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date: 08 December 2019

Opioids and Pain

Abstract and Keywords

This chapter 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 chapter 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 effects such as respiratory depression, constipation, sedation, tolerance, or opioid-induced hyperalgesia. Lastly, the chapter 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

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 reflex 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 afferent neurons, spinal interneurons, ascending tracts, and supraspinal areas. Trigeminal and dorsal root ganglia (DRG) give rise to high-threshold Aδ– and C-fibers innervating peripheral tissues (skin, muscles, joints, viscera). These specialized primary afferent 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 afferent 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, proinflammatory cytokines, and protons (Table 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 sensitize peripheral and central neurons (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 effective, even in chronic pain syndromes (Baron et al., 2013; Richards & McMahon, 2013).

Table 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

Mouse, s.c., i.p. bacterial inoculation

5.6

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

(Treuhaft & 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, Staph. aureus

6.87

(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, 1989)

Human, rheumatoid arthritis synovial fluid

7.03

(Tulamo, Bramlage, & Gabel, 1989)

Horse, Staph. aureus-induced arthritis, synovial fluid

6.2

(Newell, Franchi, Pouyssegur, & Tannock, 1993)

Nude mouse; implanted tumors

6.65

(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, & Griffiths, 1999)

Rat, mouse, implanted tumors

6.3

(Ojugo et al., 1999)

Mouse, implanted tumors

6.0

(Andersson, Lexmuller, Johansson, & Ekstrom, 1999)

Rat, bovine serum albumin (BSA)-induced arthritis

5.66

(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, Freund’s adjuvant paw inflammation;

paw incision

6.8

7.02

(Gonzalez-Rodriguez et al., 2017)

Rat, Freund’s adjuvant paw inflammation

6.82

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.

Adapted from Stein, 2018.

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 1) (Stein et al., 1990). This represented the first 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 (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.

Opioids and PainClick to view larger

Figure 1 Antinociceptive mechanisms within peripheral injured tissue (adapted from Stein, 2016). 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 effects.

Translation of Basic Research into Clinical Applications

Basic research on pain continues at a rapid pace, but translation into clinical applications has been difficult (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, flawed study design, and genetic and species differences (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 effects 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 reflecting “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 findings specific for a disease or a pathophysiological basis for individual syndromes (Mogil et al., 2010). Some studies suggested that the imaged activity may reflect 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 scientific field. 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) defines 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 defined by the IASP as the “neural process of encoding noxious stimuli.” Nociception is not synonymous with pain. Pain is always a psychological state, even 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, inflammatory) and malignant (related to cancer and its treatment) chronic pain. Non-malignant chronic pain is frequently classified into inflammatory (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 afferent 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 influences 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-inflammatory drugs (NSAIDs), serotonergic compounds, antiepileptics, and antidepressants (Stein & Kopf, 2015). Placebo treatments have also shown impressive analgesic effects, mediated by opioid and non-opioid mechanisms (Carlino, Pollo, & Benedetti, 2011). In chronic pain, treating only nociception is obviously insufficient. A bio-psycho-social 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 Korff, & 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 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.

Opioids and PainClick to view larger

Figure 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 effects.

Opioid Receptor Gene Variants

The mu-opioid receptor gene OPRM1 was among the first 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 affinity, signal transduction, and expression. Therefore, it was assumed that this might underlie occasionally diminished opioid efficacy in patients. However, as emerged from meta-analyses, these findings translate only into very small clinical effects, such as slightly higher opioid-dosing requirements for acute pain, but they do not affect chronic pain or opioid side effects. 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, efforts continue to find 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 effects 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 defined 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). 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++ influx. 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, Kieffer, & Evans, 2012; Stein, 2016; Williams et al., 2013).

Upon activation, ORs can be phosphorylated by different 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. Different 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 effects, and that this bias is ligand-specific. For example, tolerance to morphine’s anti-nociceptive effects 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 1), opioid receptor–ligand interactions apparently exhibit different 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 (inflamed) conditions. Based on these in silico studies, a prototype ligand (NFEPP) was designed that exhibited preferential cAMP inhibition, G-protein dissociation, and anti-nociceptive efficacy in injured tissue (at low pH), while typical adverse effects (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 3) (Spahn et al., 2017). These findings were attributed both to acidosis-induced conformational alterations of peripheral ORs, and to the low acid dissociation constant (pKa) of NFEPP (Spahn et al., 2017).

Opioids and PainClick to view larger

Figure 3 A novel concept to selectively activate opioid receptors in injured peripheral tissue without side effects. 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 Del Vecchio, G., Spahn, V., & Stein, C.: Novel opioid analgesics and side effects. ACS Chemical Neuroscience, 2017; 8:1638–1640. Copyright 2017 American Chemical Society.

Tolerance and Opioid-Induced Hyperalgesia (OIH)

“Tolerance” describes the phenomenon that the magnitude of a given effect decreases with repeated administration of the same agonist dose, or that increasing doses are needed to produce the same effect. MOR agonists induce potent analgesia, but also side effects, including nausea, constipation, respiratory depression, and somnolence. All these effects can be subject to tolerance development, albeit to different 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 effects are mediated by activating MOR (Gaveriaux-Ruff, 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 effects 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 inflammation 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 inflammatory and neuropathic pain, morphine tolerance was prevented by administration of the peripherally restricted MOR antagonist methylnaltrexone (Corder et al., 2017). To arrive at definitive 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).

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-Ruff, & 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 influence the affinity and/or efficacy of orthosteric ligands in vitro. However, in vivo confirmation 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 confined to ORs that are exposed to released endogenous opioids and thereby avoid side effects (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 identification 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 effective 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 2. More extensive reviews on MOR (Drewes et al., 2013; Madariaga-Mazon et al., 2017), DOR (Peppin & Raffa, 2015; Pradhan, Befort, Nozaki, Gaveriaux-Ruff, & Kieffer, 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 2 Opioid Receptors and Ligands

Receptor

Agonists

Antagonists

MOR

morphine, fentanyl, remifentanil, methadone, oxycodone, DAMGO, endomorphins, enkephalins, β-endorphin, TRV130, PZM21

CTOP, CTAP, alvimopan naloxone (-methiodide)

DOR

SNC80, enkephalins, β-endorphin, deltorphin, JNJ-20788560, ARM390, UPF-512, ADL5747, ADL5859, KNT-127

naltrindole naloxone (-methiodide)

KOR

U-50488, U69593, dynorphin nalfurafine, asimadoline

norbinaltorphimine naloxone (-methiodide)

Bifunctional and Multifunctional Ligands

Bi-/multi-functional agonists were designed with the goal of reducing side effects (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 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).

Opioids and PainClick to view larger

Figure 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 first 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; 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 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 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 efforts for discovery of new ligands and has broadened the general view on GPCR function (Bruchas & Roth, 2016; 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 effects in rodent models (Altarifi et al., 2017; DeWire et al., 2013; Kieffer, 2016; A. Manglik et al., 2016). Repeated TRV130 application did not induce anti-nociceptive tolerance in animals (Altarifi 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 (Altarifi et al., 2017) and human clinical studies (Viscusi et al., 2016), TRV130 produced adverse effects 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 differed 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 effects (Ranjan et al., 2017). Ibogaine potentiated morphine anti-nociception, prevented morphine tolerance and exhibited anti-addictive effects (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-specific 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 effects on intracellular trafficking, 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 significant anti-nociceptive effects are mediated by ORs localized on peripheral sensory neurons, and that opioid agonists elicit stronger analgesic effects in inflamed than noninflamed 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 peripheral tissue inflammation induced upregulation of ORs and their mRNAs in DRG neurons, which was dependent on neuronal electrical activity and on local cytokine production (Figure 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 influence of various inflammatory 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 inflammation, see Table 1) increased opioid agonist efficacy in vitro (Rasenick & Childers, 1989; Selley, Breivogel, & Childers, 1993). Recordings from sensory nerve fibers supplying injured tissue revealed opioid inhibition of spontaneous and stimulus-evoked action potentials (reviewed in Stein, 2016). Neuropathy is another condition influencing 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 effects (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 effects 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 inflammation, indicating that peripheral MOR significantly contribute to analgesia produced by systemically administered opioids (Weibel et al., 2013). The absence of DOR in Nav1.8 neurons aggravated both inflammatory and neuropathic hypersensitivity, and greatly lowered DOR agonist-induced anti-nociception in models of chronic pain (Gaveriaux-Ruff & Kieffer, 2011; Nozaki et al., 2012).

Recently, a novel agonist (NFEPP) was designed based on computational simulations of ligand-receptor interactions in an inflamed (acidic) environment. This agonist selectively activated MOR at acidic pH and induced peripherally mediated, injury-specific anti-nociception without affecting 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 inflammatory pain without eliciting sedation or constipation (Gonzalez-Rodriguez et al., 2017). Both NFEPP and PG-M produced equieffective 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, inflammatory, and visceral hypersensitivity (Gaveriaux-Ruff, Karchewski, Hever, Matifas, & Kieffer, 2008; Nadal, Banos, Kieffer, & Maldonado, 2006; Reiss et al., 2017). Inflammatory hypersensitivity was comparable or longer lasting in MOR-KO (Gaveriaux-Ruff 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 inflammatory hypersensitivity (Gaveriaux-Ruff 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-Ruff, 2013). Beta-endorphin-KO and preproenkephalin-KO mice showed normal acute nociception and inflammatory pain (Kieffer & Gaveriaux-Ruff, 2002; Labuz, Celik, Zimmer, & Machelska, 2016; Walwyn et al., 2016). Prodynorphin KO animals display normal inflammatory pain (Walwyn et al., 2016), recover more rapidly from neuropathic hypersensivity (Kieffer & Gaveriaux-Ruff, 2002; Xu et al., 2004), and are slightly less sensitive after nerve injury (Labuz et al., 2016). Endogenous opioids also participate in fibromyalgia. In a mouse fibromyalgia 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 fibromyalgia patients (Schrepf et al., 2016), and that endogenous opioids contribute to placebo analgesia (Carlino, Frisaldi, & Benedetti, 2014; Holmes, Tiwari, & Kennedy, 2016), to the effects 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 (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 inflammatory 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 specifically, 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 confirmed in studies demonstrating that patients with knee joint inflammation express opioid peptides in immune cells and ORs on sensory nerve terminals within synovial tissue (Mousa, Straub, Schäfer, & Stein, 2007; Stein, Hassan, Lehrberger, Giefing, & 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 effects 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, off-site, or paradoxical excitatory effects (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 inflammatory 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 effects or abuse liability (Popik, Kamysz, Kreczko, & Wrobel, 2010; Rougeot, Robert, Menz, Bisson, & Messaoudi, 2010), and produced antidepressant effects 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 Differences

Species differences 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 differences have demonstrated that even single amino acid variations in OR proteins can have measurable effects 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 different 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 findings in rats and humans (Stein et al., 1996; Zollner et al., 2008). Opioid agonists did not affect 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 fields (e.g., immunology, oncology), all these findings have to be taken into consideration when preclinical data are interpreted to predict drug effects in humans.

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 effects (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, inflammation, 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 effects 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; Griffin et al., 2016; Wasserman et al., 2015), postoperative pain (Fletcher & Martinez, 2014), in healthy volunteers (Fishbain, Cole, Lewis, Gao, & Rosomoff, 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 significant 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 defined 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, & Elashoff, 2004).

Addiction is a complex syndrome involving reward/euphoria, the urge to avoid withdrawal, craving, uncontrolled/compulsive drug use despite harmful side effects, 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).

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 insignificant, 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 effects (nausea, sedation, constipation, dizziness, etc.) and lack of analgesic efficacy 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 affective 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 findings into clinical applications has been difficult (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 effects of drug candidates (Berge, 2011; Mogil et al., 2010).

