TA | title = Reanalysis of a μ opioid receptor crystal structure reveals a covalent adduct with BU72 | journal = BMC Biology | volume = 21 | issue = 1 | pages = 213 | date = October 2023 | pmid = 37817141 | pmc = 10566028 | doi = 10.1186/s12915-023-01689-w | doi-access = free }} This large body of evidence has enabled structure-based design of a new class of opioids with functional selectivity.{{cite journal | vauthors = Faouzi A, Wang H, Zaidi SA, DiBerto JF, Che T, Qu Q, Robertson MJ, Madasu MK, El Daibani A, Varga BR, Zhang T, Ruiz C, Liu S, Xu J, Appourchaux K, Slocum ST, Eans SO, Cameron MD, Al-Hasani R, Pan YX, Roth BL, McLaughlin JP, Skiniotis G, Katritch V, Kobilka BK, Majumdar S | title = Structure-based design of bitopic ligands for the μ-opioid receptor | journal = Nature | volume = 613 | issue = 7945 | pages = 767–774 | date = January 2023 | pmid = 36450356 | pmc = 10328120 | doi = 10.1038/s41586-022-05588-y | bibcode = 2023Natur.613..767F }}

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.{{cite journal | vauthors = Dortch-Carnes J, Russell K | title = Morphine-stimulated nitric oxide release in rabbit aqueous humor | journal = Experimental Eye Research | volume = 84 | issue = 1 | pages = 185–190 | date = January 2007 | pmid = 17094965 | pmc = 1766947 | doi = 10.1016/j.exer.2006.09.014 }}{{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 = 209–220 | year = 2005 | pmid = 15893644 | doi = 10.1016/j.neuroscience.2004.12.033 | s2cid = 22410194 }}{{cite journal | vauthors = Xu J, Lu Z, Narayan A, Le Rouzic VP, Xu M, Hunkele A, Brown TG, Hoefer WF, Rossi GC, Rice RC, Martínez-Rivera A, Rajadhyaksha AM, Cartegni L, Bassoni DL, Pasternak GW, Pan YX | title = Alternatively spliced mu opioid receptor C termini impact the diverse actions of morphine | journal = The Journal of Clinical Investigation | volume = 127 | issue = 4 | pages = 1561–1573 | date = April 2017 | pmid = 28319053 | pmc = 5373896 | doi = 10.1172/JCI88760 }}

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.{{cite journal | vauthors = Chen W, Chung HH, Cheng JT | title = Opiate-induced constipation related to activation of small intestine opioid μ2-receptors | journal = World Journal of Gastroenterology | volume = 18 | issue = 12 | pages = 1391–1396 | date = March 2012 | pmid = 22493554 | pmc = 3319967 | doi = 10.3748/wjg.v18.i12.1391 |doi-access=free }}

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.{{cite journal | vauthors = Liao D, Lin H, Law PY, Loh HH | title = Mu-opioid receptors modulate the stability of dendritic spines | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 5 | pages = 1725–1730 | date = February 2005 | pmid = 15659552 | pmc = 545084 | doi = 10.1073/pnas.0406797102 | doi-access = free | bibcode = 2005PNAS..102.1725L | jstor = 3374498 | author-link4 = Horace Loh }} 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|date=October 2024}}

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.{{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 | volume = 147 | issue = 2 | pages = 447–458 | date = October 2011 | pmid = 22000021 | pmc = 3197217 | doi = 10.1016/j.cell.2011.08.043}}*{{lay source |template=cite web|vauthors = Dryden, J |url=http://news.wustl.edu/news/Pages/22805.aspx|title=Researchers block morphine’s itchy side effect|date=October 13, 2011 |website=Washington University in St. Louis }}

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.{{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 = 556–564 | date = October 2007 | pmid = 18068348 | doi = 10.1016/j.conb.2007.10.004 | s2cid = 29491629 }} The most important regulatory proteins for the MOR are the β-arrestins arrestin beta 1 and arrestin beta 2,{{cite journal | vauthors = 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 = 728–734 | date = September 2005 | pmid = 16115983 | doi = 10.1213/01.ANE.0000160588.32007.AD | doi-access = free }}{{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 = 1815–1833 | date = November 2006 | pmid = 16750901 | doi = 10.1016/j.cellsig.2006.03.015 }}{{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 = 113–121 | date = September 2007 | pmid = 17723928 | doi = 10.1016/j.pmn.2007.02.004 }} and the RGS proteins RGS4, RGS9-2, RGS14, and RGSZ2.{{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 = 853–868 | date = May 2005 | pmid = 15829256 | doi = 10.1016/j.neuropharm.2005.01.004 | s2cid = 23797166 }}{{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 }}

