Acta Anaesthesiologica Taiwanica 49 (2011) 21e25

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Review Article

Mu opioid receptors in pain management

Gavril Pasternak 1, 2 *, Ying-Xian Pan 1, 2
1
Department of Neurology, Memorial Sloan-Kettering Cancer Center, NY, USA.
2
Department of Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, NY, USA.

a r t i c l e i n f o a b s t r a c t

Article history: Most of the potent analgesics currently in use act through the mu opioid receptor. Although they are
Received 26 October 2010 classified as mu opioids, clinical experience suggests differences among them. The relative potencies of the
Received in revised form agents can vary from patient to patient, as well as the side-effect profiles. These observations, coupled with
30 November 2010
pharmacological approaches in preclinical models, led to the suggestion of multiple subtypes of mu
Accepted 3 December 2010
receptors. The explosion in molecular biology has led to the identification of a single gene encoding mu
opioid receptors. It now appears that this gene undergoes extensive splicing, in which a single gene can
Key words:
generate multiple proteins. Evidence now suggests that these splice variants may help explain the clinical
pain;
alternative splicing;
variability in responses among patients.
pharmacogenomics; Copyright Ó 2011, Taiwan Society of Anesthesiologists. Published by Elsevier Taiwan LLC. All rights
analgesics, opioid reserved.

1. Introduction need to be individualized. Opioid Rotation also illustrates differ-

Opiates have been used to manage pain for centuries. Opium,
which contains a number of alkaloids including morphine and
codeine, was eaten, smoked, and used as a tincture. After their
isolation, morphine and codeine were used individually. Thousands
of analogs have been generated in an effort to avoid some of the
difficulties encountered with opiate use, such as respiratory
depression, sedation, and constipation. Most of these agents act
through mu opiate receptors, as defined by the selectivity of their
binding for the three classes of opioid receptors that have been
cloned. This is to be expected because the structure of morphine
was used as a template for the synthesis of most of them. Clinicians
have long observed that patients can have markedly varying
responses to mu opioids. Some patients may encounter severe side
effects such as nausea and vomiting with one agent, whereas
having no difficulties at all with the other. For example, it is not
uncommon to find patients with severe nausea/vomiting from
morphine tolerating methadone without problems. Furthermore,
the analgesic activity of the opioids also can vary among patients.
One patient may find one mu opioid to be quite effective, whereas
a different drug may not work anywhere near as well. However, the
same drug may not be the best for all patients. This variability
among patients has led to the accepted paradigm that analgesics
* Corresponding author. Department of Neurology, Memorial Sloan-Kettering
Cancer Center, 1275 York Ave, New York, NY 10065, USA. Tel.: þ1 646 888 2165.
E-mail: pasterng@mskcc.org (G. Pasternak).
ences among the mu opioids. In Opioid Rotation switching patients
who are highly tolerant to one opioid to a different opioid often
restores the analgesic effectiveness and sensitivity.1,2 While all mu
drugs display tolerance with prolonged dosing, cross-tolerance is
incomplete. That is, the tolerance to the second drug may not be
as pronounced as the first, explaining why the switch is effective.
All these features have raised questions about the mechanisms of
these drugs, specifically how a single mu receptor could mediate
these actions.
2. Early studies of mu opiate receptor and multiplicity
The first opioid receptor identified in binding assays in 19733
5
was the mu receptor. A receptor for the opiates had been predicted
years earlier from a variety of traditional pharmacological
approaches and the rigid structure activity studies of morphine and
related chemical scaffolds.6e8 Because the studies used morphine-
related probes, it is not surprising that the receptors were mu.
However, several other families of opioid receptors have also been
identified (Table 1). In vivo studies led Martin to propose the exis-
tence of kappa receptors, in addition to the mu receptors.9,10 Delta
receptors, which are selective for the enkephalins, were identified11
after the isolation and identification of endogenous opioids.12e14
Indeed, it turns out that the endogenous ligand for the kappa
receptors is another endogenous opioid, dynorphin A.15,16 Work is
in progress developing new selective delta and kappa opioids for
clinical use, but for the most part the drugs available clinically are

1875-4597/$ e see front matter Copyright Ó 2011, Taiwan Society of Anesthesiologists. Published by Elsevier Taiwan LLC. All rights reserved.
doi:10.1016/j.aat.2010.12.008
22 G. Pasternak, Y.-X. Pan

Table 1
Classification of the opioid receptor families.