Areas of intense research are signaling, trafficking, and processing of ORs in sensory neurons, particularly the influence of injury and the implications for tolerance development, efficacy, and potency of opioid agonists. The recent flurry of publications on GPCR structures enables novel approaches to elucidate biased signaling and allosteric and oligomeric modulation of opioid receptor function. A field that has not received much attention is the influence of opioids on inflammation and wound healing, despite ample preclinical data (Stein & Küchler, 2013). Similarly, clinical studies on the augmentation of endogenous opioid effects 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 effects. In the wider context of pain management, however, one must not overlook the influence 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).

References

Alfaro, V., Rodenas, J., Pesquero, J., Mitjavila, M. T., Palacios, L., & Carbonell, T. (1996). Factors influencing the acid-base changes in the air-pouch exudate following carrageenan induced inflammation in rats. Inflammation Research, 45(8), 405–411. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8872514Find this resource:

Altarifi, A. A., David, B., Muchhala, K. H., Blough, B. E., Akbarali, H., & Negus, S. S. (2017). Effects of acute and repeated treatment with the biased mu opioid receptor agonist TRV130 (oliceridine) on measures of ant nociception, gastrointestinal function, and abuse liability in rodents. Journal of Psychopharmacology, 31(6), 730–739. doi:10.1177/0269881116689257Find this resource:

Anand, J. P., Boyer, B. T., Mosberg, H. I., & Jutkiewicz, E. M. (2016). The behavioral effects of a mixed efficacy anti-nociceptive peptide, VRP26, following chronic administration in mice. Psychopharmacology (Berlin), 233(13), 2479–2487. doi:10.1007/s00213-016-4296-8Find this resource:

Andersson, S. E., Lexmuller, K., Johansson, A., & Ekstrom, G. M. (1999). Tissue and intracellular pH in normal periarticular soft tissue and during different phases of antigen induced arthritis in the rat. Journal of Rheumatology, 26(9), 2018–2024. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10493685Find this resource:

Angst, M. S. (2015). Intraoperative Use of Remifentanil for TIVA: Postoperative Pain, Acute Tolerance, and Opioid-Induced Hyperalgesia. Journal of Cardiothoracic & Vascular Anesthesia, 29(Suppl 1), S16–S22. doi:10.1053/j.jvca.2015.01.026Find this resource:

Antonijevic, I., Mousa, S. A., Schäfer, M., & Stein, C. (1995). Perineurial defect and peripheral opioid analgesia in inflammation. The Journal of Neuroscience, 15(1), 165–172.Find this resource:

Ashby, B. S. (1966). pH studies in human malignant tumours. Lancet, 2(7458), 312–315. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/4161494Find this resource:

Baddack-Werncke, U., Busch-Dienstfertig, M., Gonzalez-Rodriguez, S., Maddila, S. C., Grobe, J., Lipp, M., … Muller, G. (2017). Cytotoxic T cells modulate inflammation and endogenous opioid analgesia in chronic arthritis. Journal of Neuroinflammation, 14(1), 30. doi:10.1186/s12974-017-0804-yFind this resource:

Baron, R. (2006). Mechanisms of disease: Neuropathic pain—a clinical perspective. Nature Clinical Practice. Neurology, 2(2), 95–106. doi:10.1038/ncpneuro0113Find this resource:

Baron, R., Eberhart, L., Kern, K. U., Regner, S., Rolke, R., Simanski, C., & Tolle, T. (2017). Tapentadol prolonged release for chronic pain: A review of clinical trials and 5 years of routine clinical practice data. Pain Practice: The Official Journal of the World Institute of Pain, 17(5), 678–700. doi:10.1111/papr.12515Find this resource:

Baron, R., Hans, G., & Dickenson, A. H. (2013). Peripheral input and its importance for central sensitization. Annals of Neurology, 74(5), 630–636. doi:10.1002/ana.24017Find this resource:

Basbaum, A. I., Bautista, D. M., Scherrer, G., & Julius, D. (2009). Cellular and molecular mechanisms of pain. Cell, 139(2), 267–284. doi:10.1016/j.cell.2009.09.028Find this resource:

Basso, L., Garnier, L., Bessac, A., Boue, J., Blanpied, C., Cenac, N., … Dietrich, G. (2017). T-lymphocyte-derived enkephalins reduce Th1/Th17 colitis and associated pain in mice. Journal of Gastroenterology, 53, 215–226. doi:10.1007/s00535-017-1341-2Find this resource:

Belkin, M., Reinheimer, H. S., Levy, J., & Johnson, B. (2017). Ameliorative response to detoxification, psychotherapy, and medical management in patients maintained on opioids for pain. American Journal of Addiction, 26(7), 738–743. doi:10.1111/ajad.12605Find this resource:

Berge, O. G. (2011). Predictive validity of behavioural animal models for chronic pain. British Journal Of Pharmacology, 164(4), 1195–1206. doi:10.1111/j.1476-5381.2011.01300.xFind this resource:

Bonnard, E., Poras, H., Fournie-Zaluski, M. C., & Roques, B. P. (2016). Preventive and alleviative effects of the dual enkephalinase inhibitor (Denki) PL265 in a murine model of neuropathic pain. European Journal of Pharmacology, 788, 176–182. doi:10.1016/j.ejphar.2016.05.041Find this resource:

Bonnard, E., Poras, H., Nadal, X., Maldonado, R., Fournie-Zaluski, M. C., & Roques, B. P. (2015). Long-lasting oral analgesic effects of N-protected aminophosphinic dual ENKephalinase inhibitors (DENKIs) in peripherally controlled pain. Pharmacology Research & Perspectives, 3(2), e00116. doi:10.1002/prp2.116Find this resource:

Boue, J., Basso, L., Cenac, N., Blanpied, C., Rolli-Derkinderen, M., Neunlist, M., … Dietrich, G. (2014). Endogenous regulation of visceral pain via production of opioids by colitogenic CD4(+) T cells in mice. Gastroenterology, 146(1), 166–175. doi:10.1053/j.gastro.2013.09.020Find this resource:

Boue, J., Blanpied, C., Brousset, P., Vergnolle, N., & Dietrich, G. (2011). Endogenous opioid-mediated analgesia is dependent on adaptive T cell response in mice. Journal of Immunology, 186(9), 5078–5084. doi:10.4049/jimmunol.1003335Find this resource:

Boue, J., Blanpied, C., Djata-Cabral, M., Pelletier, L., Vergnolle, N., & Dietrich, G. (2012). Immune conditions associated with CD4+ T effector-induced opioid release and analgesia. Pain, 153(2), 485–493. doi:10.1016/j.pain.2011.11.013Find this resource:

Brownstein, M. J. (1993). A brief history of opiates, opioid peptides, and opioid receptors. Proceedings of the National Academy of Sciences USA, 90(12), 5391–5393. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/8390660Find this resource:

Bruchas, M. R., & Roth, B. L. (2016). New technologies for elucidating opioid receptor function. Trends in Pharmacological Sciences, 37(4), 279–289. doi:10.1016/j.tips.2016.01.001Find this resource:

Bruehl, S., Apkarian, A. V., Ballantyne, J. C., Berger, A., Borsook, D., Chen, W. G., … Lin, Y. (2013). Personalized medicine and opioid analgesic prescribing for chronic pain: Opportunities and challenges. Journal of Pain, 14(2), 103–113. doi:10.1016/j.jpain.2012.10.016Find this resource:

Brust, T. F., Morgenweck, J., Kim, S. A., Rose, J. H., Locke, J. L., Schmid, C. L., … Bohn, L. M. (2016). Biased agonists of the kappa opioid receptor suppress pain and itch without causing sedation or dysphoria. Science Signaling, 9(456), ra117. doi:10.1126/scisignal.aai8441Find this resource:

Busch-Dienstfertig, M., Labuz, D., Wolfram, T., Vogel, N. N., & Stein, C. (2012). JAK-STAT1/3-induced expression of signal sequence-encoding proopiomelanocortin mRNA in lymphocytes reduces inflammatory pain in rats. Molecular Pain, 8, 83. doi:10.1186/1744-8069-8-83Find this resource:

Busch-Dienstfertig, M., Roth, C. A., & Stein, C. (2013). Functional characteristics of the naked mole rat mu-opioid receptor. PLoS ONE, 8(11), e79121. doi:10.1371/journal.pone.0079121Find this resource:

Cahill, C. M., Walwyn, W., Taylor, A. M., Pradhan, A. A., & Evans, C. J. (2016). Allostatic mechanisms of opioid tolerance beyond desensitization and downregulation. Trends in Pharmacological Sciences, 37(11), 963–976. doi:10.1016/j.tips.2016.08.002Find this resource:

Carlino, E., Frisaldi, E., & Benedetti, F. (2014). Pain and the context. Nature Reviews Rheumatology, 10(6), 348–355. doi:10.1038/nrrheum.2014.17Find this resource:

Carlino, E., Pollo, A., & Benedetti, F. (2011). Placebo analgesia and beyond: A melting pot of concepts and ideas for neuroscience. Current Opinion in Anesthesiology, 24(5), 540–544. doi:10.1097/ACO.0b013e328349d0c2Find this resource:

Carullo, V., Fitz-James, I., & Delphin, E. (2015). Opioid-induced hyperalgesia: A diagnostic dilemma. Journal of Pain & Palliative Care Pharmacotherapy, 29(4), 378–384. doi:10.3109/15360288.2015.1082006Find this resource:

Cayla, C., Labuz, D., Machelska, H., Bader, M., Schäfer, M., & Stein, C. (2012). Impaired nociception and peripheral opioid anti-nociception in mice lacking both kinin B1 and B2 receptors. Anesthesiology, 116(2), 448–457. doi:10.1097/ALN.0b013e318242b2eaFind this resource:

Celik, M. O., Labuz, D., Henning, K., Busch-Dienstfertig, M., Gaveriaux-Ruff, C., Kieffer, B. L., … Machelska, H. (2016). Leukocyte opioid receptors mediate analgesia via Ca(2+)-regulated release of opioid peptides. Brain, Behavior & Immunity, 57, 227–242. doi:10.1016/j.bbi.2016.04.018Find this resource:

Chan, H. C. S., McCarthy, D., Li, J., Palczewski, K., & Yuan, S. (2017). Designing safer analgesics via mu-opioid receptor pathways. Trends in Pharmacological Sciences, 38(11), 1016–1037. doi:10.1016/j.tips.2017.08.004Find this resource:

Chidambaran, V., Sadhasivam, S., & Mahmoud, M. (2017). Codeine and opioid metabolism: Implications and alternatives for pediatric pain management. Current Opinion in Anesthesiology, 30(3), 349–356. doi:10.1097/ACO.0000000000000455Find this resource:

Chou, R., Gordon, D. B., de Leon-Casasola, O. A., Rosenberg, J. M., Bickler, S., Brennan, T., … Wu, C. L. (2016). Management of postoperative pain: A clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee on Regional Anesthesia, Executive Committee, and Administrative Council. Journal of Pain, 17(2), 131–157. doi:10.1016/j.jpain.2015.12.008Find this resource:

Christoph, A., Eerdekens, M. H., Kok, M., Volkers, G., & Freynhagen, R. (2017). Cebranopadol, a novel first-in-class analgesic drug candidate: First experience in patients with chronic low back pain in a randomized clinical trial. Pain, 158(9), 1813–1824. doi:10.1097/j.pain.0000000000000986Find this resource:

Codd, E. E., Carson, J. R., Colburn, R. W., Stone, D. J., Van Besien, C. R., Zhang, S. P., … Flores, C. M. (2009). JNJ-20788560 [9-(8-azabicyclo[3.2.1]oct-3-ylidene)-9H-xanthene-3-carboxylic acid diethylamide], a selective delta opioid receptor agonist, is a potent and efficacious antihyperalgesic agent that does not produce respiratory depression, pharmacologic tolerance, or physical dependence. Journal of Pharmacology & Experimental Therapeutics, 329(1), 241–251. doi:10.1124/jpet.108.146969Find this resource:

