What is Known and Objective

Pain is broadly defined by the International Association for the Study of Pain (IASP), as ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage’.1 Pain is highly individualized and multifactorial. There are multiple ‘types’ of pain that can be categorized in several ways: in terms of pathways, ‘nociceptive pain’ results when non‐neural tissues are damaged and primary afferent fibres (mostly Aδ and C) are activated, and ‘neuropathic pain’ results when there is a primary lesion or disease or dysfunction of the peripheral or central nervous system;1 in terms of duration, ‘acute pain’ persists only during the time of tissue damage, whereas ‘chronic pain’ persists beyond the normal physiological healing time (commonly defined as lasting more than three months); in terms of location, ‘somatic’ pain emanates from injuries to skin, muscles, bone, joint, or connective tissues and ‘visceral’ pain results from the activation of nociceptors of the thoracic, pelvic or abdominal organs; and in a variety of other ways (e.g., migraine, fibromyalgia, sickle cell, etc.). It is estimated that about 100 million Americans and a similar percentage of adults worldwide (depending on age and country) suffer from persistent pain.2, 3 But pain treatments are often inadequate and new approaches are sought.4

Pain, if not adequately treated, can have a significant negative impact on quality of life, such as disruption of sleep, mood and functional capacity. These can lead to anxiety, depression and other mental health issues.5, 6 For example, a World Health Organization (WHO) study reported a 4‐fold increase in the prevalence of psychological disorders in people who suffer from persistent pain.7 The economic impact of pain, which is estimated at more than $600 billion annually, exceeds the economic burden exacted by major diseases (e.g., cardiovascular, cancer, endocrine, metabolic, GI or respiratory),8 and the problem is expected to get even worse with the ageing of the population.9

Despite the multimodal (patho)physiological nature of pain and the multiplicity of pain types, there are relatively limited pharmacologic classes of analgesics available to treat pain. The most commonly used for management of nociceptive pain are the non‐steroidal anti‐inflammatory drugs (NSAIDs), acetaminophen (paracetamol) and opioids. NSAIDs and acetaminophen are effective in treating mild‐to‐moderate pain. Opioids are the more effective for treating severe pain. NSAID‐induced analgesic activity results from the inhibition of cyclooxygenase (COX) isozymes (COX‐1 and COX‐2),10, 11 but unfortunately their use is associated with the occurrence of serious adverse effects (e.g., gastrointestinal bleeding, platelet function alteration, and cardiovascular system and organ damage).12 Although the mechanism of action of acetaminophen‐induced analgesic activity is not fully understood, it likely involves actions on the central nervous system (and an interaction between brain and spinal cord).13 Acetaminophen has less overall side effects than NSAIDs, but it causes severe liver damage when taken in excess or when combined with alcohol or other hepatically metabolized drugs or OTC preparations.14 Opioid‐induced analgesic activity is mediated through the activation of three major 7‐transmembrane GPCR (G protein‐coupled receptor) types: mu (Mu opioid receptor [MOR], MOP, OPRM1), delta (DOR, DOP, OPRD1) and kappa (KOR, KOP, OPRK1),15 but they are associated with treatment‐limiting adverse effects and abuse potential.16, 17

Currently, most opioid analgesics used in clinical practice target mu‐opioid receptors. Opioids have high clinical efficacy and also improve mood, but they cause constipation, sedation, respiratory depression at high doses, and have the potential for abuse. Centrally acting kappa‐opioid receptor agonists inhibit pain, but they are associated with limiting side effects, such as sedation, dysphoric effects and increased urine output.18 Activation of peripheral kappa‐opioid receptors produces analgesia with reduced central nervous system side effects.19-24 This approach has been suggested to offer the same pain relief as traditional centrally acting opioids, while mitigating their major adverse effects and abuse potential.24, 25