Receptor Drugs Analgesia Physical dependence Dysphoria Respiratory depression Gene

Mu Morphine Yes Yes No Yes MOR-1

Kappa Kappa1 Dynorphin A Yes No Yes No KOR-1

U50, 488H
Kappa2 Ethylketocyclazocine Yes No Yes No KOR-1/DOR-1
Kappa3 Naloxone benzoylhydrazone Yes No No No See below
Levorphanol

Delta Enkephalin Yes No ? No DOR-1

DPDPE

Three major families of opioid receptors have been proposed. Subtypes of all have been proposed using pharmacological and molecular biological approaches. The genes for all
have been established, except for kappa3. This subtype, which is important in the analgesic actions of a variety of opioid analgesics, including levorphanol and nalbuphine, is
most likely a heterodimer involving one of the truncated 6TM MOR-1 splice variants and an unknown second receptor.64 However, this remains to be confirmed. DPDPE:
[D-Pen2,D-Pen5]enkephalin.

mu. There are several mixed agonists/antagonists that interact with
both mu and kappa receptors, but they have limited use.
The first suggestion that there may be more than one class of
mu receptors came from receptor binding studies in the mid 1970s
that revealed a novel site with unusual characteristics.17 Although
mu drugs like morphine labeled it with high potency, confirming
its classification as a mu receptor, its ability to bind other drugs
clearly distinguished it from the original mu receptor seen in
receptor binding assays. The new site was termed mu1, whereas
the original morphine-selective site was termed mu2.18 Under-
standing the pharmacological significance of these two mu
receptors was facilitated by the development of selective antago-
nists that could selectively block the mu1 site and not the mu2
site.19e21 The naloxonazine-sensitive site corresponds to the mu1
site, whereas the naloxonzine-insensitive mu site is mu2. When
given in vivo, these antagonists blocked morphine analgesia, but

