Opioid receptors

J McDonald PhD
DG Lambert PhD FRCA Matrix reference 1A02,
2E01, 3E00

Opium and its derivatives have been used for to naloxone. Putative subtypes of the classical
Key points
centuries; findings of fossilized opium poppy opioid receptors have been suggested, m1, 2, and 3
The opioid system

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seeds dating as far back as 30 000 yr suggest the for MOP, d1 and 2 for DOP, and k1a, 1b, 2a, 2b, and 3
comprises four types of
use of opium by Neanderthal man. In 1799, for KOP, based on a variety of evidence such as
receptor: m- (MOP), d-
Friedrich Serturner discovered the major active the differential modulation by drugs on function-
(DOP), k-opioid and
nociceptin (NOP). ingredient of opium, which he named morphine al responses in vivo and in vitro, along with in-
and opioid pharmacology was born. Morphine complete tolerance of functional responses seen
Opioid receptors all have
and other opioid drugs act on an endogenous when using different drugs targeting the same
selective endogenous
opioidergic system which is not only involved in receptor. However, the legitimacy of these
peptides.
setting pain (nociceptive) threshold and control- pharmacologically defined subtypes is deficient
Analgesia elicited by ling nociceptive processing but also participates when placed alongside the molecular research
clinically applied opioids act
in modulation of gastrointestinal (GI) function, which reveals how individual opioid receptors
predominantly via the MOP
endocrine and autonomic function, and a pos- are encoded by a single respective gene, and that
receptor.
sible role in cognition. the knock-out of a single receptor gene leads to
Tolerance to MOP receptor Evidence for the existence of multiple opioid the loss of all functionality associated with the
analgesics maybe attenuated
receptor types was reported based on the differ- receptor. Pharmacologically defined subtypes of
by both NOP and DOP
ent anatomical location and the pharmacological receptor are the consequence of a number of pro-
receptor antagonism.
profiles of compounds that were eventually used cesses including alternative splicing of opioid
Mixed-opioids represent a to name them, that is, morphine (mu), ketocycla- receptor genes.
new focus in opioid receptor
zocine (kappa), and vas deferens (delta). In sub- To understand the process of alternative spli-
pharmacology.
sequent years, the molecular cloning, functional cing, and how it may result in different subtypes
expression, and characterization of these recep- of receptor, it is necessary to understand how
tors has been reported and it is understood that opioid receptor genes are encoded in genomic
each receptor is the product of a single gene; DNA which consists of introns and exons.
OPRM1 (m), OPRK1 (k), and OPRD1 (d). The Introns represent nucleotide sequences encoded
nociceptin orphanin FQ peptide receptor was by the gene that are removed in the formation
first reported as an opioid receptor-related clone, of RNAs, while exons represent nucleotide se-
formerly named LC132 or ORL-1, and with no quence encoded by the gene that remains in the
known endogenous ligand, the receptor was final RNA. In the case of opioid receptors, gene
dubbed ‘orphan’.1 2 Its orphan status remained splicing removes the intron sequences leaving a
until the formal identification of an endogenous messenger RNA that is translated into the final
ligand, nociceptin/orphanin FQ (N/OFQ), iso- protein structure of the receptor. Alternative spli-
J McDonald PhD lated from brain extracts, utilizing a process cing concerns how, in this process, after the
Department of Cardiovascular Sciences known as reverse pharmacology (the searching removal of the introns, the exons can be reat-
Division of Anaesthesia, Critical Care of a drug to activate a molecular cloned recep- tached in different ways resulting in different
and Pain Management
RK-CSB, Leicester Royal Infirmary tor), simultaneously by Meunier and colleagues3 RNAs and therefore leading to different opioid re-
Leicester LE2 7LX and Reinscheid and colleagues.2 ceptor proteins, that is, opioid receptor subtypes.
UK The International Union of Basic and Clinical
DG Lambert PhD FRCA Pharmacology (IUPHAR) nomenclature regards
Department of Cardiovascular Sciences MOP (m), KOP (k), and DOP (d) as ‘classical’
Cellular mechanisms of action
Division of Anaesthesia, Critical Care opioid receptors, a distinction based on the sensi- All four receptors are G-protein-coupled recep-
and Pain Management
RK-CSB, Leicester Royal Infirmary tivity to the opioid antagonist naloxone. Nociceptin tors sharing a similar seven transmembrane top-
Leicester LE2 7LX receptor (NOP) is used for the N/OFQ peptide ology (Fig. 1). G-protein-coupled receptors have
UK receptor which is currently classified as a non- no direct link with effector proteins, instead the
Tel: þ44 116 258 5291
Fax: þ44 116 285 4487 opioid member of the opioid receptor family, message is relayed via a G-protein. All four
E-mail: [email protected] based on similarities in structure and localization subtypes of receptors preferentially couple to in-
(for correspondence) to the classical opioid receptors but insensitivity hibitory G-proteins and the activation of opioid
doi:10.1093/bjaceaccp/mku041
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& The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia.
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Opioid receptors