Collett, B. J. (1998). Opioid tolerance: The clinical perspective. British Journal of Anaesthesiology, 81(1), 58–68. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/9771273Find this resource:

Collin, E., Poulain, P., Gauvain-Piquard, A., Petit, G., & Pichard-Leandri, E. (1993). Is disease progression the major factor in morphine “tolerance” in cancer pain treatment? Pain, 55(3), 319–326. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8121693Find this resource:

Comelon, M., Raeder, J., Stubhaug, A., Nielsen, C. S., Draegni, T., & Lenz, H. (2016). Gradual withdrawal of remifentanil infusion may prevent opioid-induced hyperalgesia. British Journal of Anaesthesiology, 116(4), 524–530. doi:10.1093/bja/aev547Find this resource:

Compton, P., Charuvastra, V. C., & Ling, W. (2001). Pain intolerance in opioid-maintained former opiate addicts: Effect of long-acting maintenance agent. Drug & Alcohol Dependence, 63(2), 139–146. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11376918Find this resource:

Compton, P., Miotto, K., & Elashoff, D. (2004). Precipitated opioid withdrawal across acute physical dependence induction methods. Pharmacology, Biochemistry, & Behavior, 77(2), 263–268. Retrieved from http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14751453Find this resource:

Corder, G., Tawfik, V. L., Wang, D., Sypek, E. I., Low, S. A., Dickinson, J. R., … Scherrer, G. (2017). Loss of mu opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia. Nature Medicine, 23(2), 164–173. doi:10.1038/nm.4262Find this resource:

Cummings, N. A., & Nordby, G. L. (1966). Measurement of synovial fluid pH in normal and arthritic knees. Arthritis & Rheumatism, 9(1), 47–56. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/4952418Find this resource:

Davis, K. D., Flor, H., Greely, H. T., Iannetti, G. D., Mackey, S., Ploner, M., … Wager, T. D. (2017). Brain imaging tests for chronic pain: Medical, legal and ethical issues and recommendations. Nature Reviews Neurology, 13(10), 624–638. doi:10.1038/nrneurol.2017.122Find this resource:

De Marco, R., Bedini, A., Spampinato, S., Cavina, L., Pirazzoli, E., & Gentilucci, L. (2016). Versatile picklocks to access all opioid receptors: Tuning the selectivity and functional profile of the cyclotetrapeptide c[Phe-d-Pro-Phe-Trp] (CJ-15,208). Journal of Medicinal Chemistry, 59(19), 9255–9261. doi:10.1021/acs.jmedchem.6b00420Find this resource:

Del Vecchio, G., Spahn, V., & Stein, C. (2017). Novel opioid analgesics and side effects. ACS Chemical Neuroscience, 8(8), 1638–1640. doi:10.1021/acschemneuro.7b00195Find this resource:

Dembla, S., Behrendt, M., Mohr, F., Goecke, C., Sondermann, J., Schneider, F. M., … Oberwinkler, J. (2017). Anti-nociceptive action of peripheral mu-opioid receptors by G-beta-gamma protein-mediated inhibition of TRPM3 channels. Elife, 6. doi:10.7554/eLife.26280Find this resource:

DeWire, S. M., Yamashita, D. S., Rominger, D. H., Liu, G., Cowan, C. L., Graczyk, T. M., … Violin, J. D. (2013). A G protein-biased ligand at the mu-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. Journal of Pharmacology & Experimental Therapeutics, 344(3), 708–717. doi:10.1124/jpet.112.201616Find this resource:

Diener, H. C., Holle, D., Solbach, K., & Gaul, C. (2016). Medication-overuse headache: Risk factors, pathophysiology and management. Nature Reviews Neurology, 12(10), 575–583. doi:10.1038/nrneurol.2016.124Find this resource:

Ding, H., Czoty, P. W., Kiguchi, N., Cami-Kobeci, G., Sukhtankar, D. D., Nader, M. A., … Ko, M. C. (2016). A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates. Proceedings of the National Academy of Sciences USA, 113(37), E5511–5518. doi:10.1073/pnas.1605295113Find this resource:

Drewes, A. M., Jensen, R. D., Nielsen, L. M., Droney, J., Christrup, L. L., Arendt-Nielsen, L., … Dahan, A. (2013). Differences between opioids: Pharmacological, experimental, clinical and economical perspectives. British Journal of Clinical Pharmacology, 75(1), 60–78. doi:10.1111/j.1365-2125.2012.04317.xFind this resource:

Dzau, V. J., & Pizzo, P. A. (2014). Relieving pain in America: Insights from an Institute of Medicine committee. Journal of the American Medical Association, 312(15), 1507–1508. doi:10.1001/jama.2014.12986Find this resource:

Elhabazi, K., Humbert, J. P., Bertin, I., Quillet, R., Utard, V., Schneider, S., … Simonin, F. (2017). RF313, an orally bioavailable neuropeptide FF receptor antagonist, opposes effects of RF-amide-related peptide-3 and opioid-induced hyperalgesia in rodents. Neuropharmacology, 118, 188–198. doi:10.1016/j.neuropharm.2017.03.012Find this resource:

Endres-Becker, J., Heppenstall, P. A., Mousa, S. A., Labuz, D., Oksche, A., Schäfer, M., … Zöllner, C. (2007). Mu-opioid receptor activation modulates transient receptor potential vanilloid 1 (TRPV1) currents in sensory neurons in a model of inflammatory pain. Molecular Pharmacology, 71(1), 12–18. Retrieved from http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17005903Find this resource:

Engel, C. C., von Korff, M., & Katon, W. J. (1996). Back pain in primary care: Predictors of high health-care costs. Pain, 65(2–3), 197–204. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8826507Find this resource:

Eriksen, J., Sjogren, P., Bruera, E., Ekholm, O., & Rasmussen, N. K. (2006). Critical issues on opioids in chronic non-cancer pain: An epidemiological study. Pain, 125(1–2), 172–179. Retrieved from http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16842922Find this resource:

Falchuk, K. H., Goetzl, E. J., & Kulka, J. P. (1970). Respiratory gases of synovial fluids. An approach to synovial tissue circulatory-metabolic imbalance in rheumatoid arthritis. American Journal of Medicine, 49(2), 223–231. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/5452943Find this resource:

Farr, M., Garvey, K., Bold, A. M., Kendall, M. J., & Bacon, P. A. (1985). Significance of the hydrogen ion concentration in synovial fluid in rheumatoid arthritis. Clinical & Experimental Rheumatology, 3(2), 99–104. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/4017318Find this resource:

Ferrini, F., Trang, T., Mattioli, T. A., Laffray, S., Del’Guidice, T., Lorenzo, L. E., … De Koninck, Y. (2013). Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl(-) homeostasis. Nature Neuroscience, 16(2), 183–192. doi:10.1038/nn.3295Find this resource:

Fidecka, S., Malec, D., & Langwinski, R. (1978). Central action of narcotic analgesics. II. Locomotor activity and narcotic analgesics. Polish Journal of Pharmacology & Pharmacy, 30(1), 5–16. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/25426Find this resource:

Fishbain, D. A., Cole, B., Lewis, J. E., Gao, J., & Rosomoff, R. S. (2009). Do opioids induce hyperalgesia in humans? An evidence-based structured review. Pain Medicine, 10(5), 829–839. doi:10.1111/j.1526-4637.2009.00653.xFind this resource:

Fletcher, D., & Martinez, V. (2014). Opioid-induced hyperalgesia in patients after surgery: A systematic review and a meta-analysis. British Journal of Anaesthesiology, 112(6), 991–1004. doi:10.1093/bja/aeu137Find this resource:

Flor, H., & Diers, M. (2007). Limitations of pharmacotherapy: Behavioral approaches to chronic pain. Handbook of Experimental Pharmacology, (177), 415–427. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/17087132Find this resource:

Fordyce, W. E. (1991). Opioids and treatment targets. American Pain Society Bulletin, 1(4), 1–4.Find this resource:

Fordyce, W. E. (1992). Opioids, pain and behavioral outcomes. American Pain Society Journal, 1(4), 282–284.Find this resource:

Fordyce, W. E., Fowler, R. S., & DeLateur, B. (1968). An application of behavior modification technique to a problem of chronic pain. Behaviour Research and Therapy, 6(1), 105–107. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/5644753Find this resource:

Fujita, W., Gomes, I., & Devi, L. A. (2015). Heteromers of mu-delta opioid receptors: new pharmacology and novel therapeutic possibilities. British Journal of Pharmacology, 172(2), 375–387. doi:10.1111/bph.12663Find this resource:

Galer, B. S., Lee, D., Ma, T., Nagle, B., & Schlagheck, T. G. (2005). MorphiDex (morphine sulfate/dextromethorphan hydrobromide combination) in the treatment of chronic pain: Three multicenter, randomized, double-blind, controlled clinical trials fail to demonstrate enhanced opioid analgesia or reduction in tolerance. Pain, 115(3), 284–295. doi:10.1016/j.pain.2005.03.004Find this resource:

Gallagher, F. A., Kettunen, M. I., Day, S. E., Hu, D. E., Ardenkjaer-Larsen, J. H., Zandt, R., … Brindle, K. M. (2008). Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonate. Nature, 453(7197), 940–943. doi:10.1038/nature07017Find this resource:

Gatchel, R. J., & Okifuji, A. (2006). Evidence-based scientific data documenting the treatment and cost-effectiveness of comprehensive pain programs for chronic nonmalignant pain. Journal of Pain, 7(11), 779–793. doi:10.1016/j.jpain.2006.08.005Find this resource:

Gaveriaux-Ruff, C. (2013). Opiate-induced analgesia: Contributions from mu, delta and kappa opioid receptors mouse mutants. Current Pharmaceutical Design, 19(42), 7373–7381. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/23448470Find this resource:

Gaveriaux-Ruff, C., Karchewski, L. A., Hever, X., Matifas, A., & Kieffer, B. L. (2008). Inflammatory pain is enhanced in delta opioid receptor-knockout mice. European Journal of Neuroscience, 27(10), 2558–2567. doi:10.1111/j.1460-9568.2008.06223.xFind this resource:

Gaveriaux-Ruff, C., & Kieffer, B. L. (2011). Delta opioid receptor analgesia: Recent contributions from pharmacology and molecular approaches. Behavioral Pharmacology, 22(5–6), 405–414. doi:10.1097/FBP.0b013e32834a1f2cFind this resource:

Geborek, P., Saxne, T., Pettersson, H., & Wollheim, F. A. (1989). Synovial fluid acidosis correlates with radiological joint destruction in rheumatoid arthritis knee joints. Journal of Rheumatology, 16(4), 468–472. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2746586Find this resource:

Gendron, L., Cahill, C. M., von Zastrow, M., Schiller, P. W., & Pineyro, G. (2016). Molecular pharmacology of delta-opioid receptors. Pharmacological Reviews, 68(3), 631–700. doi:10.1124/pr.114.008979Find this resource:

Gillies, R. J., Liu, Z., & Bhujwalla, Z. (1994). 31P-MRS measurements of extracellular pH of tumors using 3-aminopropylphosphonate. The American Journal of Physiology, 267(1 Pt 1), C195–C203. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8048479Find this resource:

Goins, W. F., Cohen, J. B., & Glorioso, J. C. (2012). Gene therapy for the treatment of chronic peripheral nervous system pain. Neurobiology of Disease, 48(2), 255–270. doi:10.1016/j.nbd.2012.05.005Find this resource:

Goldie, I., & Nachemson, A. (1969). Synovial pH in rheumatoid knee-joints. I. The effect of synovectomy. Acta Orthopaedica Scandinavica, 40(5), 634–641. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/5378127Find this resource:

Goldie, I., & Nachemson, A. (1970). Synovial pH in rheumatoid knee joints. II. The effect of local corticosteroid treatment. Acta Orthopaedica Scandinavica, 41(3), 354–362. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/5486188Find this resource:

Gomes, I., Ayoub, M. A., Fujita, W., Jaeger, W. C., Pfleger, K. D., & Devi, L. A. (2016). G protein-coupled receptor heteromers. Annual Review of Pharmacology & Toxicology, 56, 403–425. doi:10.1146/annurev-pharmtox-011613-135952Find this resource:

Gonzalez-Rodriguez, S., Quadir, M. A., Gupta, S., Walker, K. A., Zhang, X., Spahn, V., … Stein, C. (2017). Polyglycerol-opioid conjugate produces analgesia devoid of side effects. Elife, 6, e27081. doi:10.7554/eLife.27081Find this resource:

Granier, S., Manglik, A., Kruse, A. C., Kobilka, T. S., Thian, F. S., Weis, W. I., & Kobilka, B. K. (2012). Structure of the delta-opioid receptor bound to naltrindole. Nature, 485(7398), 400–404. doi:10.1038/nature11111Find this resource:

Grenald, S. A., Young, M. A., Wang, Y., Ossipov, M. H., Ibrahim, M. M., Largent-Milnes, T. M., & Vanderah, T. W. (2017). Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists. Neuropharmacology, 116, 59–70. doi:10.1016/j.neuropharm.2016.12.008Find this resource:

Griffin, M. L., McDermott, K. A., McHugh, R. K., Fitzmaurice, G. M., Jamison, R. N., & Weiss, R. D. (2016). Longitudinal association between pain severity and subsequent opioid use in prescription opioid dependent patients with chronic pain. Drug & Alcohol Dependence, 163, 216–221. doi:10.1016/j.drugalcdep.2016.04.023Find this resource:

Guedon, J. M., Wu, S., Zheng, X., Churchill, C. C., Glorioso, J. C., Liu, C. H., … Hao, S. (2015). Current gene therapy using viral vectors for chronic pain. Molecular Pain, 11, 27. doi:10.1186/s12990-015-0018-1Find this resource:

Gunther, T., Dasgupta, P., Mann, A., Miess, E., Kliewer, A., Fritzwanker, S., … Schulz, S. (2017). Targeting multiple opioid receptors—improved analgesics with reduced side effects? British Journal of Pharmacology. doi:10.1111/bph.13809Find this resource:

Gustavsson, A., Bjorkman, J., Ljungcrantz, C., Rhodin, A., Rivano-Fischer, M., Sjolund, K. F., & Mannheimer, C. (2012). Pharmaceutical treatment patterns for patients with a diagnosis related to chronic pain initiating a slow-release strong opioid treatment in Sweden. Pain, 153(12), 2325–2331. doi:10.1016/j.pain.2012.07.011Find this resource:

Häbler, C. (1929). Über den K- und Ca-Gehalt von Eiter und Exsudaten und seine Beziehungen zum Entzündungsschmerz. Klinische Wochenschrift, 34, 1569–1572.Find this resource:

Hassan, A. H. S., Ableitner, A., Stein, C., & Herz, A. (1993). Inflammation of the rat paw enhances axonal transport of opioid receptors in the sciatic nerve and increases their density in the inflamed tissue. Neuroscience, 55, 185–195.Find this resource:

Hauser, A. S., Chavali, S., Masuho, I., Jahn, L. J., Martemyanov, K. A., Gloriam, D. E., & Babu, M. M. (2018). Pharmacogenomics of GPCR drug targets. Cell, 172(1–2), 41–54, e19. doi:10.1016/j.cell.2017.11.033Find this resource:

Healy, J. R., Bezawada, P., Griggs, N. W., Devereaux, A. L., Matsumoto, R. R., Traynor, J. R., … Cunningham, C. W. (2017). Benzylideneoxymorphone: A new lead for development of bifunctional mu/delta opioid receptor ligands. Bioorganic & Medicinal Chemistry Letters, 27(3), 666–669. doi:10.1016/j.bmcl.2016.11.057Find this resource:

Herz, A., Millan, M. J., & Stein, C. (1989). Arthritic inflammation in rats as a model of chronic pain: Role of opioid systems. NIDA Research Monograph, 95, 110–115. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2561818Find this resource:

Holmes, R. D., Tiwari, A. K., & Kennedy, J. L. (2016). Mechanisms of the placebo effect in pain and psychiatric disorders. Pharmacogenomics Journal, 16(6), 491–500. doi:10.1038/tpj.2016.15Find this resource:

Hood, V. L., Schubert, C., Keller, U., & Muller, S. (1988). Effect of systemic pH on pHi and lactic acid generation in exhaustive forearm exercise. American Journal of Physiology, 255(3 Pt 2), F479–F485. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3414804Find this resource:

Hua, Z., Liu, L., Shen, J., Cheng, K., Liu, A., Yang, J., … Cheng, J. (2016). Mesenchymal stem cells reversed morphine tolerance and opioid-induced hyperalgesia. Scientific Reports, 6, 32096. doi:10.1038/srep32096Find this resource:

Huang, P., Chen, C., & Liu-Chen, L. Y. (2015). Detection of mu opioid receptor (MOPR) and its glycosylation in rat and mouse brains by western blot with anti-muC, an affinity-purified polyclonal anti-MOPR antibody. Methods in Molecular Biology, 1230, 141–154. doi:10.1007/978-1-4939-1708-2_11Find this resource:

Hubner, H., Schellhorn, T., Gienger, M., Schaab, C., Kaindl, J., Leeb, L., … Gmeiner, P. (2016). Structure-guided development of heterodimer-selective GPCR ligands. Nature Communications, 7, 12298. doi:10.1038/ncomms12298Find this resource:

Hutchins, G. M., & Sheldon, W. H. (1972). The pH of inflammatory exudates in acidotic diabetic rabbits. Proceedings of the Society for Experimental Biology & Medicine, 140(2), 623–627. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/5037600Find this resource:

Hutchinson, M. R., Shavit, Y., Grace, P. M., Rice, K. C., Maier, S. F., & Watkins, L. R. (2011). Exploring the neuroimmunopharmacology of opioids: An integrative review of mechanisms of central immune signaling and their implications for opioid analgesia. Pharmacological Reviews, 63(3), 772–810. doi:10.1124/pr.110.004135Find this resource:

Imam, M. Z., Kuo, A., Ghassabian, S., & Smith, M. T. (2017). Progress in understanding mechanisms of opioid-induced gastrointestinal adverse effects and respiratory depression. Neuropharmacology, 131, 238–255. doi:10.1016/j.neuropharm.2017.12.032Find this resource:

Issberner, U., Reeh, P. W., & Steen, K. H. (1996). Pain due to tissue acidosis: A mechanism for inflammatory and ischemic myalgia? Neuroscience Letters, 208(3), 191–194. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8733302Find this resource:

Jacobus, W. E., Taylor, G. J. t., Hollis, D. P., & Nunnally, R. L. (1977). Phosphorus nuclear magnetic resonance of perfused working rat hearts. Nature, 265(5596), 756–758. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/16217Find this resource:

Jamshidi, R. J., Jacobs, B. A., Sullivan, L. C., Chavera, T. A., Saylor, R. M., Prisinzano, T. E., … Berg, K. A. (2015). Functional selectivity of kappa opioid receptor agonists in peripheral sensory neurons. Journal of Pharmacology & Experimental Therapeutics, 355(2), 174–182. doi:10.1124/jpet.115.225896Find this resource:

Javelot, H., Messaoudi, M., Garnier, S., & Rougeot, C. (2010). Human opiorphin is a naturally occurring antidepressant acting selectively on enkephalin-dependent delta-opioid pathways. Journal of Physiology & Pharmacology, 61(3), 355–362. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/20610867Find this resource:

Jebens, E. H., & Monk-Jones, M. E. (1959). On the viscosity and pH of synovial fluid and the pH of blood. Journal of Bone & Joint Surgery (British), 41-B(2), 388–400. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/13641329Find this resource:

Kager, I., Mousa, S. A., Sieper, J., Stein, C., Pipam, W., & Likar, R. (2011). Blockade of intra-articular adrenergic receptors increases analgesic demands for pain relief after knee surgery. Rheumatology International, 31(10), 1299–1306. doi:10.1007/s00296-010-1489-zFind this resource:

Kieffer, B. L. (2016). Drug discovery: Designing the ideal opioid. Nature, 537(7619), 170–171. doi:10.1038/nature19424Find this resource:

Kieffer, B. L., & Gaveriaux-Ruff, C. (2002). Exploring the opioid system by gene knockout. Progress in Neurobiology, 66(5), 285–306. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/12015197Find this resource:

Klinck, M. P., Mogil, J. S., Moreau, M., Lascelles, B. D. X., Flecknell, P. A., Poitte, T., & Troncy, E. (2017). Translational pain assessment: Could natural animal models be the missing link? Pain, 158(9), 1633–1646. doi:10.1097/j.pain.0000000000000978Find this resource:

Koblish, M., Carr, R., 3rd, Siuda, E. R., Rominger, D. H., Gowen-MacDonald, W., Cowan, C. L., … Lark, M. W. (2017). TRV0109101, a G protein-biased agonist of the micro-opioid receptor, does not promote opioid-induced mechanical allodynia following chronic administration. Journal of Pharmacology & Experimental Therapeutics, 362(2), 254–262. doi:10.1124/jpet.117.241117Find this resource:

Koldajew, B., & Altschuler, M. (1930). Zur Frage über die aktive Reaktion der Exsudate bei chronischen und akuten Entzündungen. Zeitschrift für Immunitätsforschung, 69, 18–24.Find this resource:

Kringel, D., Ultsch, A., Zimmermann, M., Jansen, J. P., Ilias, W., Freynhagen, R., … Lötsch, J. (2017). Emergent biomarker derived from next-generation sequencing to identify pain patients requiring uncommonly high opioid doses. Pharmacogenomics Journal, 17, 419–426. doi:10.1038/tpj.2016.28Find this resource:

Kruegel, A. C., Gassaway, M. M., Kapoor, A., Varadi, A., Majumdar, S., Filizola, M., … Sames, D. (2016). Synthetic and receptor signaling explorations of the mitragyna alkaloids: Mitragynine as an atypical molecular framework for opioid receptor modulators. Journal of the American Chemical Society, 138(21), 6754–6764. doi:10.1021/jacs.6b00360Find this resource:

Labuz, D., Celik, M. O., Zimmer, A., & Machelska, H. (2016). Distinct roles of exogenous opioid agonists and endogenous opioid peptides in the peripheral control of neuropathy-triggered heat pain. Scientific Reports, 6, 32799. doi:10.1038/srep32799Find this resource:

Labuz, D., Mousa, S. A., Schäfer, M., Stein, C., & Machelska, H. (2007). Relative contribution of peripheral versus central opioid receptors to anti-nociception. Brain Research, 1160, 30–38. Retrieved from http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17599812Find this resource:

Labuz, D., Schmidt, Y., Schreiter, A., Rittner, H. L., Mousa, S. A., & Machelska, H. (2009). Immune cell-derived opioids protect against neuropathic pain in mice. Journal of Clinical Investigation, 119(2), 278–286. doi:36246 [pii] 10.1172/JCI36246Find this resource:

Lagard, C., Chevillard, L., Guillemyn, K., Risede, P., Laplanche, J. L., Spetea, M., … Megarbane, B. (2017). Bifunctional peptide-based opioid agonist/nociceptin antagonist ligand for dual treatment of nociceptive and neuropathic pain. Pain, 158(3), 505–515. doi:10.1097/j.pain.0000000000000790Find this resource:

Lamusuo, S., Hirvonen, J., Lindholm, P., Martikainen, I. K., Hagelberg, N., Parkkola, R., … Jaaskelainen, S. K. (2017). Neurotransmitters behind pain relief with transcranial magnetic stimulation—positron emission tomography evidence for release of endogenous opioids. European Journal of Pain, 21(9), 1505–1515. doi:10.1002/ejp.1052Find this resource:

Langford, R. M., Knaggs, R., Farquhar-Smith, P., & Dickenson, A. H. (2016). Is tapentadol different from classical opioids? A review of the evidence. British Journal of Pain, 10(4), 217–221. doi:10.1177/2049463716657363Find this resource:

Larsson, M. H., Bayati, A., Lindstrom, E., & Larsson, H. (2008). Involvement of kappa-opioid receptors in visceral nociception in mice. Neurogastroenterology & Motility, 20(10), 1157–1164. doi:10.1111/j.1365-2982.2008.01161.xFind this resource:

Law, P. Y., Reggio, P. H., & Loh, H. H. (2013). Opioid receptors: Toward separation of analgesic from undesirable effects. Trends in Biochemical Sciences, 38(6), 275–282. doi:10.1016/j.tibs.2013.03.003Find this resource:

Le Naour, M., Lunzer, M. M., Powers, M. D., Kalyuzhny, A. E., Benneyworth, M. A., Thomas, M. J., & Portoghese, P. S. (2014). Putative kappa opioid heteromers as targets for developing analgesics free of adverse effects. Journal of Medicinal Chemistry, 57(15), 6383–6392. doi:10.1021/jm500159dFind this resource:

Leadley, R. M., Armstrong, N., Lee, Y. C., Allen, A., & Kleijnen, J. (2012). Chronic diseases in the European Union: The prevalence and health cost implications of chronic pain. Journal of Pain & Palliative Care Pharmacotherapy, 26(4), 310–325. doi:10.3109/15360288.2012.736933Find this resource:

Lee, M. C., Wanigasekera, V., & Tracey, I. (2012). Imaging opioid analgesia in the human brain. Trends in Anaesthesiology & Critical Care, 2, 244–248.Find this resource:

Legrain, V., Iannetti, G. D., Plaghki, L., & Mouraux, A. (2011). The pain matrix reloaded: A salience detection system for the body. Progress in Neurobiology, 93(1), 111–124. doi:10.1016/j.pneurobio.2010.10.005Find this resource:

Levine, N., & Kelly, H. (1978). Measurement of pH in the rat epididymis in vivo. Journal of Reproductive Fertility, 52(2), 333–335. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/24738Find this resource:

Likar, R., Mousa, S. A., Steinkellner, H., Koppert, W., Philippitsch, G., Stein, C., & Schäfer, M. (2007). Involvement of intraarticular corticotropin-releasing hormone in postoperative pain modulation. Clinical Journal of Pain, 23(2), 136–142. Retrieved from http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17237662Find this resource:

Livingston, K. E., & Traynor, J. R. (2017). Allostery at opioid receptors: Modulation with small molecule ligands. British Journal of Pharmacology. doi:10.1111/bph.13823Find this resource:

Loeser, J. D., & Treede, R. D. (2008). The Kyoto protocol of IASP basic pain terminology. Pain, 137(3), 473–477. Retrieved from http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18583048Find this resource:

Machelska, H. (2011). Dual peripheral actions of immune cells in neuropathic pain. Archivum Immunologiae et Therapiae Experimentalis, 59(1), 11–24. doi:10.1007/s00005-010-0106-xFind this resource:

Madariaga-Mazon, A., Marmolejo-Valencia, A. F., Li, Y., Toll, L., Houghten, R. A., & Martinez-Mayorga, K. (2017). Mu-opioid receptor biased ligands: A safer and painless discovery of analgesics? Drug Discovery Today, 22(11), 1719–1729. doi:10.1016/j.drudis.2017.07.002Find this resource:

Madasu, M. K., Roche, M., & Finn, D. P. (2015). Supraspinal transient receptor potential subfamily V member 1 (TRPV1) in pain and psychiatric disorders. Modern Trends in Pharmacopsychiatry, 30, 80–93. doi:10.1159/000435934Find this resource:

Maddila, S. C., Busch-Dienstfertig, M., & Stein, C. (2017). B lymphocytes express POMC mRNA, processing enzymes and beta-endorphin in painful inflammation. Journal of Neuroimmune Pharmacology, 12(1), 180–186. doi:10.1007/s11481-016-9715-4Find this resource:

Maillet, E. L., Milon, N., Heghinian, M. D., Fishback, J., Schurer, S. C., Garamszegi, N., & Mash, D. C. (2015). Noribogaine is a G-protein biased kappa-opioid receptor agonist. Neuropharmacology, 99, 675–688. doi:10.1016/j.neuropharm.2015.08.032Find this resource:

Manglik, A., Kruse, A. C., Kobilka, T. S., Thian, F. S., Mathiesen, J. M., Sunahara, R. K., … Granier, S. (2012). Crystal structure of the mu-opioid receptor bound to a morphinan antagonist. Nature, 485(7398), 321–326. doi:http://www.nature.com/nature/journal/v485/n7398/abs/nature10954.html#supplementary-informationFind this resource:

Manglik, A., Lin, H., Aryal, D. K., McCorvy, J. D., Dengler, D., Corder, G., … Shoichet, B. K. (2016). Structure-based discovery of opioid analgesics with reduced side effects. Nature, 537(7619), 185–190. doi:10.1038/nature19112Find this resource:

Mansikka, H., Zhao, C., Sheth, R. N., Sora, I., Uhl, G., & Raja, S. N. (2004). Nerve injury induces a tonic bilateral mu-opioid receptor-mediated inhibitory effect on mechanical allodynia in mice. Anesthesiology, 100(4), 912–921. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/15087627Find this resource:

Mansikka, H., Zhou, L., Donovan, D. M., Pertovaara, A., & Raja, S. N. (2002). The role of mu-opioid receptors in inflammatory hyperalgesia and alpha 2-adrenoceptor-mediated antihyperalgesia. Neuroscience, 113(2), 339–349. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/12127091Find this resource:

Martins, D., Tavares, I., & Morgado, C. (2014). “Hotheaded”: The role of TRPV1 in brain functions. Neuropharmacology, 85, 151–157. doi:10.1016/j.neuropharm.2014.05.034Find this resource:

Massotte, D. (2015). In vivo opioid receptor heteromerization: Where do we stand? British Journal of Pharmacology, 172(2), 420–434. doi:10.1111/bph.12702Find this resource:

Matic, M., de Wildt, S. N., Tibboel, D., & van Schaik, R. H. N. (2017). Analgesia and opioids: A pharmacogenetics shortlist for implementation in clinical practice. Clinical Chemistry, 63(7), 1204–1213. doi:10.1373/clinchem.2016.264986Find this resource:

Mauermann, E., Filitz, J., Dolder, P., Rentsch, K. M., Bandschapp, O., & Ruppen, W. (2016). Does fentanyl lead to opioid-induced hyperalgesia in healthy volunteers? A double-blind, randomized, crossover trial. Anesthesiology, 124(2), 453–463. doi:10.1097/ALN.0000000000000976Find this resource:

McNicol, E. (2008). Opioid side effects and their treatment in patients with chronic cancer and noncancer pain. Journal of Pain & Palliative Care Pharmacotherapy, 22(4), 270–281. doi:10.1080/15360280802537225Find this resource:

Mechling, A. E., Arefin, T., Lee, H. L., Bienert, T., Reisert, M., Ben Hamida, S., … Harsan, L. A. (2016). Deletion of the mu opioid receptor gene in mice reshapes the reward-aversion connectome. Proceedings of the National Academy of Sciences USA, 113(41), 11603–11608. doi:10.1073/pnas.1601640113Find this resource:

Melik Parsadaniantz, S., Rivat, C., Rostene, W., & Reaux-Le Goazigo, A. (2015). Opioid and chemokine receptor crosstalk: A promising target for pain therapy? Nature Reviews Neuroscience, 16(2), 69–78. doi:10.1038/nrn3858Find this resource:

Menkin, V. (1934). Studies on Inflammation: X. The cytological picture of an inflammatory exudate in relation to its hydrogen ion concentration. American Journal of Pathology, 10(2), 193–210. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/19970136Find this resource:

Menkin, V. (1956). The role of hydrogen ion concentration and the cytology of an exudate. In C. C. Thomas (Ed.), Biochemical Mechanisms in Inflammation (pp. 66–103). Springfield, IL: Charles C. Thomas Publisher Ltd.Find this resource:

Menkin, V., & Warner, C. R. (1937). Studies on inflammation: XIII. Carbohydrate metabolism, local acidosis, and the cytological picture in inflammation. American Journal of Pathology, 13(1), 25–44 21. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/19970311Find this resource:

Mennini, N., Mura, P., Nativi, C., Richichi, B., Di Cesare Mannelli, L., & Ghelardini, C. (2015). Injectable liposomal formulations of opiorphin as a new therapeutic strategy in pain management. Future Science OA, 1(3), FSO2. doi:10.4155/fso.14.3Find this resource:

Meyer, K. A., Kammerling, E. M., et al. (1948). pH studies of malignant tissues in human beings. Cancer Research, 8(11), 513–518. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/18114935Find this resource:

Minett, M. S., Pereira, V., Sikandar, S., Matsuyama, A., Lolignier, S., Kanellopoulos, A. H., … Wood, J. N. (2015). Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7. Nature Communications, 6, 8967. doi:10.1038/ncomms9967Find this resource:

Mogil, J. S., Davis, K. D., & Derbyshire, S. W. (2010). The necessity of animal models in pain research. Pain, 151(1), 12–17. doi:10.1016/j.pain.2010.07.015Find this resource:

Mollica, A., Carotenuto, A., Novellino, E., Limatola, A., Costante, R., Pinnen, F., … Hruby, V. J. (2014). Novel cyclic biphalin analogue with improved anti-nociceptive properties. ACS Medicinal Chemistry Letters, 5(9), 1032–1036. doi:10.1021/ml500241nFind this resource:

Mousa, S. A., Cheppudira, B. P., Shaqura, M., Fischer, O., Hofmann, J., Hellweg, R., & Schafer, M. (2007). Nerve growth factor governs the enhanced ability of opioids to suppress inflammatory pain. Brain, 130(Pt 2), 502–513. Retrieved from http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17142830Find this resource:

Mousa, S. A., Shakibaei, M., Sitte, N., Schäfer, M., & Stein, C. (2004). Subcellular pathways of beta-endorphin synthesis, processing, and release from immunocytes in inflammatory pain. Endocrinology, 145(3), 1331–1341.Find this resource:

Mousa, S. A., Straub, R. H., Schäfer, M., & Stein, C. (2007). Beta-endorphin, met-enkephalin and corresponding opioid receptors within synovium of patients with joint trauma, osteoarthritis and rheumatoid arthritis. Annals of the Rheumatic Diseases, 66(7), 871–879. Retrieved from http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17324971Find this resource:

Mura, E., Govoni, S., Racchi, M., Carossa, V., Ranzani, G. N., Allegri, M., & van Schaik, R. H. (2013). Consequences of the 118A>G polymorphism in the OPRM1 gene: Translation from bench to bedside? Journal of Pain Research, 6, 331–353. doi:10.2147/JPR.S42040Find this resource:

Nadal, X., Banos, J. E., Kieffer, B. L., & Maldonado, R. (2006). Neuropathic pain is enhanced in delta-opioid receptor knockout mice. European Journal of Neuroscience, 23(3), 830–834. doi:10.1111/j.1460-9568.2006.04569.xFind this resource:

Newell, K., Franchi, A., Pouyssegur, J., & Tannock, I. (1993). Studies with glycolysis-deficient cells suggest that production of lactic acid is not the only cause of tumor acidity. Proceedings of the National Academy of Sciences USA, 90(3), 1127–1131. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8430084Find this resource:

Noble, F., & Cox, B. M. (1995). Differential regulation of D1 dopamine receptor- and of A2a adenosine receptor-stimulated adenylyl cyclase by mu-, delta 1-, and delta 2-opioid agonists in rat caudate putamen. Journal of Neurochemistry, 65(1), 125–133. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7790855Find this resource:

Noble, F., & Cox, B. M. (1996). Differences among mouse strains in the regulation by mu, delta 1 and delta 2 opioid receptors of striatal adenylyl cyclases activated by dopamine D1 or adenosine A2a receptors. Brain Research, 716(1–2), 107–117. doi:10.1016/0006-8993(96)00005-4Find this resource:

Noble, M., Treadwell, J. R., Tregear, S. J., Coates, V. H., Wiffen, P. J., Akafomo, C., & Schoelles, K. M. (2010). Long-term opioid management for chronic noncancer pain. Cochrane Database of Systematic Reviews (1), CD006605. doi:10.1002/14651858.CD006605.pub2Find this resource:

Nockemann, D., Rouault, M., Labuz, D., Hublitz, P., McKnelly, K., Reis, F. C., … Heppenstall, P. A. (2013). The K channel GIRK2 is both necessary and sufficient for peripheral opioid-mediated analgesia. EMBO Molecular Medicine, 5(8), 1263–1277. doi:10.1002/emmm.201201980Find this resource:

Nozaki, C., Le Bourdonnec, B., Reiss, D., Windh, R. T., Little, P. J., Dolle, R. E., … Gaveriaux-Ruff, C. (2012). Delta-opioid mechanisms for ADL5747 and ADL5859 effects in mice: Analgesia, locomotion, and receptor internalization. Journal of Pharmacology & Experimental Therapeutics, 342(3), 799–807. doi:10.1124/jpet.111.188987Find this resource:

Nozaki, C., Nagase, H., Nemoto, T., Matifas, A., Kieffer, B. L., & Gaveriaux-Ruff, C. (2014). In vivo properties of KNT-127, a novel delta opioid receptor agonist: Receptor internalization, antihyperalgesia and antidepressant effects in mice. British Journal of Pharmacology, 171(23), 5376–5386. doi:10.1111/bph.12852Find this resource:

Ojugo, A. S., McSheehy, P. M., McIntyre, D. J., McCoy, C., Stubbs, M., Leach, M. O., … Griffiths, J. R. (1999). Measurement of the extracellular pH of solid tumours in mice by magnetic resonance spectroscopy: A comparison of exogenous (19)F and (31)P probes. NMR in Biomedicine, 12(8), 495–504. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10668042Find this resource:

Olson, K. M., Lei, W., Keresztes, A., LaVigne, J., & Streicher, J. M. (2017). Novel molecular strategies and targets for opioid drug discovery for the treatment of chronic pain. Yale Journal of Biology & Medicine, 90(1), 97–110. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28356897Find this resource:

Pampus, F. (1963). [Hydrogen-ion concentration of brain tissue in space-occupying intracranial processes]. Acta Neurochirurgica (Wien), 11, 305–318. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/14059253Find this resource:

Pan, J. W., Hamm, J. R., Rothman, D. L., & Shulman, R. G. (1988). Intracellular pH in human skeletal muscle by 1H NMR. Proceedings of the National Academy of Sciences USA, 85(21), 7836–7839. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3186694Find this resource:

Pannell, M., Labuz, D., Celik, M. O., Keye, J., Batra, A., Siegmund, B., & Machelska, H. (2016). Adoptive transfer of M2 macrophages reduces neuropathic pain via opioid peptides. Journal of Neuroinflammation, 13(1), 262. doi:10.1186/s12974-016-0735-zFind this resource:

Pasternak, G. W., & Pan, Y. X. (2013). Mu opioids and their receptors: Evolution of a concept. Pharmacological Reviews, 65(4), 1257–1317. doi:10.1124/pr.112.007138Find this resource:

Peppin, J. F., & Raffa, R. B. (2015). Delta opioid agonists: A concise update on potential therapeutic applications. Journal of Clinical Pharmacy & Therapeutics, 40(2), 155–166. doi:10.1111/jcpt.12244Find this resource:

Piomelli, D., & Sasso, O. (2014). Peripheral gating of pain signals by endogenous lipid mediators. Nature Neuroscience, 17(2), 164–174. doi:10.1038/nn.3612Find this resource:

Popik, P., Kamysz, E., Kreczko, J., & Wrobel, M. (2010). Human opiorphin: The lack of physiological dependence, tolerance to anti-nociceptive effects and abuse liability in laboratory mice. Behavioural Brain Research, 213(1), 88–93. doi:10.1016/j.bbr.2010.04.045Find this resource:

Poras, H., Bonnard, E., Fournie-Zaluski, M. C., & Roques, B. P. (2015). Modulation of disulfide dual ENKephalinase inhibitors (DENKIs) activity by a transient N-protection for pain alleviation by oral route. European Journal of Medicinal Chemistry, 102, 58–67. doi:10.1016/j.ejmech.2015.07.027Find this resource:

Pradhan, A. A., Befort, K., Nozaki, C., Gaveriaux-Ruff, C., & Kieffer, B. L. (2011). The delta opioid receptor: An evolving target for the treatment of brain disorders. Trends in Pharmacological Sciences, 32(10), 581–590. doi:10.1016/j.tips.2011.06.008Find this resource:

Pradhan, A. A., Perroy, J., Walwyn, W. M., Smith, M. L., Vicente-Sanchez, A., Segura, L., … Evans, C. J. (2016). Agonist-specific recruitment of arrestin isoforms differentially modify delta opioid receptor function. Journal of Neuroscience, 36(12), 3541–3551. doi:10.1523/JNEUROSCI.4124-15.2016Find this resource:

Pradhan, A. A., Smith, M. L., Kieffer, B. L., & Evans, C. J. (2012). Ligand-directed signalling within the opioid receptor family. British Journal of Pharmacology, 167(5), 960–969. doi:10.1111/j.1476-5381.2012.02075.xFind this resource:

Prezzavento, O., Arena, E., Sanchez-Fernandez, C., Turnaturi, R., Parenti, C., Marrazzo, A., … Cobos, E. J. (2017). (+)-and (–)-Phenazocine enantiomers: Evaluation of their dual opioid agonist/sigma1 antagonist properties and anti-nociceptive effects. European Journal of Medicinal Chemistry, 125, 603–610. doi:10.1016/j.ejmech.2016.09.077Find this resource:

Psaty, B. M., & Merrill, J. O. (2017). Addressing the opioid epidemic—Opportunities in the postmarketing setting. New England Journal of Medicine, 376(16), 1502–1504. doi:10.1056/NEJMp1614972Find this resource:

Punnia-Moorthy, A. (1987). Evaluation of pH changes in inflammation of the subcutaneous air pouch lining in the rat, induced by carrageenan, dextran and Staphylococcus aureus. Journal of Oral Pathology, 16(1), 36–44. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2435877Find this resource:

Quallo, T., Alkhatib, O., Gentry, C., Andersson, D. A., & Bevan, S. (2017). G protein betagamma subunits inhibit TRPM3 ion channels in sensory neurons. Elife, 6. doi:10.7554/eLife.26138Find this resource:

Raehal, K. M., Schmid, C. L., Groer, C. E., & Bohn, L. M. (2011). Functional selectivity at the mu-opioid receptor: Implications for understanding opioid analgesia and tolerance. Pharmacological Reviews, 63(4), 1001–1019. doi:10.1124/pr.111.004598Find this resource:

Ranjan, R., Pandey, S., & Shukla, A. K. (2017). Biased opioid receptor ligands: Gain without pain. Trends in Endocrinology & Metabolism, 28(4), 247–249. doi:10.1016/j.tem.2017.01.001Find this resource:

Rasenick, M. M., & Childers, S. R. (1989). Modification of Gs-stimulated adenylate cyclase in brain membranes by low pH pretreatment: Correlation with altered guanine nucleotide exchange. Journal of Neurochemistry, 53, 219–225.Find this resource:

Reinecke, H., Weber, C., Lange, K., Simon, M., Stein, C., & Sorgatz, H. (2015). Analgesic efficacy of opioids in chronic pain: Recent meta-analyses. British Journal of Pharmacology, 172(2), 324–333. doi:10.1111/bph.12634Find this resource:

Reiss, D., Ceredig, R. A., Secher, T., Boue, J., Barreau, F., Dietrich, G., & Gaveriaux-Ruff, C. (2017). Mu and delta opioid receptor knockout mice show increased colonic sensitivity. European Journal of Pain, 21(4), 623–634. doi:10.1002/ejp.965Find this resource:

Revici, E., Stoopen, E., Frenk, E., & Ravich, R. A. (1949). The relation of pain to local physico-chemical changes. Bulletin of the Institute of Applied Biology, 1, 21–38.Find this resource:

Richards, N., & McMahon, S. B. (2013). Targeting novel peripheral mediators for the treatment of chronic pain. British Journal of Anaesthesiology, 111(1), 46–51. doi:10.1093/bja/aet216Find this resource:

Rittner, H. L., Hackel, D., Voigt, P., Mousa, S., Stolz, A., Labuz, D., … Brack, A. (2009). Mycobacteria attenuate nociceptive responses by formyl peptide receptor triggered opioid peptide release from neutrophils. PLoS Pathogens, 5(4), e1000362. doi:10.1371/journal.ppat.1000362Find this resource:

Rivat, C., & Ballantyne, J. (2016). The dark side of opioids in pain management: Basic science explains clinical observation. Pain Reports, 1, e570.Find this resource:

Roberts, N. J., Vogelstein, J. T., Parmigiani, G., Kinzler, K. W., Vogelstein, B., & Velculescu, V. E. (2012). The predictive capacity of personal genome sequencing. Science Translational Medicine, 4(133), 133ra158. doi:10.1126/scitranslmed.3003380Find this resource:

Roeckel, L. A., Le Coz, G. M., Gaveriaux-Ruff, C., & Simonin, F. (2016). Opioid-induced hyperalgesia: Cellular and molecular mechanisms. Neuroscience, 338, 160–182. doi:10.1016/j.neuroscience.2016.06.029Find this resource:

Roeckel, L.-A., Utard, V., Reiss, D., Mouheiche, J., Maurin, H., Robé, A., Audouard, E., Wood, J. N., Goumon, Y., Simonin, F., & Gaveriaux-Ruff, C. (2017). Morphine-induced hyperalgesia involves mu opioid receptors and the metabolite morphine-3-glucuronide. Scientific Reports, 7(1), 10406.Find this resource:

Roques, B. P., Fournie-Zaluski, M. C., & Wurm, M. (2012). Inhibiting the breakdown of endogenous opioids and cannabinoids to alleviate pain. Nature Reviews. Drug Discovery, 11(4), 292–310. doi:10.1038/nrd3673Find this resource:

Ross, J. R., Riley, J., Quigley, C., & Welsh, K. I. (2006). Clinical pharmacology and pharmacotherapy of opioid switching in cancer patients. The Oncologist, 11(7), 765–773. doi:10.1634/theoncologist.11-7-765Find this resource:

Rougeot, C., Robert, F., Menz, L., Bisson, J. F., & Messaoudi, M. (2010). Systemically active human opiorphin is a potent yet non-addictive analgesic without drug tolerance effects. Journal of Physiology & Pharmacology, 61(4), 483–490. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/20814077Find this resource:

Rowan, M. P., Szteyn, K., Doyle, A. P., Gomez, R., Henry, M. A., & Jeske, N. A. (2014). Beta-arrestin-2-biased agonism of delta opioid receptors sensitizes transient receptor potential vanilloid type 1 (TRPV1) in primary sensory neurons. Molecular Pain, 10, 50. doi:10.1186/1744-8069-10-50Find this resource:

Rozen, D., & Grass, G. W. (2005). Perioperative and intraoperative pain and anesthetic care of the chronic pain and cancer pain patient receiving chronic opioid therapy. Pain Practice: The Official Journal of the World Institute of Pain, 5(1), 18–32. doi:10.1111/j.1533-2500.2005.05104.xFind this resource:

Ruscheweyh, R., Wilder-Smith, O., Drdla, R., Liu, X. G., & Sandkuhler, J. (2011). Long-term potentiation in spinal nociceptive pathways as a novel target for pain therapy. Molecular Pain, 7, 20. doi:10.1186/1744-8069-7-20Find this resource:

Sasaki, K., Sumiyoshi, A., Nonaka, H., Kasahara, Y., Ikeda, K., Hall, F. S., … Sora, I. (2015). Specific regions display altered grey matter volume in mu-opioid receptor knockout mice: MRI voxel-based morphometry. British Journal of Pharmacology, 172(2), 654–667. doi:10.1111/bph.12807Find this resource:

Schepers, R. J., Mahoney, J. L., Gehrke, B. J., & Shippenberg, T. S. (2008). Endogenous kappa-opioid receptor systems inhibit hyperalgesia associated with localized peripheral inflammation. Pain, 138(2), 423–439. doi:10.1016/j.pain.2008.01.023Find this resource:

Schneider, J. P., & Kirsh, K. L. (2010). Defining clinical issues around tolerance, hyperalgesia, and addiction: A quantitative and qualitative outcome study of long-term opioid dosing in a chronic pain practice. Journal of Opioid Management, 6(6), 385–395. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21268999Find this resource:

Schreiter, A., Gore, C., Labuz, D., Fournie-Zaluski, M. C., Roques, B. P., Stein, C., & Machelska, H. (2012). Pain inhibition by blocking leukocytic and neuronal opioid peptidases in peripheral inflamed tissue. FASEB Journal, 26(12), 5161–5171.Find this resource:

Schrepf, A., Harper, D. E., Harte, S. E., Wang, H., Ichesco, E., Hampson, J. P., … Harris, R. E. (2016). Endogenous opioidergic dysregulation of pain in fibromyalgia: A PET and fMRI study. Pain, 157(10), 2217–2225. doi:10.1097/j.pain.0000000000000633Find this resource:

Schuchat, A., Houry, D., & Guy, G. P., Jr. (2017). New data on opioid use and prescribing in the United States. Journal of the American Medical Association, 318(5), 425–426. doi:10.1001/jama.2017.8913Find this resource:

Schumacher, M. A., Basbaum, A. I., & Naidu, R. K. (2015). Opioid agonists and antagonists. In B. G. Katzung & A. J. Trevor (Eds.), Basic and Clinical Pharmacology (13th ed., pp. 531–551). New York: McGraw-Hill Medical.Find this resource:

Selley, D. E., Breivogel, C. S., & Childers, S. R. (1993). Modification of G protein-coupled functions by low-pH pretreatment of membranes from NG108-15 cells: Increase in opioid agonist efficacy by decreased inactivation of G proteins. Molecular Pharmacology, 44(4), 731–741. Retrieved from http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8232223Find this resource:

Sharp, B. M. (2006). Multiple opioid receptors on immune cells modulate intracellular signaling. Brain, Behavior, & Immunity, 20(1), 9–14. Retrieved from http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16364815Find this resource:

Silver, I. A. (1975). Measurement of pH and ionic composition of pericellular sites. Philosophical Transactions of the Royal Society of London, B. Biological Sciences, 271(912), 261–272. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/239420Find this resource:

Simmen, H. P., & Blaser, J. (1993). Analysis of pH and pO2 in abscesses, peritoneal fluid, and drainage fluid in the presence or absence of bacterial infection during and after abdominal surgery. American Journal of Surgery, 166(1), 24–27. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/8328625Find this resource:

Simonin, F., Valverde, O., Smadja, C., Slowe, S., Kitchen, I., Dierich, A., … Kieffer, B. L. (1998). Disruption of the kappa-opioid receptor gene in mice enhances sensitivity to chemical visceral pain, impairs pharmacological actions of the selective kappa-agonist U-50,488H and attenuates morphine withdrawal. EMBO Journal, 17(4), 886–897. doi:10.1093/emboj/17.4.886Find this resource:

Sirohi, S., Aldrich, J. V., & Walker, B. M. (2016). Species differences in the effects of the kappa-opioid receptor antagonist zyklophin. Alcohol, 51, 43–49. doi:10.1016/j.alcohol.2015.11.012Find this resource:

Sitbon, P., Van Elstraete, A., Hamdi, L., Juarez-Perez, V., Mazoit, J. X., Benhamou, D., & Rougeot, C. (2016). STR-324, a stable analog of opiorphin, causes analgesia in postoperative pain by activating endogenous opioid receptor-dependent pathways. Anesthesiology, 125(5), 1017–1029. doi:10.1097/ALN.0000000000001320Find this resource:

Sitte, N., Busch, M., Mousa, S. A., Labuz, D., Rittner, H., Gore, C., … Schäfer, M. (2007). Lymphocytes upregulate signal sequence-encoding proopiomelanocortin mRNA and beta-endorphin during painful inflammation in vivo. Journal of Neuroimmunology, 183(1–2), 133–145. Retrieved from http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17223201Find this resource:

Smith, M. L., Hostetler, C. M., Heinricher, M. M., & Ryabinin, A. E. (2016). Social transfer of pain in mice. Science Advances, 2(10), e1600855. doi:10.1126/sciadv.1600855Find this resource:

Smith, S. M., Dart, R. C., Katz, N. P., Paillard, F., Adams, E. H., Comer, S. D., … Dworkin, R. H.; Analgesic, Anesthetic, and Addiction Clinical Trials, Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership. (2013). Classification and definition of misuse, abuse, and related events in clinical trials: ACTTION systematic review and recommendations. Pain, 154(11), 2287–2296. doi:10.1016/j.pain.2013.05.053Find this resource:

Smith, S. M., Dworkin, R. H., Turk, D. C., Baron, R., Polydefkis, M., Tracey, I., … Witter, J. (2017). The potential role of sensory testing, skin biopsy, and functional brain imaging as biomarkers in chronic pain clinical trials: IMMPACT considerations. Journal of Pain, 18(7), 757–777. doi:10.1016/j.jpain.2017.02.429Find this resource:

Soergel, D. G., Subach, R. A., Burnham, N., Lark, M. W., James, I. E., Sadler, B. M., … Webster, L. R. (2014). Biased agonism of the mu-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: A randomized, double-blind, placebo-controlled, crossover study in healthy volunteers. Pain, 155(9), 1829–1835. doi:10.1016/j.pain.2014.06.011Find this resource:

Sounier, R., Mas, C., Steyaert, J., Laeremans, T., Manglik, A., Huang, W., … Granier, S. (2015). Propagation of conformational changes during mu-opioid receptor activation. Nature, 524(7565), 375–378. doi:10.1038/nature14680Find this resource:

Spahn, V., Del Vecchio, G., Labuz, D., Rodriguez-Gaztelumendi, A., Massaly, N., Temp, J., … Stein, C. (2017). A nontoxic pain killer designed by modeling of pathological receptor conformations. Science, 355(6328), 966–969. doi:10.1126/science.aai8636Find this resource:

Spahn, V., Fischer, O., Endres-Becker, J., Schäfer, M., Stein, C., & Zöllner, C. (2013). Opioid withdrawal increases transient receptor potential vanilloid 1 activity in a protein kinase A-dependent manner. Pain, 154 (4), 598–608. doi:10.1016/j.pain.2012.12.026Find this resource:

Spahn, V., & Stein, C. (2017). Targeting delta opioid receptors for pain treatment: Drugs in phase I and II clinical development. Expert Opinion on Investigational Drugs, 26(2), 155–160. doi:10.1080/13543784.2017.1275562Find this resource:

Spetea, M., Eans, S. O., Ganno, M. L., Lantero, A., Mairegger, M., Toll, L., … McLaughlin, J. P. (2017). Selective kappa receptor partial agonist HS666 produces potent anti-nociception without inducing aversion after i.c.v. administration in mice. British Journal of Pharmacology, 174(15), 2444–2456. doi:10.1111/bph.13854Find this resource:

Starnowska, J., Costante, R., Guillemyn, K., Popiolek-Barczyk, K., Chung, N. N., Lemieux, C., … Przewlocka, B. (2017). Analgesic properties of opioid/NK1 multitarget ligands with distinct in vitro profiles in naïve and chronic constriction injury mice. ACS Chemical Neuroscience, 8(10), 2315–2324. doi:10.1021/acschemneuro.7b00226Find this resource:

Stein, C. (1993). Peripheral mechanisms of opioid analgesia. Anesthesia & Analgesia, 76, 182–191.Find this resource:

Stein, C. (1995). The control of pain in peripheral tissue by opioids. New England Journal of Medicine, 332(25), 1685–1690. Retrieved from http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7760870Find this resource:

Stein, C. (1997). Opioid treatment of chronic nonmalignant pain. Anesthesia & Analgesia, 84(4), 912–914.Find this resource:

Stein, C. (2013a). Opioids, sensory systems and chronic pain. European Journal of Pharmacology, 716, 179–187. doi:10.1016/j.ejphar.2013.01.076Find this resource:

Stein, C. (2013b). Towards safer and more effective analgesia. Veterinary Journal, 196(1), 6–7. doi:10.1016/j.tvjl.2012.09.013Find this resource:

Stein, C. (2016). Opioid Receptors. Annual Review of Medicine, 67, 433–451. doi:10.1146/annurev-med-062613-093100Find this resource:

Stein, C. (2018). Pain. In J.-M. Cavaillon & M. Singer (Eds.), Inflammation: From Molecular and Cellular Mechanisms to the Clinic (pp. 891–914). Weinheim, Germany: Wiley-VCH.Find this resource:

Stein, C., Comisel, K., Haimerl, E., Yassouridis, A., Lehrberger, K., Herz, A., & Peter, K. (1991). Analgesic effect of intraarticular morphine after arthroscopic knee surgery. New England Journal of Medicine, 325(16), 1123–1126. Retrieved from http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1653901Find this resource:

Stein, C., Hassan, A. H., Przewlocki, R., Gramsch, C., Peter, K., & Herz, A. (1990). Opioids from immunocytes interact with receptors on sensory nerves to inhibit nociception in inflammation. Proceedings of the National Academy of Sciences USA, 87(15), 5935–5939. Retrieved from http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1974052Find this resource:

Stein, C., Hassan, A. H. S., Lehrberger, K., Giefing, J., & Yassouridis, A. (1993). Local analgesic effect of endogenous opioid peptides. Lancet, 342, 321–324.Find this resource:

Stein, C., & Kopf, A. (2015). Anesthesia and treatment of chronic pain. In R. D. Miller (Ed.), Miller’s Anesthesia, 8th Edition (Vol. 8, pp. 1898–1918). Philadelphia, PA: Elsevier Saunders.Find this resource:

Stein, C., & Küchler, S. (2013). Targeting inflammation and wound healing by opioids. Trends in Pharmacological Sciences, 34(6), 303–312. doi:10.1016/j.tips.2013.03.006Find this resource:

Stein, C., & Machelska, H. (2011). Modulation of peripheral sensory neurons by the immune system: Implications for pain therapy. Pharmacological Reviews, 63, 860–881.Find this resource:

Stein, C., Pflüger, M., Yassouridis, A., Hoelzl, J., Lehrberger, K., Welte, C., & Hassan, A. H. (1996). No tolerance to peripheral morphine analgesia in presence of opioid expression in inflamed synovia. Journal of Clinical Investigation, 98(3), 793–799. doi:10.1172/JCI118852Find this resource:

Stevens, C. W. (2015). Bioinformatics and evolution of vertebrate nociceptin and opioid receptors. Vitamins & Hormones, 97, 57–94. doi:10.1016/bs.vh.2014.10.002Find this resource:

