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
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.
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.
of the µ-opioid receptor are well-characterized, though reverse-transcriptase
PCR has identified up to 10 total splice variants in humans.
More is known
about the µ-1 opioid receptor than is known about the
TRIMU 5 is a
selective agonist of the µ-2 receptor.
In 2003, a µ-3
variant was described,
which was responsive to opiate alkaloids but not opioid peptides.
They can exist
either presynaptically or postsynaptically depending upon cell types.
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.
are also found in the intestinal tract. This causes constipation,
a major side effect of µ-agonists, due to inhibition of peristaltic
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.
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.
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.
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
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.
The most important regulatory proteins for the mu opioid receptor
are the µ--arrestins Arrestin beta 1 and Arrestin beta 2,
and the RGS proteins RGS4, RGS9-2, RGS14 and RGSZ2.
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 Î˛-arrestins or RGS proteins.
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.
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.
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.
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
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