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Fig 1 The seven transmembrane structure of opioid G-protein-coupled receptors. Activation by opioid receptor ligands leads to initiation of intracellular
transduction pathways that include stimulation of potassium efflux, inhibition of VSCCs, and inhibition of adenylyl cyclase.

receptors, for example, MOP with morphine leads to a variety of are cleaved from a larger precursor protein(s); however, to date, this
cellular processes; (i) closing of voltage-sensitive calcium channels protein remains elusive (Tables 1 and 2).
(VSCCs), (ii) stimulation of potassium efflux leading to hyperpolari- The majority of opioid drugs used clinically elicit their action
zation, and (iii) reduced cyclic adenosine monophosphate (cAMP) through activation of the MOP receptor, and are mainly used to
production via inhibition of adenylyl cyclase. Overall, this results in produce analgesia, being effective against high-intensity mechanic-
reduced neuronal cell excitability leading to a reduction in transmis- al, thermal, and chemical stimuli. The prototypical MOP agonist is
sion of nerve impulses and inhibition of neurotransmitter release the alkaloid morphine, purified from opium. Semi-synthetic com-
(Fig. 1). pounds, such as diamorphine and codeine, are the result of chemical
modifications to the natural opiate morphine. Codeine represents a
partial agonist, with reduced efficacy compared with a full agonist
Endogenous and exogenous ligands like morphine acting at the MOP receptor, and for this reason is used
Endogenous opioid peptides are cleaved from pro-hormone precur- for the treatment of less severe pain. Fully synthetic MOP agonists,
sors. The endogenous DOP receptor peptides met-enkephalin and with structures unrelated to morphine, have also been identified and
leu-enkephalin (cleaved from proenkephalin and prodynorphin) give are used clinically including the piperidine series such as meperi-
rise to the KOP receptor agonists dynorphin A and B, while N/OFQ dine, fentanyl, and methadone along with the benzomorphan series
is derived from the polypeptide precursor pre-pro– N/OFQ. which include pentazocine (Table 1).
Proopiomelancortin encodes the peptide b-endorphin which has Selective antagonists are available for the classical opioid
agonist activity at the three classical opioid receptors. It is assumed receptors, naltrindole for DOP, norbinaltorphimine for KOP, and
that the endogenous MOP receptor peptides endomorphin 1 and 2 D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) for MOP. As

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 Opioid receptors

Table 1 Opioid receptor nomenclature including information on various agonists and antagonists selective for different receptor subtypes. *Spiradoline (U-62,066E) and *Enadoline
(CI-977) are KOP selective ligands that have undergone clinical trials but are not currently in use4 5

Current receptor nomenclature

DOP KOP MOP NOP

Previous nomenclature OP1, d OP2, k OP3, m OP4, LC132, ORL1

G-protein coupling Gi/o Gi/o Gi/o Gi/o
Endogenous ligand Leu-enkephalin, Met-enkephalin Dynorphin A b-Endorphins, endomorphin 1 and 2 Nociceptin/OrphaninFQ (N/OFQ)
Synthetic agonists DPDPE DSTBULET SNC-80 U69593 DAMGO Ro64-6198
Selective antagonists Naltrindole Nor-BNI CTOP J-113397 (synthetic) UFP-101