Stubbs, M., McSheehy, P. M., & Griffiths, J. R. (1999). Causes and consequences of acidic pH in tumors: A magnetic resonance study. Advances in Enzyme Regulation, 39, 13–30. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10470364Find this resource:

Szigethy, E., Knisely, M., & Drossman, D. (2017). Opioid misuse in gastroenterology and non-opioid management of abdominal pain. Nature Reviews Gastroenterology & Hepatology, 15(3), 168–180. doi:10.1038/nrgastro.2017.141Find this resource:

Treuhaft, P. S., & McCarty, D. J. (1971). Synovial fluid pH, lactate, oxygen and carbon dioxide partial pressure in various joint diseases. Arthritis & Rheumatism, 14(4), 475–484. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/5564921Find this resource:

Tulamo, R. M., Bramlage, L. R., & Gabel, A. A. (1989). Sequential clinical and synovial fluid changes associated with acute infectious arthritis in the horse. Equine Veterinary Journal, 21(5), 325–331. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2776718Find this resource:

Turnaturi, R., Arico, G., Ronsisvalle, G., Parenti, C., & Pasquinucci, L. (2016). Multitarget opioid ligands in pain relief: New players in an old game. European Journal of Medicinal Chemistry, 108, 211–228. doi:10.1016/j.ejmech.2015.11.028Find this resource:

Tzschentke, T. M., Linz, K., Frosch, S., & Christoph, T. (2017). Antihyperalgesic, antiallodynic, and anti-nociceptive effects of cebranopadol, a novel potent nociceptin/orphanin FQ and opioid receptor agonist, after peripheral and central administration in rodent models of neuropathic pain. Pain Practice: The Official Journal of the World Institute of Pain, 17(8), 1032–1041. doi:10.1111/papr.12558Find this resource:

Vadivelu, N., Mitra, S., & Hines, R. L. (2011). Peripheral opioid receptor agonists for analgesia: A comprehensive review. Journal of Opioid Management, 7(1), 55–68. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21434585Find this resource:

Valdez-Morales, E., Guerrero-Alba, R., Ochoa-Cortes, F., Benson, J., Spreadbury, I., Hurlbut, D., … Vanner, S. (2013). Release of endogenous opioids during a chronic IBD model suppresses the excitability of colonic DRG neurons. Neurogastroenterology & Motility, 25(1), 39–46, e34. doi:10.1111/nmo.12008Find this resource:

Valverde, A., & Gunkel, C. I. (2005). Pain management in horses and farm animals. Journal of Veterinary Emergency & Critical Care, 15(4), 295–307.Find this resource:

Varadi, A., Marrone, G. F., Palmer, T. C., Narayan, A., Szabo, M. R., Le Rouzic, V., … Majumdar, S. (2016). Mitragynine/corynantheidine pseudoindoxyls as opioid analgesics with mu agonism and delta antagonism, which do not recruit beta-arrestin-2. Journal of Medicinal Chemistry, 59(18), 8381–8397. doi:10.1021/acs.jmedchem.6b00748Find this resource:

Vardy, E., Sassano, M. F., Rennekamp, A. J., Kroeze, W. K., Mosier, P. D., Westkaemper, R. B., … Roth, B. L. (2015). Single amino acid variation underlies species-specific sensitivity to amphibian skin-derived opioid-like peptides. Chemistry & Biology, 22(6), 764–775. doi:10.1016/j.chembiol.2015.05.012Find this resource:

Vaupel, P. W., Frinak, S., & Bicher, H. I. (1981). Heterogeneous oxygen partial pressure and pH distribution in C3H mouse mammary adenocarcinoma. Cancer Research, 41(5), 2008–2013. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7214369Find this resource:

Vicente-Sanchez, A., & Pradhan, A. A. (2018). Ligand-directed signaling at the delta opioid receptor. Handbook of Experimental Pharmacology, in press. doi:10.1007/164_2017_39Find this resource:

Violin, J. D., Crombie, A. L., Soergel, D. G., & Lark, M. W. (2014). Biased ligands at G-protein-coupled receptors: Promise and progress. Trends in Pharmacological Sciences, 35(7), 308–316. doi:10.1016/j.tips.2014.04.007Find this resource:

Viscusi, E. R., Webster, L., Kuss, M., Daniels, S., Bolognese, J. A., Zuckerman, S., … Skobieranda, F. (2016). A randomized, phase 2 study investigating TRV130, a biased ligand of the mu-opioid receptor, for the intravenous treatment of acute pain. Pain, 157(1), 264–272. doi:10.1097/j.pain.0000000000000363Find this resource:

Voegtlin, C. (1935). The influence of the parenteral administration of certain sugars on the pH of malignant tumors. National Institutes of Health Bulletin, 164, 1–14.Find this resource:

Wacker, D., Stevens, R. C., & Roth, B. L. (2017). How ligands illuminate GPCR molecular pharmacology. Cell, 170(3), 414–427. doi:10.1016/j.cell.2017.07.009Find this resource:

Walter, C., Doehring, A., Oertel, B. G., & Lötsch, J. (2013). Mu-opioid receptor gene variant OPRM1 118 A>G: A summary of its molecular and clinical consequences for pain. Pharmacogenomics, 14(15), 1915–1925. doi:10.2217/pgs.13.187Find this resource:

Walwyn, W. M., Chen, W., Kim, H., Minasyan, A., Ennes, H. S., McRoberts, J. A., & Marvizon, J. C. (2016). Sustained suppression of hyperalgesia during latent sensitization by mu-, delta-, and kappa-opioid receptors and alpha2A adrenergic receptors: Role of constitutive activity. Journal of Neuroscience, 36(1), 204–221. doi:10.1523/JNEUROSCI.1751-15.2016Find this resource:

Wang, Y. X., Mao, X. F., Li, T. F., Gong, N., & Zhang, M. Z. (2017). Dezocine exhibits antihypersensitivity activities in neuropathy through spinal mu-opioid receptor activation and norepinephrine reuptake inhibition. Scientific Reports, 7, 43137. doi:10.1038/srep43137Find this resource:

Wasserman, R. A., Hassett, A. L., Harte, S. E., Goesling, J., Malinoff, H. L., Berland, D. W., … Brummett, C. M. (2015). Pressure pain sensitivity in patients with suspected opioid-induced hyperalgesia. Regional Anesthesia & Pain Medicine, 40(6), 687–693. doi:10.1097/AAP.0000000000000315Find this resource:

Wei, L. N., & Loh, H. H. (2011). Transcriptional and epigenetic regulation of opioid receptor genes: Present and future. Annual Review of Pharmacology & Toxicology, 51, 75–97. doi:10.1146/annurev-pharmtox-010510-100605Find this resource:

Weibel, R., Reiss, D., Karchewski, L., Gardon, O., Matifas, A., Filliol, D., … Gaveriaux-Ruff, C. (2013). Mu opioid receptors on primary afferent nav1.8 neurons contribute to opiate-induced analgesia: Insight from conditional knockout mice. PLoS ONE, 8(9), e74706. doi:10.1371/journal.pone.0074706Find this resource:

White, K. L., Robinson, J. E., Zhu, H., DiBerto, J. F., Polepally, P. R., Zjawiony, J. K., … Roth, B. L. (2015). The G protein-biased kappa-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo. Journal of Pharmacology & Experimental Therapeutics, 352(1), 98–109. doi:10.1124/jpet.114.216820Find this resource:

Williams, J. T., Ingram, S. L., Henderson, G., Chavkin, C., von Zastrow, M., Schulz, S., … Christie, M. J. (2013). Regulation of mu-opioid receptors: Desensitization, phosphorylation, internalization, and tolerance. Pharmacological Reviews, 65(1), 223–254. doi:10.1124/pr.112.005942Find this resource:

Wisner, A., Dufour, E., Messaoudi, M., Nejdi, A., Marcel, A., Ungeheuer, M. N., & Rougeot, C. (2006). Human opiorphin, a natural anti-nociceptive modulator of opioid-dependent pathways. Proceedings of the National Academy of Sciences USA, 103(47), 17979–17984. doi:10.1073/pnas.0605865103Find this resource:

Woo, Y. C., Park, S. S., Subieta, A. R., & Brennan, T. J. (2004). Changes in tissue pH and temperature after incision indicate acidosis may contribute to postoperative pain. Anesthesiology, 101(2), 468–475. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/15277931Find this resource:

Wu, H., Wacker, D., Mileni, M., Katritch, V., Han, G. W., Vardy, E., … Stevens, R. C. (2012). Structure of the human kappa-opioid receptor in complex with JDTic. Nature, 485(7398), 327–332. doi:10.1038/nature10939Find this resource:

Xu, M., Petraschka, M., McLaughlin, J. P., Westenbroek, R. E., Caron, M. G., Lefkowitz, R. J., … Chavkin, C. (2004). Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance. Journal of Neuroscience, 24(19), 4576–4584. doi:10.1523/JNEUROSCI.5552-03.2004Find this resource:

Yadlapalli, J. S., Ford, B. M., Ketkar, A., Wan, A., Penthala, N. R., Eoff, R. L., … Crooks, P. A. (2016). Antinociceptive effects of the 6-O-sulfate ester of morphine in normal and diabetic rats: Comparative role of mu- and delta-opioid receptors. Pharmacology Research, 113(Pt A), 335–347. doi:10.1016/j.phrs.2016.09.012Find this resource:

Yaksh, T. L., Woller, S. A., Ramachandran, R., & Sorkin, L. S. (2015). The search for novel analgesics: Targets and mechanisms. F1000Prime Reports, 7, 56. doi:10.12703/P7-56Find this resource:

Yekkirala, A. S., Roberson, D. P., Bean, B. P., & Woolf, C. J. (2017). Breaking barriers to novel analgesic drug development. Nature Reviews Drug Discovery, 16(8), 545–564. doi:10.1038/nrd.2017.87Find this resource:

Yen, L. T., Hsieh, C. L., Hsu, H. C., & Lin, Y. W. (2017). Targeting ASIC3 for relieving mice fibromyalgia pain: Roles of electroacupuncture, opioid, and adenosine. Scientific Reports, 7, 46663. doi:10.1038/srep46663Find this resource:

Yi, S. P., Kong, Q. H., Li, Y. L., Pan, C. L., Yu, J., Cui, B. Q., … Chang, K. J. (2017). The opioid receptor triple agonist DPI-125 produces analgesia with less respiratory depression and reduced abuse liability. Acta Pharmacologica Sinica, 38(7), 977–989. doi:10.1038/aps.2017.14Find this resource:

Zeng, C., Gao, S. G., Cheng, L., Luo, W., Li, Y. S., Tu, M., … Lei, G. H. (2013). Single-dose intra-articular morphine after arthroscopic knee surgery: A meta-analysis of randomized placebo-controlled studies. Arthroscopy, 29(8), 1450–1458, e1452. doi:10.1016/j.arthro.2013.04.005Find this resource:

Zheng, Z., Huang, X. P., Mangano, T. J., Zou, R., Chen, X., Zaidi, S. A., … Katritch, V. (2017). Structure-based discovery of new antagonist and biased agonist chemotypes for the kappa opioid receptor. Journal of Medicinal Chemistry, 60(7), 3070–3081. doi:10.1021/acs.jmedchem.7b00109Find this resource:

Zöllner, C., Mousa, S. A., Fischer, O., Rittner, H. L., Shaqura, M., Brack, A., … Schafer, M. (2008). Chronic morphine use does not induce peripheral tolerance in a rat model of inflammatory pain. Journal of Clinical Investigation, 118(3), 1065–1073. doi:10.1172/JCI25911Find this resource:

Zöllner, C., Shaqura, M. A., Bopaiah, C. P., Mousa, S. A., Stein, C., & Schäfer, M. (2003). Painful inflammation-induced increase in mu-opioid receptor binding and G-protein coupling in primary afferent neurons. Molecular Pharmacology, 64(2), 202–210.Find this resource: