25 Opioids and Pain: Basic Concepts

The Oxford Handbook of the Neurobiology of Pain
John N. Wood (ed.)
https://doi.org/10.1093/oxfordhb/9780190860509.001.0001
Published: 2018 Online ISBN: 9780190860530 Print ISBN: 9780190860509
CHAPTER
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25 Opioids and Pain 
Christoph Stein, Claire Gaveriaux-Ru
https://doi.org/10.1093/oxfordhb/9780190860509.013.9 Pages 728–769

Published: 10 July 2018
Abstract
This article reviews basic and clinical concepts on pain and mechanisms underlying opioid analgesia. It
describes the structure, function, and cellular signaling of opioid receptors; endogenous and
exogenous opioid receptor ligands; as well as the central and peripheral sites of opioid actions. The
article also presents novel opioid-based therapeutic strategies, developed from recently gained
knowledge on opioid receptor structures and signaling, pathological pain situations, and mutant
mouse lines, aimed at the reduction of side e ects such as respiratory depression, constipation,
sedation, tolerance, or opioid-induced hyperalgesia. Lastly, the article addresses clinical problems
associated with opioid use, particularly the long-term use of opioid analgesics in chronic pain.
Keywords: Opioid receptors, analgesia, ligands, peripheral, respiratory depression, sedation, constipation,
tolerance, hyperalgesia
Subject: Molecular and Cellular Systems, Neuroscience
Series: Oxford Handbooks
Collection: Oxford Handbooks Online
Acute and Chronic Pain
Basic Concepts
Pain may be roughly divided into two broad categories: physiological and pathological pain. Physiological
(acute, nociceptive) pain is an essential early warning sign that usually elicits re ex withdrawal and thereby
promotes survival by protecting the organism from (further) injury. In contrast, pathological (e.g., chronic
neuropathic) pain is an expression of the maladaptive operation of the nervous system; it is pain as a
disease (Flor & Diers, 2007; Fordyce, Fowler, & DeLateur, 1968; Stein, 2013a).
Excitatory Mechanisms
Physiological pain is mediated by a sensory system consisting of primary a erent neurons, spinal
interneurons, ascending tracts, and supraspinal areas. Trigeminal and dorsal root ganglia (DRG) give rise to
high-threshold Aδ– and C- bers innervating peripheral tissues (skin, muscles, joints, viscera). These
specialized primary a erent neurons (nociceptors) transduce noxious stimuli into action potentials and
conduct them to the dorsal horn of the spinal cord. When peripheral tissue is damaged, primary a erent
neurons are sensitized and/or directly activated by thermal, mechanical, and/or chemical stimuli. Examples
are sympathetic amines, adenosine triphosphate (ATP), neuropeptides, nerve growth factor, prostanoids,
bradykinin, proin ammatory cytokines, and protons (Table 25.1) (Basbaum, Bautista, Scherrer, & Julius,

2009). Many of these agents lead to opening of cation channels (e.g., TRPV1, P2X3) in the neuronal
membrane. This produces inward depolarizing currents and subsequent action potentials that are then
conducted along the sensory axon to the dorsal horn of the spinal cord. Thereafter, these impulses are
transmitted to spinal neurons, brainstem, thalamus, and cortex. Repeated nociceptor stimulation can
p. 730 sensitize peripheral and central neurons
p. 731
(activity-dependent plasticity, or “wind-up”). This can be sustained by changes in the expression of genes
coding for various neuropeptides, transmitters, ion channels, receptors, and signaling molecules
(transcription-dependent plasticity) in peripheral and central neurons (Baron, Hans, & Dickenson, 2013;
Basbaum et al., 2009). Both induction and maintenance of central sensitization are critically dependent on
the peripheral drive by nociceptors, indicating that therapeutic interventions targeting such neurons may
be particularly e ective, even in chronic pain syndromes (Baron et al., 2013; Richards & McMahon, 2013).
Table 25.1 pH Values in Inflamed Tissues Measured in Vivo/ex Vivo
Reference Species, tissue Lowest

pH
(Häbler, 1929) Human, abscess 5.4
(Koldajew & Altschuler, 1930) Guinea pig, intraperitoneal bacterial inoculation 5.6
Mouse, s.c., i.p. bacterial inoculation 5.8
(Menkin, 1934) Dog, turpentine-induced pleural exudate 6.6

(Voegtlin, 1935) Rat, implanted tumors 6.82
(Menkin & Warner, 1937) Dog, turpentine-induced pleural exudate 6.5
(Meyer, Kammerling, & et al., 1948) Human, malignant tumors, inflamed tissues 5.44
(Revici, Stoopen, Frenk, & Ravich, 1949) Human, malignant tumor 5.7
(Menkin, 1956) Dog, turpentine-induced pleural exudate 6.0
(Jebens & Monk-Jones, 1959) Human, osteoarthritis, joint injury, synovial fluid 6.5
(Pampus, 1963) Human, astrocytoma 5.85
(Ashby, 1966) Human, melanoma 6.4
(Cummings & Nordby, 1966) Human, rheumatoid arthritis synovial fluid 7.08
(Goldie & Nachemson, 1969) Human, rheumatoid arthritis synovial fluid 6.0
(Goldie & Nachemson, 1970) Human, rheumatoid arthritis synovial fluid 6.4
(Falchuk, Goetzl, & Kulka, 1970) Human, rheumatoid arthritis 6.84
(Treuha & McCarty, 1971) Human, arthritis 6.60
(Hutchins & Sheldon, 1972) Rabbit, diabetic skin wounds 6.9
(Silver, 1975) Rabbit, brain, wounds, ischemia 5.0
(Jacobus, Taylor, Hollis, & Nunnally, 1977) Rat, ischemic heart, intracellular 5.7
(Levine & Kelly, 1978) Rat, seminiferous tubules and epididymis 6.57+0.08
(Vaupel, Frinak, & Bicher, 1981) Mouse mammary carcinoma 5.8
(Farr, Garvey, Bold, Kendall, & Bacon, 1985) Human, rheumatoid and osteoarthritis synovial fluid 6.85
(Punnia-Moorthy, 1987) Rat, air pouch granuloma induced by carrageenan, dextran, 6.87
Staph. aureus
(Pan, Hamm, Rothman, & Shulman, 1988) Human, exercised muscle, intracellular pH 6.1
(Hood, Schubert, Keller, & Muller, 1988) Human, exercised muscle, calculated intracellular pH 6.31+0.09
(Geborek, Saxne, Pettersson, & Wollheim, Human, rheumatoid arthritis synovial fluid 7.03
1989)
(Tulamo, Bramlage, & Gabel, 1989) Horse, Staph. aureus-induced arthritis, synovial fluid 6.2
(Newell, Franchi, Pouyssegur, & Tannock, Nude mouse; implanted tumors 6.65
1993)
(Simmen & Blaser, 1993) Human, abdominal abscess 6.0
(Gillies, Liu, & Bhujwalla, 1994) Mouse, implanted tumor 6.66
(Alfaro et al., 1996) Rat, carrageenan inflammation, aspirated 6.94
(Issberner, Reeh, & Steen, 1996) Human, exercised muscle, intracutaneous pH 6.67
(Stubbs, McSheehy, & Gri iths, 1999) Rat, mouse, implanted tumors 6.3
(Ojugo et al., 1999) Mouse, implanted tumors 6.0