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(peptide)
Clinical drugs None *Spiradoline, *Enadoline Morphine, fentanyl, diamorphine, None
methadone, codeine
Mixed action Pentazocine (partial agonist) Pentazocine (partial agonist) Pentazocine (antagonist) Pentazocine (inactive)
Buprenorphine (inactive) Buprenorphine (antagonist) Buprenorphine (partial agonist) Buprenorphine (partial agonist)
Naloxone sensitivity Antagonist Antagonist Antagonist Inactive

Table 2 The key clinical effects mediated by opioid receptor subtypes and selectivity of
p presynaptically on primary afferent neurones within the dorsal horn
endogenous opioid peptides. N/OFQ, nociceptin orphanin FQ; , no affinity/effect; ,
pp ppp of the spinal cord where they inhibit glutamate release and hence
low affinity/effect; , intermediate affinity/effect; , high affinity/effect (modified
from Rang and colleagues)6 transmission of nociceptive stimuli from C- and Ad-fibres.
The periaqueductal grey (PAG) is an area of the midbrain
Clinical effect Receptor subtype
involved in the central control of nociceptive transmission. Efferent
MOP KOP DOP NOP outflow from the PAG descends to the spinal cord where it acts to
ppp inhibit nociceptive transmission in afferent fibres; this pathway is
Supraspinal: analgesia   
pp p pp pp known as the descending inhibitory control pathway. The efferent
Spinal: analgesia
ppp p
Respiratory depression   outflow from the PAG is constrained under resting conditions by the
ppp
Euphoria    actions of g-amino butyric acid (GABA). GABA is the main inhibi-
Endogenous ligand
ppp ppp ppp tory transmitter in the brain, preventing neurotransmission through
b-Endorphins 
pp ppp p p
Dynorphin A hyperpolarizing cell membranes which inhibit action potential
p ppp
Leu-enkephalin   firing, here GABA acts to reduce antinociceptive outflow from the
pp ppp
Met-enkephalin  
pp ppp p p PAG (Fig. 2). High densities of MOP receptor are found in the PAG
Dynorphin A/B
ppp
Endomorphin 1/2    and the analgesia of some opioid drugs is proposed to come about
ppp
N/OFQ    by block of the resting inhibitory GABA activity into this region of
the brain. The inhibitory effect of MOP receptor firing blocks the in-
previously described, the actions of all three receptors can be inhib- hibitory actions of GABA, removing its tonic block and stimulating
ited by the non-selective antagonist naloxone, used traditionally in antinociceptive outflow to the spinal cord.
defining opioid receptors. While the actions of N/OFQ at NOP are Major side-effects that come about from the use of MOP agonists
not inhibited by naloxone, NOP selective antagonist drugs have include respiratory depression through a reduction in the sensitivity
been developed, including a synthetic ligand J-113397 and UFP- of chemoreceptors (CNS/PNS) to hypercapnia. MOP agonists also
101, a peptide developed through modification to the endogenous inhibit GI tract secretions and peristalsis often causing constipation,
N/OFQ peptide (Table 1). and have predominantly inhibitory effects on the cardiovascular
system, thermoregulation, hormone secretion, and immune function.
Studies using MOP receptor knockout mice have defined the role
Opioid receptor types MOP plays tonically and when stimulated by exogenously applied
ligands. MOP receptor knockout mice show increased sensitivity to
m-Opioid receptor
thermal pain, implicating the receptor in this mode of nociception.
The MOP receptor was the last of the classical opioid receptors to be However, no change in threshold from pain elicited via mechanical
cloned and is located throughout the central nervous system (CNS) stimuli was seen. None of the predicted effects or side-effects of
in areas involved in sensory and motor function, including regions morphine were seen in mice lacking the MOP receptor. MOP recep-
concerned with the integration and perception of these senses, for tor knockout mice showed no change in respiratory function demon-
example, the cerebral cortex and amygdala ( part of the limbic strating no tonic role in this system. Analgesia and reward were
system). absent and investigation of acute morphine showed no respiratory
The highest density of MOP receptors are found in the caudate action. This genetic approach indicates that both the wanted and
putamen (of the basal ganglia). MOP receptors are located unwanted effects of morphine are due to action at the MOP receptor.

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Opioid receptors

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Fig 2 In the rostral ventromedial medulla (RVM), ON cells tonically inhibit the firing of OFF cells, through the release of the inhibitory neurotransmitter
GABA. OFF cell firing induces analgesia via activation of descending inhibitory control pathways to the spinal cord. MOP agonists (e.g. morphine) cause
analgesia supraspinally by inhibiting ON cells, that is, removal of the GABA-mediated inhibition resulting in the firing of OFF cells and activation of descending
inhibitory control and analgesia. NOP receptors situated at ON and OFF cells give rise to N/OFQ-mediated anti-opioid action through a direct inhibition of the
OFF cells, thus preventing MOP receptor lead activation of the descending inhibitory control pathway.

While the main analgesic effects of opioids are elicited by reduce a number of these side-effects. Indeed, methylnaltrexone, a
central activation of opioid receptors, a number of the common side- peripherally acting opioid antagonist, in clinical trials was effective
effects including reduced GI motility, urinary retention, and pruritus at treating opioid-induced constipation, while alvimopan, another
are regulated by activation of peripherally located opioid receptors. peripherally acting MOP antagonist, was shown to reduce the dur-
The use of peripherally acting opioid receptor antagonists may ation of postoperative ileus and postoperative nausea and vomiting.

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 Opioid receptors

MOP opioids are used for analgesia in both acute pain and Highest densities of the receptor are found in the olfactory bulb,
chronic pain; however, opioids produce tolerance where dose escal- cerebral cortex, nucleus accumbens, and the caudate putamen. DOP
ation is required to maintain the same degree of analgesia received. receptors are located presynaptically on primary afferents where
Accompanying escalating doses of MOP agonist is the increased they inhibit the release of neurotransmitter. Through both spinal and
prevalence of MOP-mediated side-effects. Tolerance that develops supraspinal sites, the receptor is involved in the antinociceptive/an-
to MOP agonists is influenced by the DOP receptor. In animals in algesic actions of some opioids. DOP receptor agonists have also
which the DOP receptor is blocked, either with the use of DOP se- been shown to reduce GI tract motility and cause respiratory depres-
lective antagonists or through genetic knock-out, there is a reduction sion, limiting clinical interest.
in MOP tolerance. Analgesic responses to a fixed daily morphine Interactions between MOP and DOP receptors have been sug-

