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pdb fle: 4DKL


SHOWN TO LEFT: Crystal structure of the µ-opioid receptor bound to a morphinan antagonist (shown in grey cpk style)

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PDB file: 4DKL

See Also Crystal Structure of kappa-opioid receptor.


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Crystal structure of the µ-opioid receptor bound to a morphinan antagonist. Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, Pardo L, Weis WI, Kobilka BK, Granier S Nature.2012 Mar 21

Opium is one of the world’s oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical opioids produce analgesia as well as many undesirable side effects (sedation, apnoea and dependence) by binding to and activating the G-protein-coupled µ-opioid receptor (µ-OR) in the central nervous system. Here we describe the 2.8?Ĺ crystal structure of the mouse µ-OR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most G-protein-coupled receptors published so far, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the µ-OR crystallizes as a two-fold symmetrical dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into opioid receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction.

Compared to the buried binding pocket observed in most G-protein-coupled receptors published so far, the morphinan ligand binds deeply within a large solvent-exposed pocket.

The µ--opioid receptors (MOR) are a class of opioid receptors with high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. They are also referred to as µ-opioid peptide (MOP) receptors. The prototypical µ-receptor agonist is the opium alkaloid morphine; µ- (mu) refers to morphine.

Morphine and codeine are the main active opioid alkaloids in opium and gene disruption studies in mice show that the target for the majority of the effects of opioid alkaloids, whether beneficial or adverse, is the µ-opioid (m-OR) receptor. The m-OR belongs to the c subfamily of class A G-protein-coupled receptors (GPCRs) with two closely related family members known as the d- and k-opioid receptors3.


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]

  • µ-1

More is known about the µ-1 opioid receptor than is known about the other types.

  • µ-2

TRIMU 5 is a selective agonist of the µ-2 receptor.[4]

  • µ-3

In 2003, a µ-3 variant was described,[5] which was responsive to opiate alkaloids but not opioid peptides.[6]


They can exist either presynaptically or postsynaptically depending upon cell types.

The µ--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 µ--receptors 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.

µ- receptors are also found in the intestinal tract. This causes constipation, a major side effect of µ-agonists, due to inhibition of peristaltic action.


MOR can mediate acute changes in neuronal excitability via "disinhibition" of presynaptic release of GABA (see works from Charles Chavkin and Roger Nicoll). 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.[7] 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- 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 side effects, such as sedation, euphoria and decreased respiration, tend to lessen with continued use as tolerance develops. Analgesia, 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.[8]


As with other G protein-coupled receptors, signalling by the mu opioid receptor is terminated through several different mechanisms, which are upregulated with chronic use, leading to rapid tachyphylaxis.[9] The most important regulatory proteins for the mu opioid receptor are the µ--arrestins Arrestin beta 1 and Arrestin beta 2,[10][11][12] and the RGS proteins RGS4, RGS9-2, RGS14 and RGSZ2.[13][14]

Long-term or high dose use of opioids may also lead to additional mechanisms of tolerance becoming involved. This includes downregulation of mu opioid receptor 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.[15][16][17] 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 and so reduce the effects of opioid drugs by altering downstream pathways, regardless of mu opioid receptor activation.[18][19]

Tolerance and overdoses

Opioid overdoses kill through apnea and fatal hypoxia, often aggravated by simultaneous use of alcohol, benzodiazepines or barbiturates. Substantial tolerance to respiratory depression develops quickly, and tolerant individuals can withstand larger doses (an example of Mithridatism). 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 with any of several opioid antagonists: naloxone, or naltrexone, differing primarily in their duration of action and potency. While commonly referred to as antagonists, and when used to treat an overdose they do appear to function as such, naloxone & naltrexone are inverse agonists.


Manglik, A., Kruse, A., Kobilka, T., Thian, F., Mathiesen, J., Sunahara, R., Pardo, L., Weis, W., Kobilka, B., & Granier, S. (2012). Crystal structure of the µ-opioid receptor bound to a morphinan antagonist -- This is a pdf file of the Nature Article


  1. Zhorov BS, Ananthanarayanan VS. Homology models of µ--opioid receptor with organic and inorganic cations at conserved aspartates in the second and third transmembrane domains. Arch Biochem Biophys. 37:31-49, 2000.
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