(Andersson, Lexmuller, Johansson, & Rat, bovine serum albumin (BSA)-induced arthritis 5.66
Ekstrom, 1999)
(Woo, Park, Subieta, & Brennan, 2004) Rat, plantar/ gastrocnemius incision 6.54+0.12
(Gallagher et al., 2008) Mouse, implanted subcutaneous lymphoma 6.0
(Spahn et al., 2017) Rat, Freundʼs adjuvant paw inflammation; 6.8

paw incision 7.02
(Gonzalez-Rodriguez et al., 2017) Rat, Freundʼs adjuvant paw inflammation 6.82
Adapted from Stein, 2018.
Abbreviations: s.c., subcutaneous; i.p., intraperitoneal; BSA, bovine serum albumin; NMR, nuclear magnetic resonance; MRS,
magnetic resonance spectroscopy, MRI, magnetic resonance imaging; 3-APP, 3-aminopropylphosphonate.
Inhibitory Mechanisms
Concurrent with such excitatory events, powerful endogenous mechanisms counteracting pain unfold. This
was initially proposed in the “gate control theory of pain” of 1965 and has since been corroborated and
expanded by experimental data in the central nervous system (CNS) and in the periphery. In 1990, a
“peripheral gate” was discovered at the source of pain generation by demonstrating that immune cell–
derived opioid peptides can block the excitation of nociceptors carrying opioid receptors within injured
tissue (Figure 25.1) (Stein et al., 1990). This represented the rst example of many subsequently described
neuro-immune interactions relevant to pain (Machelska, 2011; Stein, 1995; Stein & Machelska, 2011). In the
spinal cord, pain inhibition is mediated by the release of opioid peptides, gamma-amino-butyric acid
p. 732 (GABA), or glycine. During ongoing nociceptive stimulation, spinal interneurons upregulate gene
expression and production of opioid peptides (Herz, Millan, & Stein, 1989). Powerful descending inhibitory
pathways from the brainstem also become active by operating through noradrenergic, serotonergic, and
opioid systems (Basbaum et al., 2009; Schumacher, Basbaum, & Naidu, 2015). The supraspinal integration
of signals from excitatory and inhibitory neurotransmitters, and cognitive, emotional, and environmental
factors eventually results in the central perception of pain.
Figure 25.1.

Antinociceptive mechanisms within peripheral injured tissue. Opioid peptide-containing circulating leukocytes extravasate upon
activation of adhesion molecules and chemotaxis by chemokines. Subsequently, these leukocytes are stimulated by stress or
releasing agents to secrete opioid peptides. For example, corticotropin-releasing factor (CRF), interleukin-1β (IL-1) and
noradrenaline (NA; released from postganglionic sympathetic neurons) can elicit opioid release by activating their respective
CRF receptors (CRFR), IL-1 receptors (IL-1R), and adrenergic receptors (AR) on leukocytes. Exogenous opioids (EO) or endogenous
opioid peptides (OP; green triangles) bind to opioid receptors (OR) that are synthesized in dorsal root ganglia and transported
along intra-axonal microtubules to peripheral (and central) terminals of sensory neurons. The subsequent inhibition of ion
++
channels (e.g., TRPV1, Ca ) and of substance P (sP) release results in anti-nociceptive e ects.
Adapted with permission from C. Stein, Opioid Receptors, Annual Review of Medicine, 67, 433–451, © 2016, Annual Reviews.
Translation of Basic Research into Clinical Applications

Basic research on pain continues at a rapid pace, but translation into clinical applications has been di cult
p. 733 (Richards & McMahon, 2013; Yekkirala, Roberson, Bean, & Woolf, 2017). Many obstacles have been
discussed, including over-interpretation of data, reporting-bias towards neglecting negative results,
inadequate animal models, awed study design, and genetic and species di erences (Berge, 2011; Mogil,
Davis, & Derbyshire, 2010; Richards & McMahon, 2013; Yekkirala et al., 2017). Notwithstanding these issues,
animal studies are indispensable, continue to be improved, and have successfully predicted adverse side
e ects of drug candidates (Berge, 2011; Mogil et al., 2010). To better represent the complex dimensions of
human pain, natural models and the social transfer of pain have been investigated recently (Klinck et al.,
2017; Smith, Hostetler, Heinricher, & Ryabinin, 2016). For ethical reasons, many models are restricted to
days or weeks, while human chronic pain can last for months or years. Therefore, animal models may be
more cautiously termed as re ecting “persistent” pain (Berge, 2011; Yekkirala et al., 2017).
Brain imaging is another area of intense research. Numerous studies have investigated changes in patients
with various pain syndromes, but they have not provided reproducible ndings speci c for a disease or a
pathophysiological basis for individual syndromes (Mogil et al., 2010). Some studies suggested that the
imaged activity may re ect salience rather than intensity of pain (Legrain, Iannetti, Plaghki, & Mouraux,
2011). Imaging of opioid mechanisms in the human brain has been limited mostly to single-dose studies in
healthy volunteers and has not substantially advanced our understanding of pain relief or opioid use in
patients (Lee, Wanigasekera, & Tracey, 2012). Neuroimaging can only detect alterations associated with
nociceptive processes, whereas clinical pain encompasses a much more complex subjective experience that
critically relies on self-evaluation. Thus, although recent data have provided valuable information on pain
neurophysiology, current imaging techniques cannot yet provide an objective proxy, biomarker, or
predictor for clinical pain (Davis et al., 2017; Smith et al., 2017).
Genetics is another budding scienti c eld. However, with the possible exception of the metabolic enzyme
CYP2D6, pharmacogenetics is not expected to serve as a guide to individualized (“personalized”) clinical
pain therapy any time soon (Chidambaran, Sadhasivam, & Mahmoud, 2017; Drewes et al., 2013; Kringel et
al., 2017; Matic, de Wildt, Tibboel, & van Schaik, 2017; Mogil et al., 2010; Mura et al., 2013; Roberts et al.,
2012; Walter, Doehring, Oertel, & Lötsch, 2013).
Clinical Concepts: Definitions and Prevalence

The International Association for the Study of Pain (IASP) de nes pain as “an unpleasant sensory and
emotional experience associated with actual or potential tissue damage, or described in terms of such
damage” (Loeser & Treede, 2008). Nociception is neurophysiological activity in peripheral sensory neurons
(nociceptors) and higher nociceptive pathways and is de ned by the IASP as the “neural process of encoding
noxious stimuli.” Nociception is not synonymous with pain. Pain is always a psychological state, even
p. 734 though it often has a proximate physical cause. When the intricate balance between biological
(neuronal), psychological (e.g., learning, memory, distraction), and social (e.g., attention, reward) factors
becomes disturbed, chronic pain can develop (Flor & Diers, 2007; Fordyce, 1992; Fordyce et al., 1968; Stein,
2013a). Chronic pain has enormous socioeconomic costs due to health care, disability compensation, lost
workdays, and related expenses (Dzau & Pizzo, 2014; Leadley, Armstrong, Lee, Allen, & Kleijnen, 2012).
There is a tradition of distinguishing between non-malignant (e.g., neuropathic, musculoskeletal,

in ammatory) and malignant (related to cancer and its treatment) chronic pain. Non-malignant chronic
pain is frequently classi ed into in ammatory (e.g., arthritic), musculoskeletal (e.g., low back pain),
headaches, and neuropathic pain (e.g., post-herpetic neuralgia, phantom pain, complex regional pain
syndrome, diabetic neuropathy, HIV neuropathy) (Baron, 2006). Cancer pain can originate from the
invasion of the tumor into tissues innervated by primary a erent neurons (e.g., pleura, peritoneum) or
directly into peripheral nerve plexus. In the latter case, neuropathic symptoms may be predominant.
Bio-psycho-social Concept
Both cancer and non-cancer patients with chronic pain have in common the complex in uences of
biological (tissue damage), cognitive (memory, expectations), emotional (anxiety, depression), and
environmental factors (reinforcement, conditioning). Pain behaviors such as limping, medication intake, or
avoidance of activity are all subject to operant conditioning; that is, they respond to reward and
punishment. For example, pain behaviors may be positively reinforced by attention from a spouse or
healthcare provider (e.g., by inadequate use of medications). Conversely, such behaviors can be
extinguished when they are disregarded or when incremental activity is reinforced by social attention and
praise (Fordyce et al., 1968). The interplay between biological, psychological, and social factors results in
the persistence of pain and illness behaviors (Flor & Diers, 2007; Fordyce et al., 1968). Besides possible
long-term neuronal sensitization, this concept helps us understand why chronic pain may exist without
obvious physical cause.
Pain Management
The treatment of both acute (e.g., postoperative) and chronic pain remains a major challenge in clinical
medicine and public health (Chou et al., 2016; Dzau & Pizzo, 2014; Richards & McMahon, 2013). One
component of pain therapy is the use of analgesic drugs. They interfere with the generation and/or
transmission of impulses in the peripheral and/or CNS (nociception) (Yekkirala et al., 2017). Drugs currently
used in clinical pain treatment include opioids, nonsteroidal anti-in ammatory drugs (NSAIDs),
serotonergic compounds, antiepileptics, and antidepressants (Stein & Kopf, 2015). Placebo treatments have
also shown impressive analgesic e ects, mediated by opioid and non-opioid mechanisms (Carlino, Pollo, &
Benedetti, 2011). In chronic pain, treating only nociception is obviously insu cient. A bio-psycho-social

p. 735 approach addresses physical, psychological, and social skills and underscores the patients’ active
responsibility to regain control over their life by improving their function and well-being (Engel, von Kor ,
& Katon, 1996; Flor & Diers, 2007; Gatchel & Okifuji, 2006; Stein & Kopf, 2015).
Opioids
The opioid receptor family contains three pharmacologically distinct receptors, named mu-, delta-, and
kappa-receptors (MOR, DOR, KOR), which are encoded by the genes OPRM1, OPRD1 and OPRK1. Opioid
receptors (OR) are seven transmembrane G protein–coupled receptors (GPCR) that are the physiological
targets of endogenous opioid peptides (Figure 25.2). ORs are expressed on neurons and many other cell
types, including neuroendocrine, immune, heart, and skin cells (Stein & Machelska, 2011). Cloning and
sequence analysis of OR genes have demonstrated high homology (Law, Reggio, & Loh, 2013; Wei & Loh,
2011). Other receptors (sigma, orphaninFQ/nociception, epsilon) are no longer considered classical ORs.
Figure 25.2.
The opioid system is composed of the three opioid receptors mu (MOR), delta (DOR), and kappa (KOR), and of the endogenous
opioid peptides endorphins, enkephalins, and dynorphins. Opioid peptides activate opioid receptors with low receptor type
selectivity, endomorphins and endogenous morphine show selectivity for MOR. Exogenous opioids (morphine, fentanyl,
oxycodone) act selectively on MOR to elicit analgesia and other e ects.
p. 736 Opioid Receptor Gene Variants
The mu-opioid receptor gene OPRM1 was among the rst genes to be screened for functional relevance with
regard to analgesia. The human single-nucleotide polymorphism (SNP) OPRM1 118 A>G is the most
thoroughly investigated candidate to date. In vitro biochemical and molecular assays indicated altered
binding a nity, signal transduction, and expression. Therefore, it was assumed that this might underlie
occasionally diminished opioid e cacy in patients. However, as emerged from meta-analyses, these
ndings translate only into very small clinical e ects, such as slightly higher opioid-dosing requirements
for acute pain, but they do not a ect chronic pain or opioid side e ects. Thus, this SNP appears to be
without major clinical relevance as a solitary variant, and it is not a useful biomarker on which therapeutic

decisions can be based (Mura et al., 2013; Walter et al., 2013). This is probably due to the complexity of pain,
which is known to be regulated by more than 400 genes with functionally opposite variants that are
concomitantly present (Walter et al., 2013). Nonetheless, e orts continue to nd other genetic variants as
potential biomarkers by use of bioinformatics and next-generation sequencing techniques (Bruehl et al.,
2013; Busch-Dienstfertig, Roth, & Stein, 2013; Hauser et al., 2018; Kringel et al., 2017)
Endogenous Ligands
Endogenous opioid peptides are derived from the precursors proopiomelanocortin (encoding beta-
endorphin), proenkephalin (encoding Met-enkephalin and Leu-enkephalin), and prodynorphin (encoding
dynorphins). These peptides contain the common Tyr-Gly-Gly-Phe-Met/Leu sequence at their amino
terminals, known as the “opioid motif.” Beta-endorphin and the enkephalins are anti-nociceptive agents
acting at MOR and DOR. Dynorphins can elicit both pro- and anti-nociceptive e ects via N-methyl-D-
aspartate (NMDA) receptors, bradykinin receptors, and KOR, respectively. A fourth group of tetrapeptides
(endomorphins) with yet-unknown precursors do not contain the pan-opioid motif, but bind to MOR with
high selectivity. Opioid peptides and receptors are expressed throughout the central and peripheral nervous
systems, in neuroendocrine tissues, and in immune cells (Roques, Fournie-Zaluski, & Wurm, 2012;
Schumacher et al., 2015; Stein & Machelska, 2011).
Opioid Receptor Signaling

ORs (and other GPCRs) have orthosteric and allosteric binding sites. The former are de ned as the sites for
endogenous opioid peptides and standard exogenous ligands, and the latter are separate sites for
endogenous or exogenous modulators (Livingston & Traynor, 2017; Wacker, Stevens, & Roth, 2017).
p. 737 Orthosteric ligand binding triggers intracellular coupling of the receptor to Gi/o and to other proteins
(e.g., arrestins). Receptor-induced Giα protein activation by guanosine triphosphate (GTP) evokes the
dissociation of the heterotrimeric G protein–complex into α, β, and γ subunits. Giα induces inhibition of
adenylyl cyclase and cyclic AMP (cAMP) production, while β and γ subunits interact with ion channels at the
+
plasma membrane (Williams et al., 2013). This leads to opening of G protein–coupled inwardly rectifying K
+
(GIRK) channels, as well as to the inhibition of Na channels, acid-sensing ion channels (ASICs), glutamate
++
receptor currents, and Ca in ux. Together, these events attenuate neuron excitability and the release of
pro-nociceptive neuropeptides, and thereby decrease the transmission of nociceptive stimuli and
(ultimately) pain perception (Stein, 2016). Other opioid-regulated pathways include phospholipase C and
mitogen-activated protein kinase (Pradhan, Smith, Kie er, & Evans, 2012; Stein, 2016; Williams et al.,
2013).
Upon activation, ORs can be phosphorylated by di erent kinases, thereby promoting β–arrestin
recruitment, receptor desensitization, and internalization, followed either by dephosphorylation and
recycling to the cell surface, or by degradation in lysosomes. Di erent ligands at the same receptor may
trigger distinct receptor conformations that can result in signaling through distinct intracellular pathways.
This has been termed “biased signaling” or “functional selectivity.” Experimental studies have suggested
that such preferential activation of G-proteins vs. β-arrestin may entail reduced adverse e ects, and that
this bias is ligand-speci c. For example, tolerance to morphine’s anti-nociceptive e ects and physical
dependence were decreased in beta-arrestin-2 knock-out (KO) mice, while responses to methadone,
fentanyl, or oxycodone were unchanged (Raehal, Schmid, Groer, & Bohn, 2011). The resolution of MOR,
DOR, and KOR crystal structures (Granier et al., 2012; Manglik et al., 2012; Wu et al., 2012) led to further
elucidation of ligand-induced conformational changes (Sounier et al., 2015) and to structure-based
screening of possible anti-nociceptive ligands (Manglik et al., 2016).

A novel example of “biased signaling” was demonstrated recently. In the acidotic environment of peripheral
injured tissue (Table 25.1), opioid receptor–ligand interactions apparently exhibit di erent dynamics
compared to non-injured tissues (Del Vecchio, Spahn, & Stein, 2017; Spahn et al., 2017). Computer
simulations indicated that opioid ligands assume a more stable binding position at low pH than at
physiological pH, suggesting that agonists have an enhanced potential to activate the receptor under acidic
(in amed) conditions. Based on these in silico studies, a prototype ligand (NFEPP) was designed that
exhibited preferential cAMP inhibition, G-protein dissociation, and anti-nociceptive e cacy in injured
tissue (at low pH), while typical adverse e ects (respiratory depression, reward, sedation, motor
disturbance, constipation) elicited in non-injured environments (at normal pH in brain or intestinal wall)
were absent, consistent with the notion that “normal” ORs were not activated (Figure 25.3) (Spahn et al.,
2017). These ndings were attributed both to acidosis-induced conformational alterations of peripheral
p. 738 ORs, and to the low acid dissociation constant (pKa) of NFEPP (Spahn et al., 2017).
Figure 25.3.

