A History of Pain Research
Abstract and Keywords
Useful analgesic plant products have been known since antiquity. In recent times, the cell and molecular basis of damage detection and its complex relationship to pain perception have been explored in detail. A range of technical advances have given us considerable new knowledge about both the peripheral aspects of pain pathways and damage transduction as well as central mechanisms of pain modulation. Electrophysiology, imaging, genetic manipulation of animal models of pain, the role of the immune system, and genetic studies of human pain states have all provided new information. Remarkably, despite these advances, we are still uncertain about the locus of pain perception, while the development of new small-molecule analgesic drugs has had almost no success. This chapter summarizes the history of pain research and discusses present activities together with potential future routes to pain treatment.
Pain, ignored when we are in good health, is a topic that concerns us all at some time in our lives. Its significance was highlighted by Aristotle, who observed that the aim of the wise is not to secure pleasure, but to avoid pain. Research into pain has ranged from perfecting methods of torture to studying the attenuation of pain through religious belief (Goldberg, 2007; Wiech et al., 2008). Table 1 summarizes milestones in the research into pain.
Is pain a specific sense, like vision or hearing or, rather, a feature of brain function with different properties and mechanisms compared with those of the classical senses (Perl, 1971)? This has been a central point of debate over centuries, beginning with the classical definition of the five senses by Aristotle (taste, sight, touch, smell, and hearing) (Cervero, 2012), who purposely left pain, and its opposite, pleasure, off the list. Aristotle thought that the two were “passions of the soul”—“emotions of the mind” we would say in more modern language—caused by appropriate or inappropriate excitation of the five senses. This Aristotelian concept has remained in force until today, in the form of the pattern theory of pain (Cervero, 2012), which claims that the pain experience is the result of patterns of impulses in various brain systems, a sort of pain matrix. Nonetheless, the realization by the great Muslim scholar Avicenna that pain is indeed a specific sense is unquestionably the mainstream view now (Abu-Asab, 2013).
The alternative to Aristotle’s view is best exemplified by the Cartesian view of pain (Descartes, 1664) as the result of an orderly and sequential activation of a specific pain pathway from the periphery to the brain. Descartes’s famous—and much maligned—drawing of a boy with one foot close to a fire and a line linking the injured toes with the center of the brain is the archetypical illustration of the specificity theory: Pain occurs “just like pulling the end of a chord a bell rings at the other end” (Descartes dixit) (Descartes, 1664, pp. 27, 28). This interpretation requires the existence of specific injury sensors in the periphery and a specific pain pathway in the brain (Perl, 1971).
How did we arrive at a pain system in humans? The simplest organisms are driven by the hunt for nutrients and the avoidance of damaging stimuli (see the chapter by Schafer and Neely, this volume). While reflex avoidance of tissue damage may not require the perception of pain, this evolutionary pressure has driven the development of the mammalian pain system. Given the fact that avoidance of tissue damage is a fundamental evolutionarily honed mechanism for survival, it is unsurprising that molecular insights into pain mechanisms demonstrate similarities across animal species and have provided clues to understanding human pain mechanisms. Tissue damage caused by pathogens has also been linked to activation of the immune system. We have been slow to link these two events mechanistically, but it is increasingly clear that immune mediators such as cytokines and tumor necrosis factor (TNF) involved in clearing pathogens and damaged tissue may also regulate sensory neuron activity and alter pain thresholds (Feldman et al., 1998; see the chapter by Hansen and Falk, this volume).
We know that pain protects us from external injuries and self-harm. However, the occurrence of pain unlinked to protective behavior is more problematic. As a sign of organ dysfunction, pain can be useful, indicating that something is wrong. But, the occurrence of pain, particularly chronic pain associated with old age and no obvious pathology that makes life intolerable for countless numbers of people, has no positive features, as Sherrington in later life observed (Eccles & Gibson, 1979, p. 91). Many surveys of pain in humans reached the same conclusion: that 6–7% of the population have debilitating intense pain on a regular basis (Nahin, 2015).
Table 1. Milestones in Pain Research
Opium has been actively collected since prehistoric times, since approximately 3400 bce.
The brain was recognized as the seat of sensation (by Alcmaeon, Democrites, Hippocrates, and Plato).
Nerves were described in detail with functional insights from vivisection (Herophilus).
Transection of the spinal cord and loss of function were described by Galen.
Arab scholars recognized pain as a specific sensation (Avicenna [Abu Ali Sina]).
Laudanum was introduced to Western medicine in 1527 (Philippus Aureolus Theophrastus Bombastus von Hohenheim, better known by the name Paracelsus).
Detailed nervous system anatomy was described by Vesalius, da Vinci, and others.
Descartes (1662) described pain as a linear circuit from the periphery to the brain and as triggering reflex movements.
Swimmerdam developed a frog nerve muscle preparation activated by mechanical stimuli.
Foundation of the Royal Society occurred.
Hooke published Micrographia.
Isaac Newton speculated on mechanisms of nerve function in Principia.
Willow bark extract was trialed by Edward Stone in the treatment of agues (fevers).
Fothergill described trigeminal neuralgia.
Galvani demonstrated electrical activation of nerve and muscle.
Sertuner isolated morphine and studied its actions.
Bell and Magendie described sensory and motor nerves.
Muller proposed specific sensory functions for different nerves (Muller’s law).
von Helmholtz measured the speed of nerve conduction.
Origin of Species was published by Darwin.
Bernstein developed the rheotome and characterized the action potential.
Blix and Goldschneider described modality-specific sensitive skin spots.
Ramon y Cajal showed that individual neurons comprised the nervous system.
Von Frey described pain-sensitive spots.
Hoffman developed aspirin.
Sherrington described the synapse and defined nociception.
Gasser characterized sensory neuron fiber subtypes.
Levi Montalcini isolated nerve growth factor.
Melzak and Wall’s gate control theory of dorsal horn pain regulation and description of windup by Mendell were presented.
Perl (and Iggo) established the existence of functionally specialized nociceptors.
Hughes and Kosterlitz discovered opioid peptides.
Kohler and Milstein developed monoclonal antibodies.
The first animal models of neuropathic pain were developed by Bennett.
Development of BOLD functional imaging was introduced by Ogawa.
Sauer developed the Cre lox-p system for conditional gene deletion.
Lentz demonstrated that electrical stimulation of the thalamus in awake humans caused pain.
Anti-TNF was introduced for treatment of rheumatoid arthritis by Feldman.
The human genome was sequenced.
Optogenetics was invented by Miesenboch.
DREADDs and chemogenetics were developed by Roth.
The opioid abuse pandemic lowers US life expectancy.
The history of pain research has been brilliantly surveyed by Ed Perl (2007, 2011). In antiquity when life expectancy was shorter, there was more focus on acute pain. The anatomists of Alexandria in the third century bc made remarkably prescient discoveries in terms of pain mechanisms. Almeon of Croton first recognized the cognitive role of the brain in the early fifth century bce, a view shared by Democritus, Hippocrates, and Plato. However, Herophilus was the first to describe, as a result of his anatomical studies, nerves in detail and to link the brain rather than the heart to consciousness (Heinrich, 1989). He understood the role of the spinal cord in linking the brain to peripheral nerves and described the existence of nerves that were involved in sensation and the control of movement. Apparently exploiting not only dissection but also, chillingly, human vivisection of criminals, his fame is rather less than that of Galen, who 400 years later extended these studies and achieved greater recognition. Galen severed the spinal cord of piglets and showed that responses to stimuli applied below the cut were abolished (Rey, 1993). These significant findings were lost to Western thought for a millennium after the collapse of the Roman Empire. However, in the heyday of Muslim culture around 1000 ad, Avicenna wrote a standard medical text that was translated and used throughout Europe (Abu-Asab, 2013). He extended knowledge about the nervous system as the seat of consciousness and, importantly, was the first to identify pain as a specific sensation (Perl, 2011).
Our present view of the pain system was formed during the Renaissance by many remarkable scholars who returned to the study of anatomy. However, it was not until the discoveries of Galvani and the debate with Volta about animal electricity that we began to gain detailed functional insights into how the nervous system may work (Verkhratsky, Krishtal, & Petersen, 2006). The initial preparation of frog muscle and nerve was described by Swimmerdam, who used mechanical stimulation to evoke muscle movements many years before the classic experiments of Galvani.
In 1803, Galvani’s nephew, Aldini, applied electric current to the corpse of a condemned murderer, causing an eye to open and his limbs to move. This event contributed to the ideas in Mary Shelley’s novel Frankenstein, written when fascination with Galvanism and the phenomenon of electricity was at its height (Shelley, 1818). Isaac Newton had earlier written at the end of his incomparable Principia; “Members of animal bodies move at the command of the will, namely by the vibration of this electric and elastic spirit mutually propagated along the solid filaments of the nerves, from the outward organs of sense to the brain and from the brain to the muscles(Newton 1688) . Electric was a term coined by Frances Bacon to describe the force that caused bodies like amber to move together (“amber” is electrum in Latin); it is striking to see this word used by Newton a century before the discovery of electricity. The experiments of Galvani and Aldini eventually provided an insight into the nature of Newton’s elastic and electric spirit, finally giving rise to electrophysiology—the focus of many present-day studies that attempt to understand the nervous system. A full history of the development of ideas in electrophysiology has been published (Verkhratsky et al., 2006).
The much more recent progress in identifying afferent and efferent nerves is usually associated with Charles Bell and Francois Magendie in the early nineteenth century (Bell, 1811). Although sensory and motor nerves had been discussed since the time of Herophilus, the clear demonstration of a motor function for ventral roots and an afferent role for dorsal roots relied on the studies of these two rivals. The next conceptual breakthrough came from Johannes Muller, who realized that sensory afferent nerves could have precise modality-specific functions (Muller, 1844). His law of specific nerve energies articulates the fact that nerves can be sensation specific, as in the case of the optic nerve, which when activated by mechanical pressure still produces a sensation of light. We can now interpret this finding in terms of specific transduction molecules and patterns of wiring termination within the central nervous system (CNS).
As we move into the later part of the nineteenth century, progress in many areas of neuroscience had implications for the study of pain. Ramon y Cajal’s stunning anatomical studies demonstrated that the nervous system comprised distinct cell types rather than a syncytium (Ramon y Cajal & Maloine, 1909). A return to the analysis of the consequences of CNS lesions pioneered by Galen led to the view that there were distinct labeled lines for different types of somatosensory information, including pain. In addition, evidence for the crossing of spinal sensory pathways to contralateral structures was obtained in animals by Schiff and in humans by Gowers (1878). By the beginning of the twentieth century, these concepts began to be applied in the clinic for the treatment of intractable pain by partial spinal cordotomy.
Human psychophysical studies in the late nineteenth century provided information about the properties of sensory afferents in the skin. By applying thin probes to human skin, Blix and Goldschneider independently discovered spots of sensitivity for touch, heat, and cold (Perl, 2011). These spots encompass the terminals of numerous sensory neurons. Fascinatingly, electrical stimulation of defined spots was later shown to evoke the same sensations, as predicted by the studies of Muller decades before. After some debate, pain spots were found to be the most common type by von Frey (Perl, 2011). Thus, evidence for pain-specific labeled lines and specificity theory was provided by these studies. Anatomical studies linking end organs like Ruffini endings with neurons suggested that there might be a specific end organ for pain, but eventually an association between free nerve endings and pain sensations was made. One can argue that the skin itself is a sensor in the pain system.
Histological studies demonstrated that the modality-specific spots were associated with tens rather than single afferent fiber terminals; this led to speculation about forms of information coding that might confer information, so-called pattern theories. Pattern theories postulate that trains of action potentials signaling particular sensations are decoded centrally to define sensation. This theory is not necessarily inconsistent with the association of individual fibers with particular types of somatosensation. However, interactions between pain and innocuous sensation had been highlighted by Gasser, who showed that pain could be inhibited by potentiated innocuous sensation; in other words, as many of us know well, rubbing a damaged area will diminish the pain (Gasser, 1944). Gasser and Erlangen gained the Nobel Prize for their characterization of peripheral sensory nerves based on action potential velocity into A-β, A-δ, and C-fibers. Even at this early stage, Gasser realized that damage-sensing responses occur in all three classes of nerve fiber.
Thus, by the mid-twentieth century, the concepts that are routine in present-day pain research had been established, such as the existence of peripheral nerves that signal tissue damage and are required for a sensation of pain.