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.{{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 = 115–120 | date = November 2008 | pmid = 18640146 | pmc = 2597555 | doi = 10.1016/j.pbb.2008.06.019 }}{{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 = 1278–1291 | date = November 2008 | pmid = 18703670 | doi = 10.1124/mol.108.048272 | s2cid = 6310244 }}{{cite journal | vauthors = Kraus J | title = Regulation of mu-opioid receptors by cytokines | journal = Frontiers in Bioscience | volume = 1 | pages = 164–170 | date = June 2009 | issue = 1 | pmid = 19482692 | doi = 10.2741/e16 }} 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.{{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 = 105–119 | date = November 2008 | pmid = 18834930 | doi = 10.1016/j.neuroscience.2008.09.002 | s2cid = 9022097 }}{{cite journal | vauthors = Ueda H, Ueda M | title = Mechanisms underlying morphine analgesic tolerance and dependence | journal = Frontiers in Bioscience | volume = 14 | pages = 5260–5272 | date = June 2009 | issue = 14 | pmid = 19482614 | doi = 10.2741/3596 | doi-access = free }}

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).{{cite journal | last = Blok | 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}}{{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 | doi-access = free }}{{cite journal | vauthors = Shanazari AA, Aslani Z, Ramshini E, Alaei H | title = Acute and chronic effects of morphine on cardiovascular system and the baroreflexes sensitivity during severe increase in blood pressure in rats | journal = ARYA Atherosclerosis | volume = 7 | issue = 3 | pages = 111–117 | date = 2011 | pmid = 22577457 | pmc = 3347855 | doi = 10.1016/0277-9536(88)90399-1 }} 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.

Substantial tolerance to respiratory depression develops quickly, and tolerant individuals can withstand larger doses.{{cite journal | vauthors = Algera MH, Olofsen E, Moss L, Dobbins RL, Niesters M, van Velzen M, Groeneveld GJ, Heuberger J, Laffont CM, Dahan A | title = Tolerance to Opioid-Induced Respiratory Depression in Chronic High-Dose Opioid Users: A Model-Based Comparison With Opioid-Naïve Individuals | journal = Clinical Pharmacology and Therapeutics | volume = 109 | issue = 3 | pages = 637–645 | date = March 2021 | pmid = 32865832 | pmc = 7983936 | doi = 10.1002/cpt.2027 }} 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.{{cite journal | vauthors = Krantz MJ, Palmer RB, Haigney MC | title = Cardiovascular Complications of Opioid Use: JACC State-of-the-Art Review | journal = Journal of the American College of Cardiology | volume = 77 | issue = 2 | pages = 205–223 | date = January 2021 | pmid = 33446314 | doi = 10.1016/j.jacc.2020.11.002 | s2cid = 231613932 | doi-access = free }}

Opioid overdoses can be rapidly reversed through the use of opioid antagonists, naloxone being the most widely used example. 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.{{cite journal | vauthors = Houmes RJ, Voets MA, Verkaaik A, Erdmann W, Lachmann B | title = Efficacy and safety of tramadol versus morphine for moderate and severe postoperative pain with special regard to respiratory depression | journal = Anesthesia and Analgesia | volume = 74 | issue = 4 | pages = 510–514 | date = April 1992 | pmid = 1554117 | doi = 10.1213/00000539-199204000-00007 | s2cid = 24530179 }}

{{See also|List of opioids}}

• Dynorphins (e.g., dynorphin A, dynorphin B){{cite book | vauthors = Tache S, Kerr PL, Sirbu C | title=Endogenous Opioids | chapter=The Foundational Science of Endogenous Opioids and Their Receptors | series=Advances in Neurobiology | publisher=Springer International Publishing | publication-place=Cham | volume=35 | date=2024 | pages=9–26 | isbn=978-3-031-45492-9 | doi=10.1007/978-3-031-45493-6_2 | pmid=38874716 }}
• Endomorphins (endomorphin-1, endomorphin-2)
• Endorphins (e.g., β-endorphin)
• Enkephalins (leu-enkephalin, met-enkephalin, adrenorphin)