A novel concept to selectively activate opioid receptors in injured peripheral tissue without side e ects. NFEPP (purple circles)
was designed to act only at low pH in an inflamed environment (red) surrounding the peripheral nerve endings (light gray), by
decreased pKa and increased protonation (light blue triangles), a prerequisite for binding and activation of opioid receptors. The
protonated ligand binds and activates opioid receptors (dark gray); the unprotonated ligand (in healthy brain and
gastrointestinal wall) does not. NFEPP: (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenylpropionamide (gray circle insert).
Reprinted with permission from G. Del Vecchio, V. Spahn, & C. Stein, Novel opioid analgesics and side e ects, ACS Chemical
Neuroscience, 8:1638–1640, © 2017, American Chemical Society.
p. 739 Tolerance and Opioid-Induced Hyperalgesia (OIH)

“Tolerance” describes the phenomenon that the magnitude of a given e ect decreases with repeated
administration of the same agonist dose, or that increasing doses are needed to produce the same e ect.
MOR agonists induce potent analgesia, but also side e ects, including nausea, constipation, respiratory
depression, and somnolence. All these e ects can be subject to tolerance development, albeit to di erent
degrees (Collett, 1998; McNicol, 2008; Rozen & Grass, 2005; Williams et al., 2013). Experimental evidence
suggests that some agonists may induce hyperalgesia (e.g., OIH) in animal models. Studies in mice with
MOR gene inactivation have shown that these diverse e ects are mediated by activating MOR (Gaveriaux-
Ru , 2013). Some studies suggest that OIH may contribute to analgesic tolerance, although tolerance and
OIH can be dissociated (Ferrini et al., 2013; Koblish et al., 2017).
Analgesic Tolerance
Pharmacodynamic tolerance to anti-nociceptive e ects is readily inducible in animal models but has not
been unequivocally demonstrated in controlled clinical studies. Following the activation of ORs, uncoupling
of G proteins, phosphorylation, beta-arrestin recruitment, and receptor endocytosis led to receptor
desensitization in vitro (Cahill, Walwyn, Taylor, Pradhan, & Evans, 2016; Williams et al., 2013). Several
approaches have been used to reduce tolerance development (Bruchas & Roth, 2016; Law et al., 2013; Olson,
Lei, Keresztes, LaVigne, & Streicher, 2017; Yaksh, Woller, Ramachandran, & Sorkin, 2015). These include
bivalent or multivalent ligands, biased agonists, and the design of novel peripherally acting opioid agonists
(see in Opioid Agonists and Analgesia).

Tolerance development may be diminished in chronic pain (Pradhan et al., 2012). In a model of persistent
paw in ammation in rats, tolerance to morphine anti-nociception was evoked by the deletion of opioid
peptides in immune cells, indicating that endogenous OR activation promotes receptor endocytosis and
thereby counteracts tolerance (Zollner et al., 2008). Clinical studies were consistent with this notion (Stein
et al., 1996). The particular role of peripheral ORs in morphine tolerance was investigated by genetic
approaches in mice. The conditional KO (cKO) of MOR in nociceptive neurons expressing the sodium
channel Nav1.8 did not modify tolerance to morphine anti-nociception (Weibel et al., 2013). In comparison,
MOR deletion in neurons expressing the transient receptor potential vanilloid 1 receptor (TRPV1) abolished
anti-nociceptive tolerance (Corder et al., 2017). In rodent models of in ammatory and neuropathic pain,
morphine tolerance was prevented by administration of the peripherally restricted MOR antagonist
methylnaltrexone (Corder et al., 2017). To arrive at de nitive conclusions, further experiments in cKO mice
with persistent pain are required, and TRPV1 expression in brain needs to be considered (Madasu, Roche, &
Finn, 2015; Martins, Tavares, & Morgado, 2014).
p. 740 Opioid-Induced Hyperalgesia

Many animal studies have produced evidence for OIH. The putative underlying mechanisms are summarized
in recent reviews (Rivat & Ballantyne, 2016; Roeckel, Le Coz, Gaveriaux-Ru , & Simonin, 2016). Commonly
involved pathways comprise peripheral and central sensitization, descending facilitation, and
neuroimmune activation. There are more reports on mechanisms at the spinal level, but peripheral sites and
brain structures have also been investigated. At the cellular level, neurons, microglia, and astrocytes
participate (Ferrini et al., 2013). Mesenchymal stem cells transplanted into rats or mice were shown to
reverse tolerance and OIH (Hua et al., 2016). Toll-like receptors (Hutchinson et al., 2011) and MOR have been
shown to be involved in OIH (Corder et al., 2017; Roeckel et al., 2017). Other molecules comprise the TRP
family, the NMDA-glutamate system, substance P, ATP, K+/Cl– transporters, lipids, chemokines,
cytokines, serotonin, brain-derived neurotrophic factor (BDNF), and anti-opioid peptides (Elhabazi et al.,
2017; Rivat & Ballantyne, 2016; Roeckel et al., 2016).
Allosteric Modulators
Several allosteric modulators of ORs were investigated and shown to in uence the a nity and/or e cacy of
orthosteric ligands in vitro. However, in vivo con rmation is lacking so far (Livingston & Traynor, 2017). It
is an interesting concept that positive allosteric modulators may enhance the activity of endogenous opioid
peptides that are elevated during stress and pain. This activity would be con ned to ORs that are exposed to
released endogenous opioids and thereby avoid side e ects (similar to the concept of enkephalinase
inhibitors) (Livingston & Traynor, 2017; Roques et al., 2012).
Opioid Agonists and Analgesia
Many OR agonists have been developed since the identi cation of morphine as the active ingredient of
opium and the discovery of ORs (Brownstein, 1993). The opioids in clinical use are mostly MOR agonists and
have been reviewed in Drewes et al. (2013). They are e ective analgesics, although the variability of
responses among patients often requires a personalized approach (Drewes et al., 2013). ORs are expressed at
all levels of the neuraxis. Therefore, opioid agonists can inhibit pain following peripheral, spinal, cerebral,
and systemic administration.
Common examples of MOR, DOR, and KOR agonists and antagonists are shown in Table 25.2. More

extensive reviews on MOR (Drewes et al., 2013; Madariaga-Mazon et al., 2017), DOR (Peppin & Ra a, 2015;
Pradhan, Befort, Nozaki, Gaveriaux-Ru , & Kie er, 2011; Spahn & Stein, 2017), and KOR (Ranjan, Pandey, &
Shukla, 2017; Zheng et al., 2017) are available. New developments include the discovery and characterization
of bi-/multi-functional agonists, biased ligands, peripherally restricted agonists, and inhibitors of
endogenous opioid peptide degradation.
Table 25.2 Opioid Receptors and Ligands
Receptor Agonists Antagonists
MOR morphine, fentanyl, remifentanil, methadone, oxycodone, DAMGO, CTOP, CTAP, alvimopan
endomorphins, enkephalins, β-endorphin, TRV130, PZM21 naloxone (-methiodide)
DOR SNC80, enkephalins, β-endorphin, deltorphin, JNJ-20788560, ARM390, UPF-512, naltrindole naloxone (-
ADL5747, ADL5859, KNT-127 methiodide)
KOR U-50488, U69593, dynorphin nalfurafine, asimadoline norbinaltorphimine

naloxone (-methiodide)
p. 741 Bifunctional and Multifunctional Ligands

Bi-/multi-functional agonists were designed with the goal of reducing side e ects (Gunther et al., 2017;
Yekkirala et al., 2017). This strategy is based on evidence that OR form heteromers (Gomes et al., 2016;
Massotte, 2015) or interact with other GPCRs (Hubner et al., 2016; Olson et al., 2017; Yaksh et al., 2015). A
large number of such ligands have been investigated (Gunther et al., 2017; Olson et al., 2017; Yekkirala et al.,
2017) (Figure 25.4), and some were also evaluated for tolerance development in preclinical models. Less
tolerance was described for the MOR-agonist/DOR-agonist LP1; MOR-agonist/DOR-antagonists MDAN-21,
VRP26, SoRI22138, UMB425, and mitragynine/corynantheidine; MOR-agonist/CCK-antagonists RSA 504
and RSA 601; MOR-agonist/CCR5-antagonist MCC22; OR-agonist/NK1-antagonists TY027, RCCHM3, and
RCCHM6; MOR-agonist/mGluR5-antagonist MMG22; and the MOR-agonist/noradrenaline reuptake
blockers tapentadol and dezocine (Baron et al., 2017; Wang, Mao, Li, Gong, & Zhang, 2017).
Figure 25.4.

Bi- and multi-valent opioid agonists. * CB2, cannabinoid receptor-2; CCK, cholecystokinin; DOR, delta opioid receptor; GPCR, G
protein-coupled receptor; KOR, kappa opioid receptor; mGlur5, metabotropic glutamate receptor-5; MOR, mu opioid receptor;
NK1, Neurokinin 1 receptor; NRI, noradrenalin reuptake inhibitor; OFQ, OrphaninFQ/nociceptin receptor.
MOR Agonists – GPCR Agonists: Compounds that activate two or more ORs include 3-[(2R,6R,11R)-8-
hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl]-N-
phenylpropanamide, LP1 (Turnaturi, Arico, Ronsisvalle, Parenti, & Pasquinucci, 2016), morphine-6-O-
sulfate (Yadlapalli et al., 2016), biphalins (Mollica et al., 2014), N-Naphthoyl-betanaltrexamine (NNTA) and
N-2´-Indolylnaltrexamine 3 (INTA (Le Naour et al., 2014), DPI-125 (Yi et al., 2017), cyclotetrapeptide (De
Marco et al., 2016), dihydroetorphine (Gunther et al., 2017), BU08028, and SR16435 (Ding et al., 2016;
Gunther et al., 2017). The combination of MOR and cannabinoid agonists resulted in synergistic anti-
nociception (Grenald et al., 2017). In models of neuropathic and diabetic pain, the OR/OFQ agonist
cebranopadol prevented hyperalgesia (Tzschentke, Linz, Frosch, & Christoph, 2017), and a rst clinical
study showed its analgesic activity in patients (Christoph, Eerdekens, Kok, Volkers, & Freynhagen, 2017).
MOR Agonists -GPCR Antagonists: Based on previous literature showing reduced tolerance to morphine
anti-nociception by blocking DOR, several bivalent MOR-agonist/DOR-antagonists were investigated
(Fujita, Gomes, & Devi, 2015; Gendron, Cahill, von Zastrow, Schiller, & Pineyro, 2016; Hubner et al., 2016;
p. 742 Olson et al., 2017; Yaksh et al., 2015; Yekkirala et al., 2017). They comprise the DIPP- and PICPsi families,
MDAN-21, SoRI22138, UMB425 and UMB246 (Healy et al., 2017), VRP26 (Anand, Boyer, Mosberg, &
Jutkiewicz, 2016) and mitragynine/corynantheidine (Varadi et al., 2016) and others (Figure 25.4). These also
include molecules that activate MOR and are antagonists at sigma-1 (Prezzavento et al., 2017),
Nociceptin/OrphaninFQ (NOP/OFQ) (Lagard et al., 2017), cannabinoid, CCR5 and CXCR4 (Melik
Parsadaniantz, Rivat, Rostene, & Reaux-Le Goazigo, 2015), neurokinin-1 (Starnowska et al., 2017),
glutamate mGluR5, and cholecystokinin receptors (Figure 25.4).
MOR Agonists – Noradrenalin Reuptake Inhibitors: Tramadol produces analgesia by activating MOR and
blocking noradrenaline/serotonin reuptake, but it requires metabolism by CYP2D6 and has been shown to
cause confusion in the clinical setting. Tapentadol analgesia requires MOR activation and norepinephrine
reuptake inhibition, but no metabolic activation (Langford, Knaggs, Farquhar-Smith, & Dickenson, 2016).
Dezocine (a popular drug in China) produces anti-nociception in rats by activating MOR and blocking
norepinephrine reuptake (Wang et al., 2017).
Biased Agonists
The knowledge gain on biased signaling and OR structures has led to extensive screening e orts for
discovery of new ligands and has broadened the general view on GPCR function (Bruchas & Roth, 2016;
p. 743 Wacker et al., 2017). New MOR, DOR, or KOR ligands were shown to preferentially activate G-proteins
over beta-arrestins in vitro and to evoke anti-nociception in preclinical models in vivo (Koblish et al., 2017;
Madariaga-Mazon et al., 2017; Violin, Crombie, Soergel, & Lark, 2014). The Gi-biased MOR agonists TRV130
and PZM21 exerted low beta-arrestin recruitment, anti-nociception, and reduced adverse e ects in rodent
models (Altari et al., 2017; DeWire et al., 2013; Kie er, 2016; A. Manglik et al., 2016). Repeated TRV130
application did not induce anti-nociceptive tolerance in animals (Altari et al., 2017; DeWire et al., 2013; A.

Manglik et al., 2016). In healthy human volunteers, TRV130 produced inhibition of experimental pain, less
respiratory depression and vomiting, but more nausea, dizziness, somnolence, and headache than
morphine (Soergel et al., 2014). In further animal (Altari et al., 2017) and human clinical studies (Viscusi et
al., 2016), TRV130 produced adverse e ects similar to those of conventional opioids; that is, nausea,
dizziness, vomiting, and constipation. In mice, another biased MOR agonist (TRV0109101) induced anti-
nociception, tolerance, and constipation, but no OIH, and it reversed morphine- and fentanyl-induced OIH
but not fentanyl-induced tolerance (Koblish et al., 2017).
Biased agonism was also shown for KOR, both in vitro and in preclinical models. The KOR agonists U50488
and salvinorin di ered in downstream kinase activation. U50488 was shown to regulate extracellular-
regulated kinase, while salvinorin elicited c-Jun kinase and induced homologous desensitization (Jamshidi
et al., 2015). A few new G-protein-biased KOR ligands produced anti-nociception and fewer unwanted KOR
e ects (Ranjan et al., 2017). Ibogaine potentiated morphine anti-nociception, prevented morphine
tolerance and exhibited anti-addictive e ects (Maillet et al., 2015). RB-64 induced anti-nociception and
aversion but no sedation (White et al., 2015). Triazole 1.1 and HS666 elicited anti-nociception with reduced
sedation, without dysphoria or decrease of dopamine tone in the nucleus accumbens (Brust et al., 2016;
Spetea et al., 2017). These preclinical studies suggest the potential of G-protein-biased KOR agonists.
There is also ample evidence for biased agonism at DOR (Cahill et al., 2016; Gendron et al., 2016; Vicente-
Sanchez & Pradhan, 2018). This has been reviewed with scrutiny and emphasis on ligand-speci c signaling
and receptor regulation (Gendron et al., 2016). In the context of anti-nociception, DOR internalization,
desensitization, resensitization, as well as coupling to beta-arrestins and kinases were studied (Cahill et al.,
2016). Despite disparities in receptor signaling and e ects on intracellular tra cking, practically all DOR
agonists exhibited anti-nociceptive tolerance (Gendron et al., 2016; Nozaki et al., 2014), with the exception
of JNJ-20788560. Contrasting data have been reported for ARM390 (Codd et al., 2009; Pradhan et al., 2016).
Peripheral Opioid Receptors and Agonists
Over 25 years ago, evidence began to emerge that signi cant anti-nociceptive e ects are mediated by ORs
localized on peripheral sensory neurons, and that opioid agonists elicit stronger analgesic e ects in
in amed than nonin amed tissue of animals and humans (Stein, 1993, 1995; Stein et al., 1991; Stein et al.,
1990). These observations stimulated extensive research into the underlying mechanisms. It was found that
p. 744 peripheral tissue in ammation induced upregulation of ORs and their mRNAs in DRG neurons, which
was dependent on neuronal electrical activity and on local cytokine production (Figure 25.1) (Stein, 2016;
Stein & Machelska, 2011). Studies in those models also showed that the peripherally directed axonal
transport of ORs in DRG neurons was increased (Hassan, Ableitner, Stein, & Herz, 1993) and that the