Damage Detection: The Concept of the Nociceptor
Technical advances have often provided the insights that lead to paradigm shifts in understanding the nervous system. The development of electrical recording techniques enabled an analysis of nervous system function first at the level of nerves and then single neurons. Voltage- or calcium-sensitive dyes and genetically encoded calcium indicators have complemented electrical recordings (Sepehri Rad et al., 2017). As these techniques have developed, so our view of the mechanisms involved in somatosensation and pain has evolved.
As noted, human psychophysical studies led to the view that modality-specific spots for heat and cold sensation occur in skin. Initially, there was confusion about the existence of specific pain spots, but von Frey identified areas equivalent to the site of termination of many sensory neurons that responded to a range of painful stimuli (Perl 2011). Gasser (1944) characterized the conduction velocities of sensory nerves to provide us with the useful subdivision of A-β, A-δ, and C fibers that is related to fiber diameter. Recordings from multiple nerve fibers led to the most common association of pain with unmyelinated C fibers and A-δ fibers. A surprisingly recent finding came from the work of Perl, who provided incontrovertible evidence for the existence of specialized damage-sensing neurons, so-called nociceptors (Burgess & Perl, 1967). Perl recorded from many single units and demonstrated that there was no simple relationship between fiber diameter and sensory modality. For example, A-δ neurons could be activated by innocuous hair movements, while a subset was clearly activated only by tissue-damaging stimuli. Perl showed that noxious mechanoreceptors could be found in the A-δ population that were unresponsive to any other stimuli. He later identified neurons that were responsive to many damaging stimuli—the polymodal nociceptors—as well as neurons that were silent. These seminal articles have been collectively reviewed (Mason, 2007).
Pain: Specificity, Intensity, or Pattern? A Long-Lasting Debate
How is information encoded by nociceptors to evoke a sensation of pain in the brain? Three theories exist involving specific nociceptor-activated pain pathways, pain pathways that exploit sensory neurons that signal pain depending on the intensity of the stimulus, or pattern theories of complex information coding (Perl, 2011).
The fact that specificity and pattern interpretations have survived to our day—the very influential “gate control theory” of pain is another turn of the pattern theory (Melzack & Wall, 1965)—suggests that these ideas have elements of truth. It is now beyond doubt that there are specific injury detectors in the periphery (skin, muscle, viscera) (Belmonte & Cervero, 1996), and this supports a specificity arrangement of the sensors used by the brain to collect information. There are also neurons in the spinal cord and brain that process this injury-related information (Cervero, Iggo, & Ogawa, 1976; Christensen & Perl, 1970). But, this specificity arrangement works mainly—or only—for very acute and brief painful stimuli: a pinprick, a small burn, and the like. If we consider more intense and long-lasting injuries, inflammatory processes, or, even more, neurological diseases causing neuropathic pain, then the specificity interpretation is extremely insufficient (Cervero, 2012).
Long-lasting injuries, inflammation and neuropathic lesions trigger brain mechanisms that include nonspecific neuronal responses, including activation of brain areas concerned not only with sensation but also with emotional and cognitive responses (Tracey & Bushnell, 2009). The pain experience then becomes much more than a simple sensory process, and the implications of patterns of activity are more useful as tools to explain what is going on (Melzack, 1999).
One solution to the specificity pattern challenge is therefore to consider that there is not a single type of pain—and therefore one mechanism that can explain this one pain—but many pains, from very acute to chronic and from the normal defensive response of the individual to the complexities of neurological disease (Cervero & Laird, 1991). As such, we talk today of nociceptive, inflammatory, or neuropathic pains as distinct aspects of the pain experience, with different properties and produced by different mechanisms, ranging from a simple chain of events in very acute pain to a complex interaction of many systems in chronic and pathological pain (Cervero & Laird, 1991).
Polymodal and Modality-Specific Nociceptors
The strong electrophysiological evidence for polymodal nociceptors creates a potential anomaly. How can we distinguish different sorts of pain, for example, cold from heat or mechanical pain, if nociceptors are polymodal? Clues to answer this question have come from the application of live cell imaging in anesthetized animals that express the calcium indicator GCaMP in their sensory neurons. Such studies allow us to observe the remarkable plasticity of sensory neurons in live animals in real time (Emery, Luiz, Sikandar, et al., 2016). The levels of polymodality noted in the literature from electrophysiological studies are enormously variable, ranging from 11% (Fang, McMullan, Lawson, & Djouhri, 2005) to 90% (Baumann, Simone, Shain, & LaMotte, 1991).
A-δ fibers also include nociceptors that are polymodal (Djouhri & Lawson, 2004). What is the basis of this variability? There are three potential explanations. Extracellular recording from fibers, using for example microneurography, may sometimes provide information from more than one axon (Mano, Iwase, & Toma, 2006). Second, we now know that inflammation can convert modality specific nociceptors to polymodal nociceptors, as occurs in tissue culture and perhaps during tissue preparation during in vivo studies (Emery, Luiz, Sikandar, et al., 2016). Finally, the intensity of the stimulus can recruit nociceptors to respond to events to which they are normally unresponsive: Application of very intense painful stimuli of any description can cause an explosive release of chemical mediators from the skin that activate up to 100% of all nociceptors (Simone & Kajander, 1996). There is thus extensive plasticity and redundancy in the primary sensory neuron populations.
This complexity is very clearly demonstrated in the transduction of cold pain. Aversive cold at levels that do not cause massive tissue damage is detected by a set of specialized sensory neurons (around 20%) that express the transient receptor potential (TRP) channel TRPM8 (TRP melastatin 8), combined with a set of potassium channels implicated in cold sensing. The TRPM8+ neurons do not express the sodium channel Nav1.8 that is noted to be essential for cold behavior at subzero temperatures (Zimmermann et al., 2007). However, extreme cold evokes dramatic escape behavior in mice quite distinct from responses to less intense cold. Temperatures below zero degrees activate a larger population of neurons that contain sodium channel Nav1.8; eventually, at more extreme cold temperatures all nociceptive fibers and neurons are activated (Simone & Kajander, 1996). There is thus a graded response to cold, involving different sets of neurons and transduction mechanisms as the temperature falls and tissue damage occurs (Luiz et al., 2019).
Redundancy is also apparent in heat sensing. Noxious heat has recently been shown to be detected by three redundant receptors that contribute to nociceptor depolarization. TRP Melastatin 3 (TrpM3), TRP vanilloid 1 (TRPV1), and TRP Ankyrin 1 (TRPA1) are found within the TRPV1-expressing set of sensory neurons (Vandewauw et al., 2018). A role for calcium-activated calcium channels in cold sensing has also been described (Cho et al., 2012). Early claims that TRPV2 is a heat sensor have subsequently been disproved (Woodbury et al., 2004).
Mechanotransduction involves a range of potassium channels (Chemin et al., 2005), TRP channels (Quick et al., 2012), and the pre-eminent mechanosensors Piezo1 and Piezo2, both present in sensory neurons (Coste et al., 2012). Although innocuous sensation is dependent on Piezo2 (Ranade et al., 2014), allodynia in neuropathic pain is also Piezo2 dependent (Eijkelkamp et al., 2013). However, the slowly adapting mechanotransduction channel involved in mechanical pain is yet to be identified.
Redundancy and plasticity within peripheral sensory neurons help reconcile the apparently diverse data concerning polymodality in the literature. Many neurons are modality specific in conditions other than intense painful stimulation. However, this changes in inflamed states and in situations of extreme tissue damage. The relative surgical expertise of different investigators in inducing inflammatory-mediated increase in polymodality can help explain discrepancies in the literature. In addition, specificity theory and intensity theory can be reconciled, depending on the levels of tissue damage and evoked pain.
The coding issue for spinal cord relay neurons is also intriguing (Spiller, 1905). The activity in the superficial dorsal horn of the spinal cord retains modality specificity, as shown by Basbaum’s team (Zhang, Cavanaugh, Nemenov, & Basbaum, 2013). Destruction of TRPV1 heat-sensing neurons abolishes heat-activated neurons in laminae I and V of the dorsal horn without effect on noxious mechanosensation, while ablation of MrgPrd4 neurons reduces dorsal horn responses to graded mechanical stimuli with no effect on heat. Cold activation in the dorsal horn was unchanged in either model. Thus, peripheral modality-specific input is retained within the spinal cord. Even in the thalamus, modality-specific neurons have been detected. The evidence for labeled lines in the periphery and CNS is strong. Do polymodal nociceptors reinforce modality-specific pathways in some way, perhaps through action on neurons with a wide dynamic range (Willis & Coggeshall, 1991)? Their contribution remains uncertain.
Pain Sensitization: Central and Peripheral Mechanisms
The term sensitization is associated with a mixed array of definitions: a nonassociative learning process (psychology); the induction of an adaptive response of the immune system (immunology); the creation of galvanic corrosion cells in an alloy (metallurgy); reverse tolerance to a drug (pharmacology); and even the title of a song by Kylie Minogue. So, what does sensitization mean in the pain field?
The concept was first used by Perl (Burgess, Perl, & Iggo, 1973) to qualify the progressively increased response of nociceptors to repeated stimuli. These studies demonstrated that the sensitivity of peripheral nociceptors increases after an injury, thus giving a possible explanation for the hyperalgesia that appears at a site of injury (Campbell, Meyer, & LaMotte, 1979; Treede, Meyer, Raja, & Campbell, 1992). As such, the use of the word is in line with the psychology, immunology, and pharmacology definitions.
The molecular basis of peripheral nervous system hyperalgesia depends on the actions of a number of mediators, including cyclooxygenase (COX) products like prostaglandin E2 (PGE2) acting through G protein–coupled receptors (GPCRs) to activate adenylate cyclase and protein kinase A (PKA), as well as mediators like nerve growth factor (NGF) acting through tyrosine kinase receptors to potentiate mechanical hyperalgesia (Di Castro, Drew, Wood, & Cesare, 2006). Importantly, opioids have a clear role in effecting analgesia through actions on primary sensory neurons, acting through Gi-coupled GPCRs to lower cyclic adenosine monophosphate (cAMP) levels and enhance potassium channel activity (see the opioids and pain chapter, this volume). Thus, peripheral excitability is a key determinant of pain chronification. For example, the Ferreira group used PGE2 priming to induce long-term hyperactive excitability of peripheral nociceptors that depend on the activity of PKA and protein kinase C (PKC), and the sensory neuron–specific tetrodotoxin (TTX)–resistant channel Nav1.8 (Villarreal et al., 2009). This channel is known to be enhanced in its activity by phosphorylation on intracellular serine residues. Consistent with this, brain-derived neurotrophic factor (BDNF) release from primary sensory neurons can evoke long-term pain states in male mice (Sikandar et al., 2018) (see the chapter by Sikander and Sommer, this volume). There are other pain syndromes that rely on priming events, followed by repeated insults that evolve widespread alterations in pain that may be more plausibly explained by peripheral mechanisms involving the immune system (Irani & Vincent, 2016; see the chapter by Bennett, this volume). For now, the evidence that peripheral drive is a key element in driving reversible central changes in pain pathways seems good.
A much larger body of literature than that concerning peripheral mechanisms is the use of “sensitization” to qualify a central process whereby increased excitability develops in CNS nociceptive pathways following an injury, which in turn leads to pain hypersensitivity or even chronic pain conditions (Woolf, 1983). Whereas the concept of nociceptor sensitization is well supported by the literature (see Belmonte & Cervero, 1996) and its causal relationship with hyperalgesia at the site of injury (primary hyperalgesia) is well established (Treede et al., 1992), there is controversy about the functional significance of central sensitization and its role in chronic pain (Cervero, 2014; Sandkuhler, 2009).
The idea that pain hypersensitivity could be caused by enhanced CNS excitability was first found in the work of MacKenzie (1909) at the beginning of the twentieth century. McKenzie proposed that increased activity in pain afferents triggered by a peripheral injury would cause an “irritable focus” [sic] in the segments of the spinal cord that received such enhanced input. This focus of irritation would generate increased pain sensitivity as well as greater motor and autonomic reflexes driven by and linked to the originating injury. Several reports in the 1960s and 1970s showed increased excitability of spinal cord neurons following repeated noxious stimulation of the periphery (see Willis, 1985), including a frequency-dependent excitability increase of dorsal horn neurons caused by repeated C-fiber stimulation, known as “windup” (Mendell, 1966). This phenomenon was described some years before synaptic long-term potentiation (LTP) was discovered in 1973 (Bliss & Lomo, 1973).
The concept of central sensitization finally crystalized in the 1980s when Woolf (1983) described an increase in spinal reflexes following a period of noxious stimulation, extending the concept of peripheral sensitization to the CNS and suggesting a possible mechanism for pain hypersensitivity. However, a key question linked to the idea of central sensitization is to what extent such increases in excitability were dependent on sustained peripheral input (Baron, Hans, & Dickenson, 2013).
One interesting point, not often mentioned, is that the phenomenon of windup decreases if peripheral stimulation is maintained for more than 20 or 30 seconds (Schouenborg & Sjolund, 1983), which suggests exhaustion of the hyperexcitability process. Also, sensitization of neurons, which initially was reported to be independent of sustained peripheral input (McMahon & Wall, 1984; Wall & Woolf, 1984), was later shown to decrease or even disappear if the activation of the nociceptive input was not maintained (Cervero, 2000; Werner, Lassen, Pedersen, & Kehlet, 2002). Moreover, the process of central sensitization is a common property of many CNS systems, including the LTP linked to memory generation and other such synaptic excitability processes (Sandkuhler, 2000). The process known as central sensitization is not a unique property of the pain system, and, in any case, it is not sufficiently long lasting to generate a chronic hyperexcitable state.
There is also controversy about the relationship between central sensitization and pain hypersensitivity. Such a relationship has become a useful explanation for many chronic pain states (Cervero, 2014), particularly those where a peripheral input is unclear. The rationale is that chronic pain without an obvious peripheral cause must be due to a persistent state of central sensitization (Woolf, 2011). This is, of course, impossible to prove or disprove as we cannot obtain direct evidence linking pain perception with neuronal excitability in either experimental animals or patients. However, pharmacological evidence from studies of the actions of substance P suggests that such correlation may not be warranted (Hill, 2000). Many animal studies have shown that Substance P antagonists or genetic deletion of the receptor for substance P [Neurokinin-1 (NK1) receptor] reduce or abolish central sensitization as expressed by increased excitability of CNS nociceptive pathways and reflexes together with a loss of pain behavior in animal models. Yet, several clinical trials in a variety of acute and chronic pain conditions failed to demonstrate significant analgesic properties of NK1 receptor antagonists (Hill, 2000), calling into question the usefulness of animal models of central sensitization as predictors of analgesic activity in chronic pain.
Central sensitization is a useful shorthand to describe transient increases in excitability in the CNS following—and maintained by—excitation of peripheral nociceptors. This process may be necessary to start a chronic pain state, but it is not sufficient to maintain it.
It is surprising that relatively little is known about the central mechanism of hyperalgesia compared to the insights we have about peripheral mechanisms. Synaptic plasticity involving glutamate receptors in the spinal cord has been frequently invoked as a mechanism, although how contralateral pain arises is less certain. The time course of this event can be relatively rapid; for example, within an hour of capsaicin treatment to human volunteers, the result is a contralateral milder painful sensation (Enax-Krumova, Pohl, Westermann, & Maier, 2017). This must involve some CNS events to explain the precise localization of the pain on the opposite limb. Nonetheless, peripheral input does seem to be essential for chronic pain when even phantom limb pain and neuropathic pain can both be reversed by lidocaine applied to sensory neurons or ganglia (Haroutounian et al., 2014; Vaso et al., 2014).
Pain, Religion, and Society
Pain is an essential element of human life and has always occupied a central role in social traditions and behaviors. However, the specific framework of a society and its rules and beliefs are different between cultures, and although pain, as a societal factor, is present in them all, the influence on individual behaviors is also different.
Historically, Western societies have been influenced by the Judeo–Christian view of the world, based on the teachings of the Bible. In these societies, pain is interpreted as God’s punishment for Adam and Eve’s original sin and, as such, something unavoidable that must be endured. Women are singled out with the curse of childbirth pain: “In pain thou shalt bring forth children” (Cervero, 2012, p. 100), as a specific punishment for having induced Adam to eat from the forbidden fruit. It is very telling that we need to find an explanation for childbirth pain, in this case as God’s punishment, presumably because it does not make much sense that the process of perpetuating our species should be painful.
From this starting point, Western societies regard pain as a test of character, an inevitable aspect of our lives that will constantly remind us of our failures. Being a punishment, it is also proportional to the crime; hence, there is the feeling that diseases are more painful the more we have sinned. The whole interpretation of pain rests on feelings of guilt, punishment, retribution, and redemption, the very essence of Judeo–Christian tradition. There are many examples throughout the Bible of pain as a retribution for sin.
This link between religion and pain is more acutely visible among Christians, focused on the painful death of Christ, nailed to a cross, an instrument of torture that became the universal icon of the religion. The Catholic version of Christianity goes even further, with profuse illustrations and images in churches and books of the blood and torture of Christ and of other saints, often reenacted in ceremonies, such as processions and other acts where penitents inflict various forms of pain on themselves.
Pain in these societies not only is ever present and inevitable, but also, because it is God’s punishment, should not be avoided or relieved as this would go against His wish. In fact, because pain is the consequence of our sins, its endurance would bring our salvation, a process known as redemptive suffering (O’Malley, 1997). Hence, there was initial resistance to the introduction of anesthesia, especially for women in labor (Meyer, 2015), and more recently to euthanasia (see http://www.vatican.va/roman_curia/pontifical_academies/acdlife/documents/rc_pa_acdlife_doc_20001209_eutanasia_en.html). For Christians, only death and entering Heaven will relieve us of pain; our transit through life must be a journey across a vallis lacrimarum, a “vale of tears” (Psalm 84:6).
The Islamic tradition is somewhat similar, as it is also rooted in Judeo–Christian beliefs, though it has a few variations. Pain is not Allah’s punishment to humankind, as only good deeds can come from Him, but He tolerates the inevitable presence of pain and suffering on Earth and will reward the sufferer with a pain-free afterlife. Also, pain is often seen as necessary to protect us from injury and, as such, a good feature of our lives. The Islamic tradition places more emphasis on pain as a purification process than as a punishment, but, as with the Christian tradition, the eventual reward can only be obtained after death (Choong, 2015; Lovering, 2006).
There are, of course, many other cultures and societies around the world with different views and approaches to pain. Eastern societies are often influenced by Buddhist teachings that see human nature as imperfect, like the rest of worldly things, and pain as an inevitable aspect of human life. However, they think that pain can be conquered on Earth through self-improvement, like any other shortcomings of human nature, a process that may take more than just one lifetime, but that eventually would lead to the ability to control your pain (Free, 2002).
Some aspects of the social interpretation of pain are common through most cultures. These include considering pain as a test of character and praising the ability of an individual to endure pain as a positive aspect of personality. In the end, there is also a desire to eliminate or reduce pain on Earth, and all cultures have developed, from the beginning of time, methods directly or indirectly aimed at pain relief.
Natural products with analgesic properties have been known since antiquity. The two classes of drugs that are commonly still used and best understood are the opioids and anti-inflammatory drugs such as aspirin, initially derived from plant products like willow bark.
The use of opium to alleviate pain has been known since Egyptian times, and opium seeds have been found in Neolithic settlements. In the sixteenth century, Paracelsus described the use of laudanum, an opioid-based tincture, as an analgesic (Rey, 1993). Sertuner isolated the active ingredient morphine around 1804, although it was not until 1925 that the structure was determined (Devereaux, Mercer, & Cunningham, 2018). The unfortunate side effects of opioids were recognized through government action to ban the drugs from the period around 1914. Sadly, overprescription by unscrupulous producers and medical practitioners has led to an explosion of opioid-associated deaths in the United States in recent years, focusing attention on the massive problem of chronic pain, which is so poorly treated and understood. The endogenous opioid peptides met and leu enkephalin, first discovered by Hughes in 1975, as well as exogenous opioid drugs, act though GPCRs to mute neuronal activity through pertussis toxin–sensitive Gi-mediated pathways. They inhibit the actions of adenylate cyclase (activated by inflammatory mediators) and can diminish calcium currents and enhance inwardly rectifying potassium currents to inhibit neuronal activity (Siuda et al., 2015; see chapter by Stein and Gaveriaux-Ruff, this volume). Interestingly, using the opioid antagonist naloxone, Levine et al. showed that the placebo effect, so problematic in pain clinical trials, is mediated by the actions of endogenous opioids (Levine, Gordon, & Fields, 1978).
Another plant product that has potential as an analgesic is tetrahydrocannabinol, present in cannabis plants. Similar to opium, cannabis not only has been used for its euphoric properties, but also has useful analgesic properties. Acting through two GPCR receptors, CB1 and CB2, found on immune cells, nociceptive neurons, and within the CNS, cannabinoid drugs also activate G-mediated pathways influencing potassium channel and calcium channel activity as well as PKA and mitogen-activated protein (MAP) kinase activity. There are synergies between opioid and cannabinoid action, suggesting that they modulate similar, but not identical, intracellular pathways. The arachidonic acid metabolite anandamide is the endogenous activator of CB receptors discovered in 1992 (Devane et al., 1992).
Anti-inflammatory drugs derived from willow bark were also known by Hippocrates in the fourth century bc. However, the first meaningful clinical trial was carried out by Stone; this was described in a paper presented to the Royal Society (Stone, 1763). He used willow tree extract, which tasted as bitter as the Peruvian bark that was used to treat malarial fevers, and found that it was effective in 50 subjects. The famous aphorism “where ills abound there cures will be found” was ascribed to Stone, who had isolated a useful treatment from a plant associated with marsh ground where many people suffered aches and pain. However, the actual statement in the paper was rather less succinct (Wood, 2015).
Salicylic acid was isolated from willow bark in 1827, and by 1987, Hofmann had succeeded in synthesizing acetylsalicylic acid for clinical use. The locus of action of these drugs on eicosanoid synthesis was discovered in the late twentieth century, and subsequent development of compounds that block COX has resulted in extremely potent analgesics, some of which have fallen by the wayside because of cardiovascular side effects. Paracetamol, discovered in the late nineteenth century, only came into common use after the 1950s. This remarkably effective analgesic does not seem to act on COXs but may enhance the activity of anandamide by blocking uptake. Recent evidence suggests that paracetamol acts through CB1 receptors in the rostroventral medulla (RVM) to elicit analgesia centrally (Klinger-Gratz et al., 2018). Cannabinoids have been suggested as useful for treating some neuropathic pains, but their side effects in terms of reducing mental function make them undesirable as mainstream analgesics.
Other natural products that have been considered as analgesics include toxins that are potent channel blockers and are derived from conus snails or insects. Usually, the structural constraints on cheap production of these compounds, as well as their lack of oral availability, have blocked clinical development. Interestingly, some compounds, such as Prialt, a Cav2.2 blocker derived from omega conotoxin 7a, is a potent analgesic in clinical use, although it has deleterious effects on signaling throughout the CNS that preclude its use outside opioid-resistant cancer pain (Safavi-Hemami, Brogan, & Olivera, 2019).
Plant products have also stimulated the development of small-molecule analgesics. COX-1 and COX-2 antagonists are extremely effective in many pain conditions, although gastric and cardiovascular side effects are problematic (Langford & Mehta, 2006). Similarly, opioid agonists are marvelous analgesics with well-known side effect issues, particularly addiction, that make their use problematic. Weak agonists like tramadol are nonetheless commonly used (Bravo, Mico, & Berrocoso, 2017). Serendipity also has played a role in analgesic development, with the realization that gabapentin is not a gamma-aminobutyric acid (GABA) mimetic but an analgesic that acts on calcium channel expression (Patel & Dickenson, 2016).
Directed research aimed at the development of small-molecule analgesics has focused on a number of other peripheral targets. First, voltage-gated sodium channels are known to play a key role in pain pathways, as demonstrated by the effects of local anesthetics in treating many pain conditions (see chapter by Cummins, Waxman, & Wood, this volume) (Emery, Luiz, & Wood, 2016). An association between particular sodium channel isotypes and some pain syndromes has fueled a research effort to make subtype-selective channel blockers that may be analgesic with fewer side effects than global sodium channel blockers like lidocaine. Second, some antiepileptic drugs that are useful analgesics have been employed. The mechanism of action of such drugs (e.g., valproate) is little understood (Sidhu & Sadhotra, 2016). Many of these compounds are considered sodium channel blockers, and others are thought to act on calcium channels or the GABA system. However, new classes of analgesic drugs have yet to appear after many years and billions of dollars’ worth of effort.
In the area of biologicals, progress has been made. Monoclonal antibodies (Kohler & Milstein, 1976) or neutralizing receptor bodies that remain in the circulation for months can be used to mop up hyperalgesic mediators such as TNF or NGF (Feldman et al., 1998; Miller, Block, & Malfait, 2018). Other cytokines, such as interleukin (IL) 1 are also potential targets. This is a promising area of analgesic development.
Nonpharmacological Pain Relief
The use of drugs to treat pain is well documented, with the earliest archaeological evidence dating to the Neolithic age (Bushak, 2016), right through ancient Middle Eastern cultures, to our days (Katz, 2007). However, there is also evidence from very early historical times that methods other than drugs were also used in attempts to relieve pain.
Some of these methods included surgical interventions. Evidence of cranial trepanations for therapeutic purposes, with the subsequent survival of the patients, can be seen in skulls from both ancient Egyptian and Native American cultures (Faria, 2015). It is not absolutely clear that all of these procedures were only aimed at relieving pain, but the underlying interpretation is that making holes in the skull would allow bad spirits to leave the patient, taking with them the symptoms of disease, which in many cases would include pain.
The development of general anesthesia in the late nineteenth century made it possible to carry out complex surgical procedures, including many that directly interfered with the CNS. A simple view of the pain pathway as a linear conductor from the periphery to the brain resulted in surgical interventions aimed at interrupting this pathway at any level. So, section of peripheral nerves or of spinal pathways (chordotomy) was introduced for pain relief (Leriche, 1940; White & Sweet, 1969). The most popular chordotomy was that of the anterolateral quadrant of the spinal cord, in the understanding that this would interrupt the transmission through the spinothalamic tract, the “pain pathway” to the brain (Lahuerta, Bowsher, Lipton, & Buxton, 1994). Though successful in the short term, these chordotomies often produced a return of the pain, sometimes even more intense, after a few months, and their use was limited to patients who were terminally ill (White, Sweet, Hawkins, & Nilges, 1950). Other surgical lesions developed for pain relief included the dorsal columns of the spinal cord, the central commissure, the dorsal root entry zone, and restricted lesions of several CNS structures, such as the pituitary, the amygdala, and other such nuclei (Nathan, Smith, & Cook, 1986; Romanelli, Esposito, & Adler, 2004).
A particularly dramatic form of brain surgery for pain relief was the performance of a frontal lobotomy (Freeman & Watts, 1948). This intervention was first developed by Egas Moniz in the 1930s for the treatment of severe psychosis as an alternative to restraining or sedating these patients (Tierney, 2000). The widespread use of frontal lobotomies in psychiatric patients made it possible to study in detail the neurological deficits resulting from this operation, such as alterations in pain sensation. It was noted that the change of personality induced by the operation included an indifference to pain, such that the patient was not bothered anymore by painful sensations (Koskoff, Dennis, & et al., 1948). Therefore, frontal lobotomies were performed on patients with terminal cancer who had intense pain even though they did not have psychiatric disease; later, the procedure was also extended to patients with longer life expectancy and with intense chronic pain (Watts & Freeman, 1948). The introduction in the 1950s of powerful drugs to control psychotic states and the use of pharmacological treatments for chronic pain made these dramatic surgical interventions obsolete.
Many forms of physical therapy have been used over the years to treat pain. Baths, both hot and cold; massage; exercise; as well as techniques using external forms of energy have been claimed to have beneficial effects to relieve pain. Notably among them is the use of electrical currents applied to various parts of the body in many different ways and from several sources. Ancient Greeks recommended standing on electric fishes to treat diseases, including pain, with the discharges received (Macdonald, 1993). As electricity-delivering apparatus were developed during the nineteenth century, their use to treat various forms of pain increased. Both electrical currents and electromagnetic discharges were reputed to have pain-relieving properties (Macdonald, 1993).
Following the publication of the gate control theory (Melzack & Wall, 1965), a new field of pain treatment was developed by using electrical stimulation of peripheral nerves in attempts to “close the gate” to painful stimuli. This procedure, known as transcutaneous electrical nerve stimulation (TENS), produced an entire industry of devices of various kinds to deliver many different patterns of electrical pulses of variable intensities to activate peripheral nerve fibers and reduce pain (Gildenberg, 2006). The development of TENS also opened the door to a whole new field of “neuromodulation,” whereby electrical stimulation was applied to various parts of the peripheral nervous system and CNS in order to reduce pain (Gildenberg, 2006). The list of sites targeted with electrical stimulation for pain relief is quite long and includes virtually every level of the brain and spinal cord.
Spinal Cord Stimulation
The first reports of the electrical treatment of pain come from Scribinius (ad 15), who showed that a torpedo electric eel sting could alleviate his gout-associated pain (Gildenberg, 2006).
Shealy and coworkers first reported that pain could be attenuated by spinal cord stimulation (Shealy, 1967). More than 25,000 neurostimulators are implanted annually as a result of this effective treatment. Remarkably, there is no consensus view on how this intervention works (Jensen & Brownstone, 2018). The original aim was to harness elements of gate control as proposed by Melzak and Wall, but as the treatment is mainly effective in neuropathic pain, this working hypothesis fails. A number of potential mechanisms have been analyzed, but the mechanism remains uncertain. This is also the case for treatment with green light, a therapy that appears to have major benefits in animal models (Ibrahim et al., 2017).
Finally, it should be pointed out that many of the so-called alternative or complementary techniques used currently for pain treatment have their origins in traditional nonpharmacological methods of pain relief, including acupuncture, meditation, yoga, and other such forms of therapy (Chen & Michalsen, 2017). Drug-free pain treatments offer a wide range of approaches and techniques, many of which are still in use today. Their utility is a subject of debate.