Opioid receptors Opioid receptors are seven‐transmembrane spanning G protein‐coupled receptors.26 They are located and extensively distributed throughout the brain, spinal cord and the periphery.22, 27, 28 They are also expressed on autonomic nervous system neurons and on immune cells.29 Opioid receptor signalling cascades are initiated through transduction via pertussis toxin‐sensitive G‐protein subunits (e.g., G i 1, G i 2, G i 3, G o 1, G o 2) and pertussis toxin‐insensitive subunits (e.g., G z and G 16 ).30 Signal transduction involves the activation of inwardly rectifying potassium ion (K+) channels (K ir ) on post‐synaptic pain‐pathway neurons and inhibition of voltage‐dependent calcium (Ca2+) channels on presynaptic neurons in these pathways.30, 31 Changes in K+ and Ca2+ concentrations lead to neuronal hyperpolarization, decreased neuronal excitability and inhibition of neurotransmitter release (due to inhibition of Ca2+‐dependent vesicular migration and emptying).26, 30, 31 G protein‐coupled signalling events that are transduced through secondary messenger pathways ultimately lead to inhibition of pain transmission as well as other opioid receptor‐mediated physiologic effects (e.g., constipation, sedation, respiratory depression and ‘liking’).15, 32 The KOR in the enteric nervous system is mediated via a subset of these pathways (Fig. 1).26 Figure 1 Open in figure viewer PowerPoint Signal transduction of agonist activation of 7‐transmembrane G protein‐coupled receptors (subunits α, β, γ). The highlighted pathway is thought to be more prominent in the enteric nervous system. Opioid receptors are part of an extensive endogenous opioid system. They are activated by endogenous opioid peptides, including the endorphins and Met‐ and Leu‐enkephalin (Tyr‐Gly‐Gly‐Phe‐Met and Tyr‐Gly‐Gly‐Phe‐Leu, respectively).33 Dynorphin A (Tyr‐Gly‐Gly‐Phe‐Leu‐Arg‐Arg‐Ile‐Arg‐Pro‐Lys‐Leu‐Lys) and dynorphin B (rimorphin) (Tyr‐Gly‐Gly‐Phe‐Leu‐Arg‐Arg‐Gln‐Phe‐Lys‐Val‐Val‐Thr) are endogenous opioid peptides associated with kappa‐opioid receptors.34, 35 The endogenous opioid peptides function as hormones or neuromodulators to regulate a large variety of physiological processes.33 To date, three major types of opioid receptors have been identified, designated mu (μ, MOR, MOP), delta (δ, DOR, DOP) and kappa (κ, KOR, KOP), as have subtypes of each of the major types.15 An additional, opioid‐like receptor designated ORL‐1 (NOP) has been identified.36 ORL1 (OPRL1) was proposed to be a novel member of the opioid family based on its sequence homology with the opioid receptors,36, 37 but ORL1 is different from typical opioid receptors in that it has low binding affinity for classical opioid agonists and antagonists. The endogenous ligand for ORL1 is the heptadecapeptide (17 amino acid) nociception (orphanin FQ). ORL1 mediates both antinociceptive (spinally) and pro‐nociceptive (supraspinally) effects.38-40 Opioid analgesics show varying affinity for MOR, DOR and KOR, with usually negligible affinity for ORL1 (Table 1).33-36, 41-44 Table 1. Mammalian opioid receptors and their endogenous peptides Opioid receptor Symbols Chromosome Endogenous peptide(s) Tissue expression Opioid receptor Mu‐1 μ OPRM1 MOR 6q25.2 β‐endorphins Superior cervical ganglion brain MOR1 Enkephalins Skeletal muscle Endomorphin‐1 Testis Endomorphin‐2 Opioid receptor kappa‐1 κ OPRK1 KOR 8q11.23 Dynorphin A/B Brain KOR1 α‐neoendorphin Ovary β‐neoendorphin Thyroid Intestine Brain (cerebellum) Opioid receptor delta‐1 δ OPRD1 DOR‐1 1p35.3 Enkephalins Pancreas β‐endorphins Ovary Opiate receptor‐like‐1 OPRL1 20q13.33 Nociception/Orphanin FQ Spinal cord ORL1 Neural tube KOR3 Retina NOCIR Brain Mu opioid receptor has been the most extensively studied and targeted opioid receptor type for drug discovery. MORs mediate analgesia and reward; MOR communicates with central dopaminergic reward pathways and multiple other neurotransmitter systems that are involved in euphoria, reward, and physical and psychological dependence.15 Consequently, MOR agonists are the most widely used opioids for pain, as well as the ones that are most misused and abused.