• Codeine
• Fentanyl
• Heroin
• Hydrocodone
• Hydromorphone
• Levorphanol
• Methadone
• Morphine
• Oxycodone
• Oxymorphone
• Pethidine (meperidine){{cite book| vauthors = Bryant B, Knights K |title=Pharmacology for Health Professionals | edition = 3rd |publisher=Mosby Australia|year=2010|location=Chatswood|isbn=978-0-7295-3929-6}}{{cite journal | vauthors = Kelly E | title = Efficacy and ligand bias at the μ-opioid receptor | journal = Br J Pharmacol | volume = 169 | issue = 7 | pages = 1430–1446 | date = August 2013 | pmid = 23646826 | pmc = 3724102 | doi = 10.1111/bph.12222 | url = | quote = In some cases, agonists have such low efficacy that they cannot achieve the maximum response that a full agonist does, even when occupying all the receptors present in the tissue (Figure 1B); these agonists are called partial agonists. For example, with MOP receptors, ligands such as buprenorphine, meperidine and pentazocine behave as partial agonists in many cell signalling assays (McPherson et al., 2010).}}
• Tianeptine{{cite journal |vauthors=Samuels BA, Nautiyal KM, Kruegel AC, Levinstein MR, Magalong VM, Gassaway MM, Grinnell SG, Han J, Ansonoff MA, Pintar JE, Javitch JA, Sames D, Hen R |date=September 2017 |title=The Behavioral Effects of the Antidepressant Tianeptine Require the Mu-Opioid Receptor |url= |journal=Neuropsychopharmacology |volume=42 |issue=10 |pages=2052–2063 |doi=10.1038/npp.2017.60 |pmc=5561344 |pmid=28303899}}

• Buprenorphine{{cite journal | vauthors = Gress K, Charipova K, Jung JW, Kaye AD, Paladini A, Varrassi G, Viswanath O, Urits I | title = A comprehensive review of partial opioid agonists for the treatment of chronic pain | journal = Best Pract Res Clin Anaesthesiol | volume = 34 | issue = 3 | pages = 449–461 | date = September 2020 | pmid = 33004158 | doi = 10.1016/j.bpa.2020.06.003 | url = }}
• Butorphanol (or antagonist){{cite journal | vauthors = Hoskin PJ, Hanks GW | title = Opioid agonist-antagonist drugs in acute and chronic pain states | journal = Drugs | volume = 41 | issue = 3 | pages = 326–344 | date = March 1991 | pmid = 1711441 | doi = 10.2165/00003495-199141030-00002 | url = }}
• Dezocine{{cite journal | vauthors = O'Brien JJ, Benfield P | title = Dezocine. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy | journal = Drugs | volume = 38 | issue = 2 | pages = 226–248 | date = August 1989 | pmid = 2670517 | doi = 10.2165/00003495-198938020-00005 | url = }}{{cite journal | vauthors = Ye RR, Jiang S, Xu X, Lu Y, Wang YJ, Liu JG | title = Dezocine as a potent analgesic: overview of its pharmacological characterization | journal = Acta Pharmacol Sin | volume = 43 | issue = 7 | pages = 1646–1657 | date = July 2022 | pmid = 34737418 | pmc = 9253008 | doi = 10.1038/s41401-021-00790-6 | url = }}
• Nalbuphine{{cite book | vauthors = Bidlack JM | title = Mixed κ/μ partial opioid agonists as potential treatments for cocaine dependence | chapter = Mixed Kappa/Mu Partial Opioid Agonists as Potential Treatments for Cocaine Dependence | series = Adv Pharmacol | volume = 69 | pages = 387–418 | date = 2014 | publisher = Elsevier | pmid = 24484983 | doi = 10.1016/B978-0-12-420118-7.00010-X | isbn = 978-0-12-420118-7 | url = }} (or antagonist)
• Oliceridine
• Pentazocine (or antagonist)
• Tramadol{{cite book | vauthors = Furlan AD, Murphy L | title=Clinical Pain Management | chapter=Opioids | publisher=Wiley | date=9 March 2022 | isbn=978-1-119-70115-6 | doi=10.1002/9781119701170.ch18 | pages=188–197}} (or partial agonist)
• 7-Hydroxymitragynine