perineural barrier was disrupted, thus facilitating access of opioid agonists to their receptors (Antonijevic,
Mousa, Schäfer, & Stein, 1995). These events were ascribed to the in uence of various in ammatory
mediators such as bradykinin, nerve growth factor, and prostaglandins (Stein, 2016; Stein & Machelska,
2011). Furthermore, it was shown that G-protein coupling of ORs was augmented (Zöllner et al., 2003), and
that low pH (as in in ammation, see Table 25.1) increased opioid agonist e cacy in vitro (Rasenick &
Childers, 1989; Selley, Breivogel, & Childers, 1993). Recordings from sensory nerve bers supplying injured
tissue revealed opioid inhibition of spontaneous and stimulus-evoked action potentials (reviewed in Stein,
2016). Neuropathy is another condition in uencing opioid receptor expression in peripheral sensory
neurons (Machelska, 2011; Stein & Machelska, 2011). For example, upregulation of ORs and accumulation of
opioid peptide-producing immune cells was detected at the site of nerve injury, accompanied by enhanced
anti-nociceptive activity of opioid agonists (Celik et al., 2016; Stein, 2016). Thus, the expression, axonal
transport, signaling, and accessibility of ORs on DRG neurons are augmented, suggesting that tissue or
nerve injury are prerequisites to “unmasking” peripheral opioid e ects (Stein, 1993, 2016). Opioid peptides
and receptors are also expressed by immune cells (Sharp, 2006; Stein & Machelska, 2011), and there is
evidence that they contribute to analgesia (Celik et al., 2016).
Peripherally acting agonists were developed with the idea that OR activation at the site of pain generation
will trigger analgesia without the adverse e ects mediated by ORs in the CNS (Stein, 2013a). This concept
has been investigated extensively by pharmacological approaches and by using cKO mice (reviewed in Stein,
1993, 2016; Stein & Machelska, 2011). For example, the absence of mu ORs in peripheral nociceptive neurons
did not change morphine anti-nociception in models of acute pain (Corder et al., 2017; Weibel et al., 2013),
but decreased morphine and fentanyl antihyperalgesia in a model of persistent paw in ammation,
indicating that peripheral MOR signi cantly contribute to analgesia produced by systemically administered
opioids (Weibel et al., 2013). The absence of DOR in Nav1.8 neurons aggravated both in ammatory and
neuropathic hypersensitivity, and greatly lowered DOR agonist-induced anti-nociception in models of
chronic pain (Gaveriaux-Ru & Kie er, 2011; Nozaki et al., 2012).
Recently, a novel agonist (NFEPP) was designed based on computational simulations of ligand-receptor
interactions in an in amed (acidic) environment. This agonist selectively activated MOR at acidic pH and
induced peripherally mediated, injury-speci c anti-nociception without a ecting locomotor activity,
reward, bowel movements, or respiration (Spahn et al., 2017). Another novel peripherally acting analgesic is
morphine covalently attached to hyperbranched polyglycerol (PG-M). This conjugate was shown to release
morphine selectively in injured tissue. PG-M produced peripherally mediated analgesia in a model of
p. 745 in ammatory pain without eliciting sedation or constipation (Gonzalez-Rodriguez et al., 2017). Both
NFEPP and PG-M produced equie ective anti-nociception to conventional opioid agonists.
Endogenous Analgesia: Central Mechanisms
Spinal cord interneurons produce opioids that, together with noradrenergic and serotonergic pathways,
contribute to the descending pain inhibition from the brainstem. An endogenous opioid analgesic tone was
revealed in mutant mice lacking individual components of the opioid system. DOR-KO mice show
aggravated neuropathic, in ammatory, and visceral hypersensitivity (Gaveriaux-Ru , Karchewski, Hever,
Matifas, & Kie er, 2008; Nadal, Banos, Kie er, & Maldonado, 2006; Reiss et al., 2017). In ammatory
hypersensitivity was comparable or longer lasting in MOR-KO (Gaveriaux-Ru et al., 2008; Mansikka,
Zhou, Donovan, Pertovaara, & Raja, 2002; Walwyn et al., 2016). An endogenous tone at MOR was shown in
neuropathic mechanical allodynia, but not in thermal hyperalgesia (Mansikka et al., 2004). In addition,

MOR-KO animals showed augmented gray matter volume of periaqueductal and altered connections of
pain-aversion nodes (Mechling et al., 2016; Sasaki et al., 2015). Mice lacking KOR showed augmented
sensitivity to visceral chemical stimulation (Simonin et al., 1998), neuropathic pain (Xu et al., 2004),
unchanged response to colorectal distension (Larsson, Bayati, Lindstrom, & Larsson, 2008), and augmented
in ammatory hypersensitivity (Gaveriaux-Ru et al., 2008; Schepers, Mahoney, Gehrke, & Shippenberg,
2008). An additive contribution to the anti-nociceptive tone at each receptor was found in triple
MOR/DOR/KOR-KO animals (Gaveriaux-Ru , 2013). Beta-endorphin-KO and preproenkephalin-KO mice
showed normal acute nociception and in ammatory pain (Kie er & Gaveriaux-Ru , 2002; Labuz, Celik,
Zimmer, & Machelska, 2016; Walwyn et al., 2016). Prodynorphin KO animals display normal in ammatory
pain (Walwyn et al., 2016), recover more rapidly from neuropathic hypersensivity (Kie er & Gaveriaux-
Ru , 2002; Xu et al., 2004), and are slightly less sensitive after nerve injury (Labuz et al., 2016). Endogenous
opioids also participate in bromyalgia. In a mouse bromyalgia model, electroacupuncture-induced
analgesia was abolished by the antagonist naloxone (Yen, Hsieh, Hsu, & Lin, 2017). It was also found that
MOR availability was reduced in brain regions of bromyalgia patients (Schrepf et al., 2016), and that
endogenous opioids contribute to placebo analgesia (Carlino, Frisaldi, & Benedetti, 2014; Holmes, Tiwari, &
Kennedy, 2016), to the e ects of transcranial magnetic stimulation (Lamusuo et al., 2017), and to congenital
insensitivity to pain caused by a Nav1.7-null mutation (Minett et al., 2015).
Peripheral Mechanisms
Opioid peptide-containing immune cells extravasate and accumulate in peripheral injured tissues
(Baddack-Werncke et al., 2017; Cayla et al., 2012; Celik et al., 2016; Labuz et al., 2009; Mousa, Cheppudira, et
al., 2007; Stein, 2013b; Stein & Machelska, 2011). These cells upregulate the gene expression of opioid
peptide precursors and the enzymatic machinery for their processing into functionally active peptides
p. 746 (Busch-Dienstfertig, Labuz, Wolfram, Vogel, & Stein, 2012; Mousa, Shakibaei, Sitte, Schäfer, & Stein,
2004; Sitte et al., 2007). In response to stress, catecholamines, corticotropin releasing factor, cytokines,
chemokines, opioid ligands or bacteria, leukocytes secrete opioid peptides, which then activate peripheral
ORs and produce analgesia by inhibiting the excitability of nociceptors, the release of excitatory
neuropeptides, or both (Celik et al., 2016; Rittner et al., 2009; Stein & Machelska, 2011).
Further studies showed that endogenous opioid anti-nociception was dampened by naloxone or by T-
lymphocyte depletion in a mouse model of in ammatory pain. Proenkephalin was expressed in T-
lymphocytes and dendritic cells (Boue, Blanpied, Brousset, Vergnolle, & Dietrich, 2011) and, more precisely,
in Th1 and Th2 CD4 cells (Boue et al., 2012). In a similar study in rats, proopiomelanocortin transcripts and
beta-endorphin were expressed by B-lymphocytes in lymph nodes (Maddila, Busch-Dienstfertig, & Stein,
2017). In rodent models of visceral pain, endogenous pain regulation was mediated by CD4 lymphocyte-
derived opioids (Boue et al., 2014; Valdez-Morales et al., 2013) and, more speci cally, by enkephalins (Basso
et al., 2017). There is also evidence for endogenous analgesia mediated by opioid released from CD8
lymphocytes in a mouse model of antigen-collagen-induced arthritis (Baddack-Werncke et al., 2017). Anti-
nociception elicited by corticotropin-releasing-factor administered onto damaged nerves of wild-type mice
was absent in mice lacking proenkephalin, prodynorphin, or beta-endorphin (Labuz et al., 2016). Polarized
M2 macrophages were shown to release high amounts of opioid peptides to induce anti-nociception in this
neuropathy model (Pannell et al., 2016). In response to exogenous opioids, opioid peptides produced by
immune cells at the nerve lesion site produce anti-nociception, as shown by studies in opioid peptide- and
OR-KO mice (Celik et al., 2016).
The clinical relevance of these mechanisms has been con rmed in studies demonstrating that patients with
knee joint in ammation express opioid peptides in immune cells and ORs on sensory nerve terminals within
synovial tissue (Mousa, Straub, Schäfer, & Stein, 2007; Stein, Hassan, Lehrberger, Gie ng, & Yassouridis,
1993). After knee surgery, pain and analgesic consumption were increased by blocking the interaction

between the endogenous opioids and their receptors with intraarticular naloxone or adrenergic antagonists
(Kager et al., 2011; Stein et al., 1993), and were diminished by stimulating opioid peptide secretion (Likar et
al., 2007) or by intraarticular morphine administration (Stein et al., 1991; Zeng et al., 2013).
Augmenting Endogenous Opioid Analgesia

Opioid peptides are susceptible to rapid extracellular degradation by aminopeptidase N and neutral
endopeptidase (“enkephalinases”). Preventing this degradation by inhibitors (in the CNS or in peripheral
tissues) has been shown to produce analgesic e ects in many animal models and in some human trials
(Bonnard et al., 2015; Roques et al., 2012; Schreiter et al., 2012). This strategy avoids unphysiologically high
concentrations of exogenous agonists at (ubiquitously distributed) receptors, and, thus, diminishes the risk
for development of receptor downregulation, tolerance, desensitization, o -site, or paradoxical excitatory
p. 747 e ects (Roques et al., 2012). The combination of the peptidase inhibitors bestatin and thiorphan
(Schreiter et al., 2012) and the dual enkephalinase inhibitor PL265 inhibited hyperalgesia in preclinical
models of in ammatory and neuropathic pain (Bonnard, Poras, Fournie-Zaluski, & Roques, 2016; Bonnard
et al., 2015; Poras, Bonnard, Fournie-Zaluski, & Roques, 2015). Other preclinical approaches used
administration of viruses or cells overexpressing opioid peptides (Goins, Cohen, & Glorioso, 2012; Guedon et
al., 2015). The human natural peptide opiorphin protects enkephalins from degradation. It produced anti-
nociception equipotent to morphine (Wisner et al., 2006), displayed no constipating e ects or abuse
liability (Popik, Kamysz, Kreczko, & Wrobel, 2010; Rougeot, Robert, Menz, Bisson, & Messaoudi, 2010), and
produced antidepressant e ects via DOR activation (Javelot, Messaoudi, Garnier, & Rougeot, 2010; Rougeot
et al., 2010). Opiorphin loading of liposomes improved its activity (Mennini et al., 2015). Recently, STR-324,
a stable analog of opiorphin, was found to produce anti-nociception in a model of incisional
hypersensitivity (Sitbon et al., 2016).
Species Di erences
Species di erences are an important consideration (Chan, McCarthy, Li, Palczewski, & Yuan, 2017; Imam,
Kuo, Ghassabian, & Smith, 2017; Pasternak & Pan, 2013; Stevens, 2015). Numerous studies on intra- and
inter-species di erences have demonstrated that even single amino acid variations in OR proteins can have
measurable e ects on the structure-activity of the receptor (Busch-Dienstfertig et al., 2013; Nockemann et
al., 2013; Pasternak & Pan, 2013; Stevens, 2015; Vardy et al., 2015). Extensive alternative splicing of the MOR
gene has been described in di erent species and strains, possibly enabling divergent anatomical
distributions, expression levels, oligomers, recycling, and intracellular signaling events (Pasternak & Pan,
2013). In addition, disparate (sometimes opposite) CNS or intestinal phenomena were detected in mice

versus rats or humans (e.g., G-protein activation, adenylyl cyclase, locomotion) (Fidecka, Malec, &
Langwinski, 1978; Huang, Chen, & Liu-Chen, 2015; Imam et al., 2017; Kruegel et al., 2016; Labuz, Mousa,
Schäfer, Stein, & Machelska, 2007; Noble & Cox, 1995, 1996; Sirohi, Aldrich, & Walker, 2016). For example,
chronic DOR activation led to OIH in rats but not in mice, whereas MOR-induced OIH occurred in all tested
species (Rowan et al., 2014). A recent study reported that tolerance to opioid-induced analgesia was
dependent on MOR expressed in DRG neurons in mice (Corder et al., 2017), contrary to ndings in rats and
+
humans (Stein et al., 1996; Zollner et al., 2008). Opioid agonists did not a ect K currents (Dembla et al.,
2017; Nockemann et al., 2013) or TRPV1 channels (Dembla et al., 2017; Quallo, Alkhatib, Gentry, Andersson,
& Bevan, 2017; Rowan et al., 2014) in mouse DRG neurons, but they did so in rat (Endres-Becker et al., 2007;
+
Nockemann et al., 2013; Rowan et al., 2014; Spahn et al., 2013). Studies on gene expression of K channels
suggested a greater similarity between humans and rats than between humans and mice (Nockemann et al.,
2013). As in other elds (e.g., immunology, oncology), all these ndings have to be taken into consideration
when preclinical data are interpreted to predict drug e ects in humans.
p. 748
Clinical Problems Associated with Opioid Use
In contrast to the experimental literature, there is a lack of carefully controlled clinical studies that
unequivocally demonstrate the development of pharmacodynamic tolerance in opioid analgesia (Galer, Lee,
Ma, Nagle, & Schlagheck, 2005; Schneider & Kirsh, 2010). Incomplete cross-tolerance between opioids may
explain clinical observations that switching drugs (“opioid rotation”) is occasionally useful in patients with
inadequate pain relief or intolerable side e ects (Ross, Riley, Quigley, & Welsh, 2006). Importantly,
pharmacokinetic (e.g., altered distribution or metabolism of the opioid) and learned tolerance (e.g.,
compensatory skills developed during mild intoxication), as well as increased nociceptive stimulation by
tumor growth, in ammation, or neuroma formation, are possible reasons for increased dose requirements
(Collett, 1998; Collin, Poulain, Gauvain-Piquard, Petit, & Pichard-Leandri, 1993).
There is an ongoing debate whether opioids paradoxically induce hyperalgesia (OIH) in humans. At high
doses, occasionally encountered in extreme cancer pain, allodynia has been observed and attributed to
neuroexcitatory e ects of opioid metabolites (Carullo, Fitz-James, & Delphin, 2015). Similar phenomena
have also been reported in patients with chronic non-malignant pain (e.g., migraine) (Belkin, Reinheimer,
Levy, & Johnson, 2017; Diener, Holle, Solbach, & Gaul, 2016; Gri n et al., 2016; Wasserman et al., 2015),
postoperative pain (Fletcher & Martinez, 2014), in healthy volunteers (Fishbain, Cole, Lewis, Gao, &
Rosomo , 2009; Mauermann et al., 2016; Ruscheweyh, Wilder-Smith, Drdla, Liu, & Sandkuhler, 2011), and
in opioid addicts (Compton, Charuvastra, & Ling, 2001). Upon closer scrutiny, it appears that most studies
have in fact shown withdrawal-induced hyperalgesia, a well-known phenomenon following the abrupt
cessation of opioids (Comelon et al., 2016; Fishbain et al., 2009; Spahn et al., 2013). With the possible
exception of headache (Diener et al., 2016), conclusive evidence is lacking that clinically signi cant OIH
occurs during the perioperative or chronic administration of usual opioid doses in patients (Angst, 2015;
Fishbain et al., 2009; Fletcher & Martinez, 2014; Schneider & Kirsh, 2010).
Dependence is not synonymous with tolerance. Physical dependence is de ned as a state of adaptation that
is manifested by a withdrawal syndrome elicited by abrupt cessation, rapid dose reduction, and/or
administration of an antagonist (Smith et al., 2013). All opioids produce clinically relevant physical
dependence, even when administered for only a relatively short period of time (Compton, Miotto, &
Elasho , 2004).
Addiction is a complex syndrome involving reward/euphoria, the urge to avoid withdrawal, craving,
uncontrolled/compulsive drug use despite harmful side e ects, and other drug-related aberrant behaviors
(e.g., altering prescriptions, manipulating healthcare providers, drug hoarding, or unsanctioned dose
escalation) (Smith et al., 2013). Currently, an estimated 2 million individuals in the United States have

opioid use disorder (addiction) associated with prescription opioids (Psaty & Merrill, 2017; Schuchat, Houry,
& Guy, 2017).
p. 749 Long-Term Opioid Use in Chronic Pain

In contrast to acute and cancer-related pain, the long-term use of opioids in chronic non-cancer (e.g.,
neuropathic, musculoskeletal) pain is not appropriate. So far, randomized controlled trials (RCTs) have only
been conducted for a maximum duration of three months. In meta-analyses, the reduction of pain scores
was clinically insigni cant, and epidemiological data suggest that quality of life or functional capacity are
not improved (Eriksen, Sjogren, Bruera, Ekholm, & Rasmussen, 2006; Reinecke et al., 2015). Adverse side
e ects (nausea, sedation, constipation, dizziness, etc.) and lack of analgesic e cacy led to the dropout of
high numbers of subjects, both in RCTs and in uncontrolled observational studies beyond three months
(Gustavsson et al., 2012; Noble et al., 2010; Reinecke et al., 2015; Szigethy, Knisely, & Drossman, 2017).
Psychosocial outcome parameters were rarely investigated and showed only modest improvement. Thus,
consistent with the multifactorial nature of chronic pain, it is highly unlikely that opioids alone can produce
an analgesic response if, for example, there is a major a ective component or if learned pain behavior is the
main problem (Fordyce, 1991; Stein, 1997). Notwithstanding, opioids are prescribed widely, and addiction,
overdoses, death rates, and misuse have reached epidemic proportions (Psaty & Merrill, 2017; Schuchat et
al., 2017; Szigethy et al., 2017). Thus, the use of opioids as a sole treatment modality in chronic non-
malignant pain is strongly discouraged. Instead, chronic pain requires a multidisciplinary approach
encompassing various pharmacological and non-pharmacological (psychological, physiotherapeutic)
treatment strategies (Schuchat et al., 2017; Stein, 2013a; Szigethy et al., 2017).
Conclusion
Basic research on pain and analgesia continues at a rapid pace, but translation of ndings into clinical
applications has been di cult (Richards & McMahon, 2013; Yekkirala et al., 2017). Not only therapeutic but
also diagnostic approaches (e.g., brain imaging, genetics) are being investigated, but these have only rarely
reached practical applicability in patients (Chidambaran et al., 2017; Davis et al., 2017; Lee et al., 2012; Matic
et al., 2017; Mogil et al., 2010; Walter et al., 2013). Many obstacles have been discussed (Berge, 2011; Galer et
al., 2005; Mogil et al., 2010; Richards & McMahon, 2013; Yekkirala et al., 2017). Notwithstanding, animal
studies are indispensable, continue to be improved, and have successfully predicted adverse side e ects of
drug candidates (Berge, 2011; Mogil et al., 2010).
Areas of intense research are signaling, tra cking, and processing of ORs in sensory neurons, particularly
the in uence of injury and the implications for tolerance development, e cacy, and potency of opioid
agonists. The recent urry of publications on GPCR structures enables novel approaches to elucidate biased
signaling and allosteric and oligomeric modulation of opioid receptor function. A eld that has not received
p. 750 much attention is the in uence of opioids on in ammation and wound healing, despite ample preclinical
data (Stein & Küchler, 2013). Similarly, clinical studies on the augmentation of endogenous opioid e ects
are needed (Livingston & Traynor, 2017; Roques et al., 2012; Schreiter et al., 2012).
The epidemic of opioid misuse illustrates the persistent problems resulting from non-selective activation of
ubiquitous ORs throughout central and peripheral compartments. Thus, the potential of peripheral actions
is increasingly recognized by researchers and clinicians (Baron et al., 2013; Piomelli & Sasso, 2014; Richards
& McMahon, 2013; Roques et al., 2012; Stein, 2016; Vadivelu, Mitra, & Hines, 2011; Valverde & Gunkel, 2005;
Yekkirala et al., 2017; Zeng et al., 2013). These endeavors should eventually lead to novel pain medications
with fewer side e ects. In the wider context of pain management, however, one must not overlook the
in uence of psycho-social factors and the important role of non-pharmacological therapeutic approaches

(Fordyce, 1992; Schuchat et al., 2017; Stein, 1997, 2013a). It is therefore important that theoretical,
experimental, and clinical researchers establish direct contacts and that such collaborations be nurtured by
academic institutions, funding bodies, and industry.
Acknowledgments
This work was supported by Bundesministerium für Bildung und Forschung (0316177B/C1, 01EC1403E,
01EC1403F) (CS), the Helmholtz Virtual Institute “Multifunctional Biomaterials for Medicine” (CS), and the
University of Strasbourg (CG-R). This work has also been funded by the European Union Seventh
Framework programme (FP7-Health-2013-Innovation) under grant agreements 1602919 (CG-R) and
602891 (CS and CG-R).
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The Oxford Handbook of the Neurobiology of Pain

John N. Wood (ed.)

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https://doi.org/10.1093/oxfordhb/9780190860509.013.9 Pages 728–769

Acute and Chronic Pain

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Reference Species, tissue Lowest

(Häbler, 1929) Human, abscess 5.4

(Menkin, 1934) Dog, turpentine-induced pleural exudate 6.6

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(Menkin & Warner, 1937) Dog, turpentine-induced pleural exudate 6.5

(Menkin, 1956) Dog, turpentine-induced pleural exudate 6.0

(Pampus, 1963) Human, astrocytoma 5.85

(Ashby, 1966) Human, melanoma 6.4

(Falchuk, Goetzl, & Kulka, 1970) Human, rheumatoid arthritis 6.84

(Treuha & McCarty, 1971) Human, arthritis 6.60

(Hutchins & Sheldon, 1972) Rabbit, diabetic skin wounds 6.9

(Silver, 1975) Rabbit, brain, wounds, ischemia 5.0

(Vaupel, Frinak, & Bicher, 1981) Mouse mammary carcinoma 5.8

(Gillies, Liu, & Bhujwalla, 1994) Mouse, implanted tumor 6.66

(Alfaro et al., 1996) Rat, carrageenan inflammation, aspirated 6.94

(Ojugo et al., 1999) Mouse, implanted tumors 6.0

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(Gallagher et al., 2008) Mouse, implanted subcutaneous lymphoma 6.0

(Spahn et al., 2017) Rat, Freundʼs adjuvant paw inflammation; 6.8

(Gonzalez-Rodriguez et al., 2017) Rat, Freundʼs adjuvant paw inflammation 6.82

Adapted from Stein, 2018.

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Translation of Basic Research into Clinical Applications

Clinical Concepts: Definitions and Prevalence

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There is a tradition of distinguishing between non-malignant (e.g., neuropathic, musculoskeletal,

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Opioid Receptor Signaling

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p. 739 Tolerance and Opioid-Induced Hyperalgesia (OIH)

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p. 740 Opioid-Induced Hyperalgesia

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Table 25.2 Opioid Receptors and Ligands

Receptor Agonists Antagonists

KOR U-50488, U69593, dynorphin nalfurafine, asimadoline norbinaltorphimine

p. 741 Bifunctional and Multifunctional Ligands

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Augmenting Endogenous Opioid Analgesia

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p. 749 Long-Term Opioid Use in Chronic Pain

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