Recent Developments in Pain Research
Fortunately, many of the accompanying chapters deal with contemporary approaches to pain mechanisms. The modern era of pain research can be linked to two seminal events: the demonstration of the existence of nociceptors by Perl and genetic advances, particularly the ability to clone genes encoding the molecules that make up the pain system. The tsunami of information that has resulted from the analysis of nociceptive mechanisms, mainly in mice, has sadly not been matched by equivalent progress in drug development. Knockout mouse studies have implicated some hundreds of genes in pain processing in mice (http://www.jbldesign.com), and some targets, like the NK1 receptor for substance P, have proved attractive enough for pharma to develop antagonists, none of which are analgesic in humans (Hill, 2000). Human genetic studies have also implicated a number of new targets in pain states in well over a thousand publications (https://humanpaingenetics.org/hpgdb/; see also chapter by Cox, Kurth, & Woods, this volume).
As well as new drug targets, new methodologies have allowed us to examine pain-related neuronal activity in both humans and rodents using imaging strategies.
Bold Functional Imaging
Roy & Sherrington (1890) first commented on the altered blood flow associated with neuronal activity. The hemodynamic response was exploited by Ogawa and coworkers, who used functional magnetic resonance imaging (fMRI) to compare oxygenated and deoxygenated heme as an index of blood flow in the brain (Ogawa, Lee, Nayak, & Glynn, 1990). Blood oxygen level–dependent (BOLD) imaging relies on the different magnetic properties of heme, which correlates with increased metabolic activity and blood flow in the brain. However, the temporal and spatial resolution of fMRI is limited. A single voxel encompasses millions of neurons and billions of synapses. The requirement for glucose that drives the fMRI hemoglobin signal exploits the release of nitric oxide (NO) from astrocytes to increase blood flow, also giving slow temporal resolution some seconds after the activation of neurons. Thus, functional imaging is an insensitive measure of intense neuronal activity. Worse, the statistical methods used in early articles are unreliable (Eklund, Nichols, & Knutsson, 2016). Thus, functional imaging that shows correlative changes in blood flow may be interpreted as giving insights into neuronal function in various experimental paradigms but usually does not allow causal inferences to be made. Intriguingly, pain-free humans show the same BOLD responses in the putative pain matrix as do normal people with noxious stimulation (Salomons, Iannetti, Liang, & Wood, 2016).
Genetically encoded calcium indicators, in contrast, have provided important new insights into our understanding of neuronal circuits and function. The discovery of green fluorescent protein (GFP) resulted in the development of a range of calcium-dependent fluorescent indicators (Chalfie, 2009). The GCaMP series of proteins has allowed the visualization of neuronal activity dependent on increased intracellular calcium levels and given useful insight into sensory neuron function in vivo (Anderson, Zheng, & Dong, 2018). A further development of so-called CAMPARI proteins allows the irreversible labeling of activated neurons for later classification using techniques such as RNA-Seq (RNA sequencing), while viral labeling of neuronal circuits using the CANE technique is fully described in the chapter by Todd and Wang (Sakurai et al., 2016; Zeisel et al., 2018). Transcriptional profiling has given unprecedented insights into the range of neuronal subsets found in rodents and humans; for example, 23 distinct sets of sensory neurons and 30 different types of dorsal horn neurons have been identified (see http://mousebrain.org/ from the Linnarsson laboratory; Zeisel et al., 2018). The transcriptional profiles also allow us to interrogate the function of neuronal subsets using cellular ablation, silencing, or activation (see chapter by Emery and Ernfors, this volume).
Gender-Specific Pain Mechanisms
It is a truth, occasionally disputed, that males and females are genetically, physiologically, and neurologically distinguishable. Unsurprisingly, there are distinct pain mechanisms in male and female mice that involve, for example, the participation of microglia in the development of neuropathic pain. While microglia play an important role in neuropathic pain in male mice, similar pain levels seem to involve T cells rather than microglia in female mice (Sorge et al., 2015). There is a remarkable divergence in incidence of some pain syndromes, such as fibromyalgia in males and females, with considerably more females presenting with more severe pain problems than men. It may well be that immunological factors play a role in this gender specificity, but this is still a work in progress (Totsch & Sorge, 2017; see chapter by Bennett, this volume). The realization that different pain mechanisms occur in a gender-specific way adds support for the view that multiple redundant pain mechanisms are at play in outbred humans.
The redundancy and plasticity of the pain system mean that magic bullet, single-reagent, small-molecule drug development is unlikely to succeed. Even in inbred mice, different models of pain show distinct cell and molecular correlates, implying multiple mechanisms of damage sensing and pain (Bangash et al., 2018). However, we should not ignore the potent effects of opioid peptides in pain modulation, as well as the essential role of sodium channels in electrical transmission in pain pathways. Combination therapy using drugs focused on different aspects of sensory neuron activation does show promising activity in animal models, for example, sodium channel Nav1.7 antagonists and enkephalinase inhibitors (Deuis et al., 2017) or combinations of opioids and lidocaine (Kolesnikov, Chereshnev, & Pasternak, 2000). Commercial considerations over intellectual property IPintl issues have unfortunately slowed pharma interest in such approaches. An area that has proved very useful is the application of humanized monoclonal antibodies to neutralize inflammatory modulators such as TNF and NGF, and it should be exploitable with other mediators in some pain conditions.
Looking to the future, major advances are now being made in gene therapy. With adeno-associated virus (AAV) and lentiviral vectors, the possibility of targeting exogenous genes to sensory neurons using specific promoters is now being realized (Guedon et al., 2015). The exploitation of designer receptor exclusively activated by designer drugs (DREADDs) to develop reversible gene therapy where neurons are silenced in a reversible drug-dependent manner is also very attractive (Roth, 2016; see chapter by Seguela, this volume). It should in principal be simple to gene edit key elements in the pain pathway (e.g., sodium or calcium channels using clustered regularly interspaced short palindromic repeats (CRISPR)–based gene excision; Akcakaya et al., 2018). Mimicking the pain-free state found in SCN9A (Nav1.7 channel) loss-of-function mutants is an obvious approach (Cox et al., 2006). In summary, we now have a good appreciation of the complexity of mechanisms involved in pain and new tools for manipulating pain pathways, particularly in the periphery. Mechanistic distinction of pain states in clinical trials is the key to developing useful therapies. It would be more than disappointing if new effective treatments for pain did not develop over the next decade.
We thank the Wellcome Trust for its invaluable support and Arthritis UK and the EU 2020 framework for their important contribution.
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