• Oliceridine{{cite journal | vauthors = Azevedo Neto J, Costanzini A, De Giorgio R, Lambert DG, Ruzza C, Calò G | title = Biased versus Partial Agonism in the Search for Safer Opioid Analgesics | journal = Molecules | volume = 25 | issue = 17 | date = August 2020 | page = 3870 | pmid = 32854452 | pmc = 7504468 | doi = 10.3390/molecules25173870 | doi-access = free | url = }}
• PZM21
• SHR9352{{cite journal | vauthors = Li X, He W, Chen Y, Yang G, Wan H, Zhang L, Hu Q, Feng J, Zhang Z, He F, Bai C, Zhang L, You L, Tao W | title = Discovery of SHR9352: A Highly Potent G Protein-Biased μ-Opioid Receptor Agonist | journal = ACS Omega | volume = 2 | issue = 12 | pages = 9261–9267 | date = December 2017 | pmid = 31457439 | pmc = 6645658 | doi = 10.1021/acsomega.7b01452 | url = }}
• SR-17018
• Tegileridine{{cite journal | vauthors = Dhillon S | title = Tegileridine: First Approval | journal = Drugs | volume = 84 | issue = 6 | pages = 717–720 | date = June 2024 | pmid = 38771484 | doi = 10.1007/s40265-024-02033-4 | url = }}
• TRV734{{cite journal | vauthors = James IE, Skobieranda F, Soergel DG, Ramos KA, Ruff D, Fossler MJ | title = A First-in-Human Clinical Study With TRV734, an Orally Bioavailable G-Protein-Biased Ligand at the μ-Opioid Receptor | journal = Clin Pharmacol Drug Dev | volume = 9 | issue = 2 | pages = 256–266 | date = February 2020 | pmid = 31286645 | doi = 10.1002/cpdd.721 | url = }}

• Loperamide{{cite journal | vauthors = Malinky CA, Lindsley CW, Han C | title = DARK Classics in Chemical Neuroscience: Loperamide | journal = ACS Chem Neurosci | volume = 12 | issue = 16 | pages = 2964–2973 | date = August 2021 | pmid = 34346690 | doi = 10.1021/acschemneuro.1c00382 | url = }}{{cite journal | vauthors = Vandenbossche J, Huisman M, Xu Y, Sanderson-Bongiovanni D, Soons P | title = Loperamide and P-glycoprotein inhibition: assessment of the clinical relevance | journal = J Pharm Pharmacol | volume = 62 | issue = 4 | pages = 401–412 | date = April 2010 | pmid = 20604828 | doi = 10.1211/jpp.62.04.0001 | url = }}

• Chloroxymorphamine{{cite journal | vauthors = Caruso TP, Takemori AE, Larson DL, Portoghese PS | title = Chloroxymorphamine, and opioid receptor site-directed alkylating agent having narcotic agonist activity | journal = Science | volume = 204 | issue = 4390 | pages = 316–318 | date = April 1979 | pmid = 86208 | doi = 10.1126/science.86208 | url = }}{{cite journal | vauthors = Caruso TP, Larson DL, Portoghese PS, Takemori AE | title = Pharmacological studies with an alkylating narcotic agonist, chloroxymorphamine, and antagonist, chlornaltrexamine | journal = J Pharmacol Exp Ther | volume = 213 | issue = 3 | pages = 539–544 | date = June 1980 | pmid = 6162947 | doi = | url = }}
• Methoclocinnamox{{cite book | vauthors = Woods JH, Lewis JW, Winger G, Butelman E, Broadbear J, Zernig G | editor=National Institute on Drug Abuse | chapter = Methoclocinnamox: A μ Partial Agonist With Pharmacotherapeutic Potential for Heroin Abuse | title=NIDA Research Monograph | publisher=National Institute on Drug Abuse | series=DHEW publication | issue=v. 147 | year=1995 | chapter-url=https://books.google.com/books?id=MtPF6qZ9l9wC&pg=PA195 | access-date=9 August 2024 | pages=195–219}}
• Oxymorphazone{{cite journal | vauthors = Ling GS, Galetta S, Pasternak GW | title = Oxymorphazone: a long-acting opiate analgesic | journal = Cell Mol Neurobiol | volume = 4 | issue = 1 | pages = 1–13 | date = March 1984 | pmid = 6204757 | doi = 10.1007/BF00710938 | url = | pmc = 11572834 }}{{cite journal | vauthors = France CP, Jacobson AE, Woods JH | title = Irreversible and reversible narcotic agonists: discriminative and analgesic effects of buprenorphine, oxymorphazone, and morphine | journal = NIDA Res Monogr | volume = 49 | issue = | pages = 136–142 | date = March 1984 | pmid = 6207431 | doi = | url = }}