Kappa‐opioid receptors Kappa‐opioid receptors are encoded by a single gene, OPRK1, which is located on human chromosome 8q11·2.45 KORs, similar to MORs, are widely expressed throughout the brain, spinal cord and the periphery.46, 47 More than 1300 human OPRK1 single‐nucleotide polymorphisms (SNPs) are recorded in the National Center for Biotechnology Information (NCBI) database,48 which translates into wide genetic variation among the population. OPRK1 polymorphisms (but not OPRM or OPRD polymorphisms) alter pain sensitivity to muscle pressure and heat.49 For example, OPRK1 rs7016778 A allele (genotype AA/AT) is associated with higher muscle pressure pain threshold than is wild genotype TT and rs7824175 C allele (genotype CC/CG) is associated with lower pain threshold than is wild type (genotype GG). Those with OPRK1 rs643799C allele (genotype CC/CT) have lower thermal pain threshold than wild type (genotype TT).49 However, OPRK1 SNPs accounted for only 34–43% of the variability in the measured mechanical and thermal pain thresholds. Interestingly, sensitivity to visceral pain was unaffected by polymorphisms in other opioid receptor genes.49 Thus, polymorphisms in OPRK1 expression may play a role in pain threshold and vulnerability to certain types of pain, but not others. Compared with brain‐accessible agonists, the analgesic effects of peripherally restricted agonists are not accompanied by sedative effect, respiratory depression or abuse potential. However, when KOR agonists penetrate the brain, they cause hallucination, dysphoric effects and aversion.50-53 Second‐messenger studies suggest that the dysphoric effects of KOR agonists involve G protein‐coupled recruitment of β‐arrestin and activation of p38 MAPK (mitogen‐activated protein kinase), whereas the analgesic effect is independent of such downstream signalling.54 The CNS‐mediated side effects of KOR agonists have seriously limited their clinical development; but newer peripherally restricted KOR agonists have prompted renewed attention.55 Studies examining peripherally restricted KOR agonists have demonstrated dose‐dependent reduction in both visceral and somatic pain, without the undesirable CNS side effects.56

Mechanisms of peripheral KOR‐induced analgesia Kappa‐opioid receptor agonists can produce analgesia by at least two mechanisms: (i) a direct inhibitory effect on neuronal transport of pain signalling and (ii) an indirect anti‐inflammatory action.57 The first mechanism is a well‐known action of opioids that is summarized and depicted in Fig. 2.15 The second mechanism is a more indirect opioid action that recruits other systems.58-60 Damage to tissues results in the release not only of ions and chemicals that produce or amplify signals related to pain (e.g., H+, K+, histamine, kinins, prostaglandins, etc.), but also of proinflammatory substances (which contribute to healing processes) such as leukotrienes, cytokines, interleukins and many others. Inflammation in the periphery results in an increase in leucocyte‐derived opioids that then bind to and activate local opioid receptors.29, 61 Inflammation in peripheral tissues also signals the CNS to increase the synthesis of opioid receptors in the dorsal root ganglion (DRG) and expedite their distribution centrally and peripherally.29, 62-64 Peripheral opioid analgesic mechanisms predominate over central mechanisms as the duration and severity of inflammation increases.65 Figure 2 Open in figure viewer PowerPoint KOR activation by opioid agonists inhibits presynaptic Ca2+ influx, which decreases the release of neurotransmitters, and enhances post‐synaptic K+ efflux, which hyperpolarizes the neuron. Kappa‐opioid receptor agonist activation of peripheral KORs blocks inflammatory pain by several mechanisms, including reducing the activity of inflammatory mediators at multiple points along the inflammation cascade.29, 51, 56, 65, 66 They decrease the expression of adhesion molecules, inhibit cell trafficking, slow the release and expression of tissue necrosis factor (TNF) and decrease the levels of substance P and calcitonin gene‐related peptide (CGRP) in joint tissue, mediators which have been strongly linked to inflammation and arthritis.29, 67 Selective KOR agonists, such as bremazocine and U‐50488H,68, 69 have long been known to produce peripheral antinociception in animal models of inflammation.51, 70, 71 These anti‐inflammatory effects are reversed by non‐selective inhibition of nitric oxide synthase (NOS), suggesting the involvement of NO pathways in the control of peripheral inflammation.51, 70, 71