Fig. 1. Schematic of the human mu opioid receptor (OPRM1) gene structure and alternative splicing. A. Gene structure of the human OPRM1 gene. Exons and introns are showed by
boxes and horizontal lines, respectively. Intron size is indicated below the introns as kilobases (kb). Promoters are showed by arrows. B. Alternatively spliced variants of the human
OPRM1 gene. Exon composition for each alternatively spliced variant was showed by appropriate exon boxes. The lines between exons are introns that are spliced out during
splicing. Translation start and stop points are shown by bars below and above exon boxes, respectively. From the literature.68
Mu opioid receptors in pain management
not respiratory depression or the inhibition of gastrointestinal
transit or many of the signs of physical dependence.22e27 Together,
these studies implied that drugs such as morphine were acting
through more than one mu receptor.
3. Molecular biology of mu opiate receptors
The opiate receptors were first cloned in 1992 with the isolation
of the delta receptor DOR-1 by two independent groups.28,29 This
initial report confirmed the existence of the receptors within the G-
protein coupled receptor family, one of the largest families of
receptors known. Based on these structures, the other members of
the opiate receptor family were quickly cloned, including the
mu30
32 and the kappa1 receptors.33e35 Soon after, yet another
receptor was identified with a strong homology to the opiate
receptors36e41 but which was subsequently found to have a previ-
ously unknown peptide as its endogenous ligand, orphanan FQ/
nociceptin.42,43
The mu receptors are the most important class of receptors
clinically. Most of the drugs used clinically act through these
receptors and understanding their actions is important in defining
their pharmacology. Pharmacological studies suggested more than
one class of mu opiate receptor. This has now been confirmed at the
molecular level. Although only a single mu receptor gene has been
reported, the receptor undergoes extensive alternative splicing to
generate a host of splice variants (Fig. 1).
After the cloning of MOR-1, much effort was placed on con-
firming its pharmacological relevance. The first studies involved
using an antisense approach in which very short sequences of
antisense targeted specific sequences of the mRNA, leading to its
degradation.44,45 These initial reports quickly established that
MOR-1 was critical in the production of morphine analgesia.
However, the antisense approach can be used more extensively to
perform antisense mapping to assess the presence of specific exons
Fig. 2. Schematic of the human OPRM1 carboxyl terminal splice variants’ structures and amino acid sequences predicted from downstream exons of exon 3. The common receptor
structure of all the human carboxyl terminal splice variants is indicated by heavy lines across the lipid bilayer of the cell membrane. Splice junctions between exons are indicated by
arrows. The amino acid sequences predicted from different downstream exons are shown on the right along with the indicated splice variants. Potential phosphorylation sites are
indicated by the italic letters and the following symbols on the top of the letters. D: cAMP- and cGMP-dependent protein kinase phosphorylation site; p: tyrosine kinase phos-
phorylation site; *: casein kinase II phosphorylation site.
23
within the mRNA responsible for making a protein.46e48 Certain
exon targets were important in morphine analgesia, including
exons 1 and 4. However, antisense probes targeting exons 2 and 3
had little effect on morphine although they significantly dimin-
ished the activity of heroin and morphine-6b-glucuronide. Thus, at
the molecular level there does appear to be receptor differences for
these mu opiates.
The association of MOR-1 with morphine analgesia was further
confirmed by the generation of several different knockout animals
in which the MOR-1 gene was disrupted. In all of these different
knockout animals, which targeted exons 1, 2, and/or 3, morphine
lost all activity.49e52 However, in one exon 1 knockout mouse,
heroin and M6G were still analgesic. This was quite confusing and it
was initially suggested that these drugs were activating alternative
opioid receptors, such as delta or kappa1. This possibility was
eliminated with the finding that the residual heroin and morphine-
6b-glucuronide analgesia remained in a triple knockout mouse,
which had the same disruption of exon 1 of MOR-1 and additional
disruptions of the delta (DOR-1) and kappa1 (KOR-1) receptors.
What made this particular knockout mouse interesting was the
continuous presence of a number of MOR-1 splice variants.52 Some
of these, under the control of the exon 11 promoter, do not contain
exon 1, perhaps explaining their continuous expression.
The splice variants associated with the mu opiate receptor can
be separated into two categories based on their promoter. The gene
encoding MOR-1 is quite complex with two distinct promoters. The
primary one is associated with exon 153,54 and generates a number
of variants that are spliced at the 30 end in mice, rats, and humans
(Fig. 1).55e62 These are interesting from several perspectives. They
are full length seven transmembrane domain G-protein coupled
receptors. Structurally, they differ only at the very tip of the intra-
cellular C-terminus. The initial opiate receptor cloned, MOR-1,
contains 12 amino acids at the very tip of the C-terminus encoded
by exon 4 (Fig. 2). In the other C-terminus spliced variants, these 12
24
Table 2
Opioid analgesia in MOR-1 knockout mice.
Drug ED50 value (mg/kg, s.c.)
Exon 1 KO Exon 11 KO
WT KO Shift WT KO
Morphine 5.0 >100 >20 1.6 2.6
Methadone 1.5 1.6
M6G 3.8 8.5 2.3 0.92 19.3
Heroin 1.2 4.0 2.7 0.58 3.2
Fentanyl 0.024 0.230
WT and KO mice with a disruption of exon 1 of MOR-1 were tested with the indi-
cated drug and their ED50 values determined.52 Other groups of mice were gener-
ated with a disruption of exon 11. WT and KO mice were tested with the indicated
drug and their ED50 values determined.64
ED50, median effective dose; WT, wildtype; KO, knockout.
amino acids are replaced with different sequences of varying
lengths. However, these differences are quite limited and the basic
structure of the receptor with its seven transmembrane domains
and binding pocket are identical among them (Fig. 2). Thus, these
splice variants share a common binding pocket and they all show
high affinity and selectivity for mu opiates, as shown in receptor
binding assays. Although the splicing has little effect on the ability
of the mu opioids to bind to the receptor, the small structural
differences do impact the ability of mu opioids to activate the
different splice variants. These differences in the activation profiles
of various mu opioids for the receptor variants may help explain the
subtle, but clear, differences among the various mu opioids seen
clinically.
The second set of variants is associated with exon 11, which is
located approximately 30 kilobases upstream of exon 1.57,63 These
variants include a number with quite unique structures. Unlike the
exon 1-associated variants, which all encode full length, seven
transmembrane domain receptors, many of the exon 11-associated
variants generate truncated variants with only six transmembrane
domains. Despite their unique structure, there is much evidence
now to suggest that they are pharmacologically important. This
derives from studies on mice in which all the exon 11-containing
variants are lost because of disruption of this region of the gene
(Table 2).64 Interestingly, morphine analgesia was not affected.
However, the analgesic actions of heroin and the morphine
metabolite morphine-6b-glucuronide were significantly reduced.
Looking at the drugs, it is apparent that the analgesic actions of mu
opioids can be differentiated at the molecular level.
4. The future
Pain management remains an art, dependent on the individu-
alization of care. Not all patients can be managed with the same
drugs. Indeed, the complexity of the clinical responses has long been
evident. Many factors may play a role, but evidence is accumulating
that much of this variability may result from the complexity of mu
receptors. Early work from our laboratory proposed two subtypes,
mu1 and mu2, based on selective antagonists.18,20,65 Studies
showing differences between morphine and morphine-6b-glucu-
ronide further implied a third subtype.48,66,67 However, the
molecular biology of the mu opioid receptor gene reveals the exis-
tence of dozens of mu receptor splice variants. Correlating these
splice variants to the pharmacologically defined receptors has
proven difficult. However, it seems likely that they play an impor-
tant role in why patients respond so differently. As our under-
standing progresses, the critical question is whether or not we can
use this knowledge to develop novel and useful analgesic lacking
the detrimental actions of the currently available drugs.
G. Pasternak, Y.-X. Pan
Acknowledgments
This work was supported, in part, from grants from the National
Institute on Drug Abuse to GWP (DA02615, DA07242, DA06241 and
DA00220) and YXP (DA013997 and DA029244).
Shift
1.6
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