• Cyclazocine{{cite journal | vauthors = Archer S, Glick SD, Bidlack JM | title = Cyclazocine revisited | journal = Neurochem Res | volume = 21 | issue = 11 | pages = 1369–1373 | date = November 1996 | pmid = 8947927 | doi = 10.1007/BF02532378 | url = }}
• Cyprodime{{cite journal | vauthors = Márki A, Monory K, Otvös F, Tóth G, Krassnig R, Schmidhammer H, Traynor JR, Roques BP, Maldonado R, Borsodi A | title = Mu-opioid receptor specific antagonist cyprodime: characterization by in vitro radioligand and [35S]GTPgammaS binding assays | journal = Eur J Pharmacol | volume = 383 | issue = 2 | pages = 209–214 | date = October 1999 | pmid = 10585536 | doi = 10.1016/s0014-2999(99)00610-x | url = }}
• Diprenorphine{{cite journal | vauthors = Lewis JW, Husbands SM | title = The orvinols and related opioids--high affinity ligands with diverse efficacy profiles | journal = Curr Pharm Des | volume = 10 | issue = 7 | pages = 717–732 | date = 2004 | pmid = 15032698 | doi = 10.2174/1381612043453027 | url = }}
• Levallorphan{{cite journal | vauthors = Dykstra LA | title = Butorphanol, levallorphan, nalbuphine and nalorphine as antagonists in the squirrel monkey | journal = J Pharmacol Exp Ther | volume = 254 | issue = 1 | pages = 245–252 | date = July 1990 | pmid = 2164093 | doi = | url = }}
• Nalmefene{{cite journal | vauthors = Green M, Veltri CA, Grundmann O | title = Nalmefene Hydrochloride: Potential Implications for Treating Alcohol and Opioid Use Disorder | journal = Subst Abuse Rehabil | volume = 15 | issue = | pages = 43–57 | date = 2024 | pmid = 38585160 | pmc = 10999209 | doi = 10.2147/SAR.S431270 | doi-access = free | url = }}
• Nalodeine{{cite book| vauthors = Martin WR | chapter = The Evolution of Concepts of Opioid Receptors| veditors = Pasternak G |title=The Opiate Receptors| chapter-url= https://books.google.com/books?id=vhfyBwAAQBAJ&pg=PA4 |date=17 April 2013|publisher=Springer Science & Business Media|isbn=978-1-60761-990-1|pages=4–}}
• Nalorphine{{cite journal | vauthors = Dykstra LA | title = Butorphanol, levallorphan, nalbuphine and nalorphine as antagonists in the squirrel monkey | journal = J Pharmacol Exp Ther | volume = 254 | issue = 1 | pages = 245–252 | date = July 1990 | pmid = 2164093 | doi = | url = }}
• Naloxone{{cite journal | vauthors = Saari TI, Strang J, Dale O | title = Clinical Pharmacokinetics and Pharmacodynamics of Naloxone | journal = Clin Pharmacokinet | volume = 63 | issue = 4 | pages = 397–422 | date = April 2024 | pmid = 38485851 | pmc = 11052794 | doi = 10.1007/s40262-024-01355-6 | url = }}
• Naltrexone{{cite journal | vauthors = Sudakin D | title = Naltrexone: Not Just for Opioids Anymore | journal = J Med Toxicol | volume = 12 | issue = 1 | pages = 71–75 | date = March 2016 | pmid = 26546222 | pmc = 4781804 | doi = 10.1007/s13181-015-0512-x | url = }}
• Samidorphan{{cite journal | vauthors = Chaudhary AM, Khan MF, Dhillon SS, Naveed S | title = A Review of Samidorphan: A Novel Opioid Antagonist | journal = Cureus | volume = 11 | issue = 7 | pages = e5139 | date = July 2019 | pmid = 31523568 | pmc = 6741386 | doi = 10.7759/cureus.5139 | doi-access = free | url = }}

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

• 6β-Naltrexol{{cite journal | vauthors = Yancey-Wrona J, Dallaire B, Bilsky E, Bath B, Burkart J, Webster L, Magiera D, Yang X, Phelps M, Sadee W | title = 6β-naltrexol, a peripherally selective opioid antagonist that inhibits morphine-induced slowing of gastrointestinal transit: an exploratory study | journal = Pain Med | volume = 12 | issue = 12 | pages = 1727–1737 | date = December 2011 | pmid = 22123184 | doi = 10.1111/j.1526-4637.2011.01279.x | url = }}
• Alvimopan{{cite journal | vauthors = Camilleri M | title = Alvimopan, a selective peripherally acting mu-opioid antagonist | journal = Neurogastroenterol Motil | volume = 17 | issue = 2 | pages = 157–165 | date = April 2005 | pmid = 15787936 | doi = 10.1111/j.1365-2982.2005.00640.x | url = }}
• Axelopran{{cite journal | vauthors = Long DD, Armstrong SR, Beattie DT, Campbell CB, Church TJ, Colson PJ, Dalziel SM, Jacobsen JR, Jiang L, Obedencio GP, Rapta M, Saito D, Stergiades I, Tsuruda PR, Van Dyke PM, Vickery RG | title = Discovery of Axelopran (TD-1211): A Peripherally Restricted μ-Opioid Receptor Antagonist | journal = ACS Med Chem Lett | volume = 10 | issue = 12 | pages = 1641–1647 | date = December 2019 | pmid = 31857840 | pmc = 6912869 | doi = 10.1021/acsmedchemlett.9b00406 | url = }}
• Bevenopran{{cite journal | vauthors = Pannemans J, Vanuytsel T, Tack J | title = New developments in the treatment of opioid-induced gastrointestinal symptoms | journal = United European Gastroenterol J | volume = 6 | issue = 8 | pages = 1126–1135 | date = October 2018 | pmid = 30288274 | pmc = 6169055 | doi = 10.1177/2050640618796748 | url = }}
• Methylnaltrexone{{cite journal | vauthors = Yuan CS, Israel RJ | title = Methylnaltrexone, a novel peripheral opioid receptor antagonist for the treatment of opioid side effects | journal = Expert Opin Investig Drugs | volume = 15 | issue = 5 | pages = 541–552 | date = May 2006 | pmid = 16634692 | doi = 10.1517/13543784.15.5.541 | url = }}
• Naldemedine{{cite journal | vauthors = Stern EK, Brenner DM | title = Spotlight on naldemedine in the treatment of opioid-induced constipation in adult patients with chronic noncancer pain: design, development, and place in therapy | journal = J Pain Res | volume = 11 | issue = | pages = 195–199 | date = 2018 | pmid = 29391826 | pmc = 5774487 | doi = 10.2147/JPR.S141322 | doi-access = free | url = }}
• Naloxegol{{cite journal | vauthors = Corsetti M, Tack J | title = Naloxegol: the first orally administered, peripherally acting, mu opioid receptor antagonist, approved for the treatment of opioid-induced constipation | journal = Drugs Today (Barc) | volume = 51 | issue = 8 | pages = 479–489 | date = August 2015 | pmid = 26380386 | doi = 10.1358/dot.2015.51.8.2364896 | url = }}

• Naloxone (with oral administration){{cite journal | vauthors = Leppert W | title = Oxycodone/naloxone in the management of patients with pain and opioid-induced bowel dysfunction | journal = Curr Drug Targets | volume = 15 | issue = 1 | pages = 124–135 | date = January 2014 | pmid = 24020972 | doi = 10.2174/13894501113149990210 | url = }}