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dose were lost after 5 days in wild-type mice; however, in gested based on the pharmacology of DOP agonists in vivo and
DOP-receptor knockout mice, no such tolerance could be deter- in vitro, and the effects of DPDPE have been tested in mice lacking
mined after 8 days administration.7 In humans, this strategy could be the MOP receptor which showed, dependent on the response mea-
achieved through the administration of two drugs, a MOP agonist sured, that DPDPE displayed various actions from ineffective to
and DOP antagonist; however, there are currently no DOP antago- fully and partially effective. In mice lacking the MOP receptor, re-
nists licensed for clinical use in man, and with this in mind, the chal- spiratory depression of DOP agonists was absent which further sug-
lenge has been to discover non-selective drugs that can act as both gests cross-talk between the MOP and DOP receptors or that DOP
an agonist at the MOP receptor while antagonizing the DOP. Those agonists have activity at the MOP receptors in vivo, the latter is un-
drugs of interest include UFP-505 a non-selective bi-functional likely since even the most selective DOP compound deltorphin
compound which interacts with both the DOP and MOP receptor showed attenuated responses in MOP receptor knock-out animals.
through distinct binding interactions, and MDAN-21 a bivalent Interestingly, co-administration of a MOP agonist such as morphine
ligand in which the pharmacologically active region ( pharmaco- with a sub-antinociceptive dose of leu-enkephalin, a DOP agonist,
phore) of oxymorphone (MOP agonist) is attached to a naltrindole has a synergistic analgesic action. Such an approach could be useful
(DOP antagonist) pharmacophore by way of a 21-atom linker.8 9 in limiting the dose of morphine required for analgesia, therefore
Bivalent ligands with MOP agonism and DOP antagonism not only attenuating the development of tolerance. To re-emphasize, there are
have a reduced tolerance profile but also have improved antinocicep- currently no clinically available DOP ligands.
tion, along with decreased physical dependence when compared
with morphine. Hence, the development of ‘mixed-opioids’ repre-
k-Opioid receptor
sents a potential strategy to design novel classes of analgesics.
While the focused development and use of mixed opioids repre- The KOP receptor was the second of the opioid receptor family to be
sents a new therapeutic strategy, there are already a number of cloned. The prototypical agonist of the k-receptor is the non-peptide
opioid drugs in current use which have mixed sites of action. For benzomorphan, ketocyclazocine the actions of which have been
example, pentazocine behaves as a partial agonist at DOP and KOP shown to be distinct from those elicited by stimulation of the MOP
receptors resulting in analgesia, while at MOP receptors, it is an an- receptor (e.g. sedation without marked effects on heart rate). Two
tagonist, the consequence of which is reduced risk of respiratory de- synthetic KOP receptor agonists, spiradoline (U-62,066E) and ena-
pression. Other mixed opioids in clinical use include buprenorphine, doline (CI-977), have undergone clinical trials for their analgesic
a drug with partial agonist activity at MOP and NOP receptors. actions. While spiradoline produced promising analgesia in animals,
Buprenorphine has a bell-shaped response curve for its analgesic ac- clinical data show that spiradoline produces adverse effects such as
tivity in vivo such that at low and intermediate doses, an analgesic diuresis, sedation, and dysphoria at doses lower than those needed
response results, at higher doses, the analgesic response is decreased for analgesic effects. Enadoline produced similar side-effects, in-
back to baseline. The complex pharmacology associated with bupre- cluding sedation, confusion, dizziness along with increased urinary
norphine may be explained by its agonist activity at MOP, resulting output, and feelings of depersonalization. The side-effects elicited
in analgesia at low and intermediate doses, and NOP, resulting in an by these and other KOP receptor agonists have as yet limited their ef-
anti-opioid/anti-analgesic action at higher doses (see later). fective clinical usage. However, it has been shown recently that
KOP agonists, such as enadoline, may have neuroprotective actions
via their ability to inhibit post-ischaemic glutamate release. The ad-
vantage of KOP receptor agonists over other opioid ligands is that
d-Opioid receptor
they do not cause respiratory depression, although their effective use
The DOP receptor was the first to be cloned and shows restricted may be limited by dysphoria; this is not seen in all subjects.
distribution relative to the other opioid receptors. Highly selective
agonists that are peptide (DSTBULET), cyclic peptide (DPDPE),
Nociceptin receptor
and synthetic/non-peptidic (SNC-80) in structure are available for
the DOP receptor, along with high-affinity antagonists, for example, At the cellular level, N/OFQ produces similar actions to those of the
the non-peptide naltrindole. All these ligands are experimental only. classical opioids resulting in reduced neuronal excitability and

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Opioid receptors

inhibition of transmitter release. Initial studies concentrated on the bi-functional, mixed-opioids. This represents an important shift and
role of N/OFQ and NOP in pain. However, exogenous administra- one that will hopefully lead to new clinically effective analgesics
tion of N/OFQ has been shown to have effects on locomotion, stress with reduced side-effect profiles.
and anxiety, feeding, learning and memory, reward/addiction, and
urogenital activity.10
Declaration of interest
N/OFQ under laboratory conditions has a pronociceptive, anti-
analgesic effect when applied supraspinally, while spinally, N/OFQ None declared.
causes analgesia at high doses and hyperalgesia at low doses.
Nociceptin earned its name from the conclusions of the original
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