• β-Chlornaltrexamine{{cite journal | vauthors = Portoghese PS, Larson DL, Jiang JB, Takemori AE, Caruso TP | title = 6beta-[N,N-Bis(2-chloroethyl)amino]-17-(cyclopropylmethyl)-4,5alpha-epoxy-3,14-dihydroxymorphinan(chlornaltrexamine) a potent opioid receptor alkylating agent with ultralong narcotic antagonist actitivty | journal = J Med Chem | volume = 21 | issue = 7 | pages = 598–599 | date = July 1978 | pmid = 209185 | doi = 10.1021/jm00205a002 | url = }}{{cite journal | vauthors = Portoghese PS, Larson DL, Jiang JB, Caruso TP, Takemori AE | title = Synthesis and pharmacologic characterization of an alkylating analogue (chlornaltrexamine) of naltrexone with ultralong-lasting narcotic antagonist properties | journal = J Med Chem | volume = 22 | issue = 2 | pages = 168–173 | date = February 1979 | pmid = 218009 | doi = 10.1021/jm00188a008 | url = }}
• β-Funaltrexamine{{cite journal | vauthors = Ward SJ, Portoghese PS, Takemori AE | title = Pharmacological characterization in vivo of the novel opiate, beta-funaltrexamine | journal = J Pharmacol Exp Ther | volume = 220 | issue = 3 | pages = 494–498 | date = March 1982 | pmid = 6121045 | doi = | url = }}
• Clocinnamox{{cite journal | vauthors = Comer SD, Burke TF, Lewis JW, Woods JH | title = Clocinnamox: a novel, systemically-active, irreversible opioid antagonist | journal = J Pharmacol Exp Ther | volume = 262 | issue = 3 | pages = 1051–1056 | date = September 1992 | pmid = 1326622 | doi = | url = }}{{cite journal | vauthors = Burke TF, Woods JH, Lewis JW, Medzihradsky F | title = Irreversible opioid antagonist effects of clocinnamox on opioid analgesia and mu receptor binding in mice | journal = J Pharmacol Exp Ther | volume = 271 | issue = 2 | pages = 715–721 | date = November 1994 | pmid = 7965787 | doi = | url = }}
• Methocinnamox{{cite journal | vauthors = Jordan CG, Kennalley AL, Roberts AL, Nemes KM, Dolma T, Piper BJ | title = The Potential of Methocinnamox as a Future Treatment for Opioid Use Disorder: A Narrative Review | journal = Pharmacy | volume = 10 | issue = 3 | date = April 2022 | page = 48 | pmid = 35645327 | pmc = 9149874 | doi = 10.3390/pharmacy10030048 | doi-access = free | url = }}{{cite journal | vauthors = Broadbear JH, Sumpter TL, Burke TF, Husbands SM, Lewis JW, Woods JH, Traynor JR | title = Methocinnamox is a potent, long-lasting, and selective antagonist of morphine-mediated antinociception in the mouse: comparison with clocinnamox, beta-funaltrexamine, and beta-chlornaltrexamine | journal = J Pharmacol Exp Ther | volume = 294 | issue = 3 | pages = 933–940 | date = September 2000 | pmid = 10945843 | doi = | url = }}
• Naloxazone{{cite journal | vauthors = Pasternak GW, Childers SR, Snyder SH | title = Naloxazone, a long-acting opiate antagonist: effects on analgesia in intact animals and on opiate receptor binding in vitro | journal = J Pharmacol Exp Ther | volume = 214 | issue = 3 | pages = 455–462 | date = September 1980 | pmid = 6105201 | doi = | url = }}
• Naloxonazine{{cite journal | vauthors = Hahn EF, Pasternak GW | title = Naloxonazine, a potent, long-lasting inhibitor of opiate binding sites | journal = Life Sci | volume = 31 | issue = 12–13 | pages = 1385–1388 | date = 1982 | pmid = 6292633 | doi = 10.1016/0024-3205(82)90387-3 | url = }}

• BMS-986121
• BMS‐986122{{cite journal | vauthors = Livingston KE, Traynor JR | title = Allostery at opioid receptors: modulation with small molecule ligands | journal = Br J Pharmacol | volume = 175 | issue = 14 | pages = 2846–2856 | date = July 2018 | pmid = 28419415 | pmc = 6016636 | doi = 10.1111/bph.13823 | url = }}{{cite journal | vauthors = Zhu L, Cui Z, Zhu Q, Zha X, Xu Y | title = Novel Opioid Receptor Agonists with Reduced Morphine-like Side Effects | journal = Mini Rev Med Chem | volume = 18 | issue = 19 | pages = 1603–1610 | date = 2018 | pmid = 30009707 | doi = 10.2174/1389557518666180716124336 | url = }}{{cite journal | vauthors = Kandasamy R, Hillhouse TM, Livingston KE, Kochan KE, Meurice C, Eans SO, Li MH, White AD, Roques BP, McLaughlin JP, Ingram SL, Burford NT, Alt A, Traynor JR | title = Positive allosteric modulation of the mu-opioid receptor produces analgesia with reduced side effects | journal = Proc Natl Acad Sci U S A | volume = 118 | issue = 16 | pages = | date = April 2021 | pmid = 33846240 | pmc = 8072371 | doi = 10.1073/pnas.2000017118 | doi-access = free | url = }}
• Comp5{{cite journal | vauthors = González AM, Jubete AG | title = Dualism, allosteric modulation, and biased signaling of opioid receptors: Future therapeutic potential | journal = Rev Esp Anestesiol Reanim (Engl Ed) | volume = 71 | issue = 4 | pages = 298–303 | date = April 2024 | pmid = 37683976 | doi = 10.1016/j.redare.2022.06.009 | url = }}{{cite journal | vauthors = Pryce KD, Kang HJ, Sakloth F, Liu Y, Khan S, Toth K, Kapoor A, Nicolais A, Che T, Qin L, Bertherat F, Kaniskan HÜ, Jin J, Cameron MD, Roth BL, Zachariou V, Filizola M | title = A promising chemical series of positive allosteric modulators of the μ-opioid receptor that enhance the antinociceptive efficacy of opioids but not their adverse effects | journal = Neuropharmacology | volume = 195 | issue = | pages = 108673 | date = September 2021 | pmid = 34153316 | pmc = 8410669 | doi = 10.1016/j.neuropharm.2021.108673 | url = }}
• Hydroxynorketamine (HNK){{cite journal | vauthors = Gomes I, Gupta A, Margolis EB, Fricker LD, Devi LA | title = Ketamine and major ketamine metabolites function as allosteric modulators of opioid receptors | journal = Mol Pharmacol | volume = 106| issue = 5| pages = 240–252| date = August 2024 | pmid = 39187388 | doi = 10.1124/molpharm.124.000947 | pmc = 11493337 | pmc-embargo-date = November 1, 2025 | url = }}
• Ignavine{{cite journal | vauthors = Hovah ME, Holzgrabe U | title = Bivalent and bitopic ligands of the opioid receptors: The prospects of a dual approach | journal = Med Res Rev | volume = 44| issue = 6| pages = 2545–2599| date = May 2024 | pmid = 38751227 | doi = 10.1002/med.22050 | url = }}
• Ketamine
• MS1{{cite journal | vauthors = Bisignano P, Burford NT, Shang Y, Marlow B, Livingston KE, Fenton AM, Rockwell K, Budenholzer L, Traynor JR, Gerritz SW, Alt A, Filizola M | title = Ligand-Based Discovery of a New Scaffold for Allosteric Modulation of the μ-Opioid Receptor | journal = J Chem Inf Model | volume = 55 | issue = 9 | pages = 1836–43 | date = September 2015 | pmid = 26347990 | pmc = 4703110 | doi = 10.1021/acs.jcim.5b00388 | url = }}
• Norketamine
• Oxytocin{{cite journal | vauthors = Meguro Y, Miyano K, Hirayama S, Yoshida Y, Ishibashi N, Ogino T, Fujii Y, Manabe S, Eto M, Nonaka M, Fujii H, Ueta Y, Narita M, Sata N, Yada T, Uezono Y | title = Neuropeptide oxytocin enhances μ opioid receptor signaling as a positive allosteric modulator | journal = J Pharmacol Sci | volume = 137 | issue = 1 | pages = 67–75 | date = May 2018 | pmid = 29716811 | doi = 10.1016/j.jphs.2018.04.002 | url = | doi-access = free }}{{cite journal | vauthors = Miyano K, Yoshida Y, Hirayama S, Takahashi H, Ono H, Meguro Y, Manabe S, Komatsu A, Nonaka M, Mizuguchi T, Fujii H, Higami Y, Narita M, Uezono Y | title = Oxytocin Is a Positive Allosteric Modulator of κ-Opioid Receptors but Not δ-Opioid Receptors in the G Protein Signaling Pathway | journal = Cells | volume = 10 | issue = 10 | date = October 2021 | page = 2651 | pmid = 34685631 | pmc = 8534029 | doi = 10.3390/cells10102651 | doi-access = free | url = }}{{cite journal | vauthors = Mizuguchi T, Miyano K, Yamauchi R, Yoshida Y, Takahashi H, Yamazaki A, Ono H, Inagaki M, Nonaka M, Uezono Y, Fujii H | title = The first structure-activity relationship study of oxytocin as a positive allosteric modulator for the µ opioid receptor | journal = Peptides | volume = 159 | issue = | pages = 170901 | date = January 2023 | pmid = 36347314 | doi = 10.1016/j.peptides.2022.170901 | url = }}

• Δ⁹-Tetrahydrocannabinol (THC) (weak)
• Cannabidiol (weak){{cite journal | vauthors = Burford NT, Traynor JR, Alt A | title = Positive allosteric modulators of the μ-opioid receptor: a novel approach for future pain medications | journal = Br J Pharmacol | volume = 172 | issue = 2 | pages = 277–286 | date = January 2015 | pmid = 24460691 | doi = 10.1111/bph.12599 | pmc = 4292945 | url = }}
• Salvinorin A (weak)

• BMS-986124

• SCH-202676 (highly non-selective){{cite journal | vauthors = Fawzi AB, Macdonald D, Benbow LL, Smith-Torhan A, Zhang H, Weig BC, Ho G, Tulshian D, Linder ME, Graziano MP | title = SCH-202676: An allosteric modulator of both agonist and antagonist binding to G protein-coupled receptors | journal = Mol Pharmacol | volume = 59 | issue = 1 | pages = 30–37 | date = January 2001 | pmid = 11125021 | doi = 10.1124/mol.59.1.30 | url = }}

• δ-opioid receptor
• κ-opioid receptor

{{reflist|2}}

• {{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}}

Category:Opioid receptors

Category:Human proteins