History of pain

From a historical perspective, the view on pain has changed throughout the years as a result of significant advances in research methodologies. Many attempts have been made to define pain; while philosophers provided the first abstract concepts through pondering, scientists have constructed empirical theories by integrating available knowledge at that time. As a result, these attempts produced a variety of theoretical and functional definitions for pain, suggesting the difficulty in defining this complex phenomenon.

Pain is considered the oldest medical problem and the universal physical affliction of mankind¹. Therefore, it is not surprising that the first contemplation of pain can be tracked all the way back to Ancient Greece, where the understanding of pain and its treatment occupied many poets, tragedians, and philosophers.

The oldest written information on pain can be found in the epic mythological poems by Homer (~850 BC) in which pain was related to emotion. In his poems, Homer referred to pain as a state of mind consisting an emotional suffering². “Pain” (or “Ponos” in Greek) was used as a synonym to “Algos” and

“Odyni”, which were used to point the torture of man as a result of war or injury throughout the long way journey of returning². Most of the heroes in Greek mythology were not only trained in battle but also in healing practice, where herbal substances such as Nepenthes, or opium, were often used for emotional pain relief³.

For the Greek philosophers, pain was used to be a phenomenon that should be defined by pondering over its nature (what is pain?), cause (why people are in pain?), origin (what is the center of pain), and purpose (what is the utility of pain?). The first who contemplated about the concept of pain were Pythagoras (570-495 BC) and Antiphon (500 BC). Interestingly, to realize what pain was, they had to contrast it with pleasure. Pythagoras have argued that pleasure is a goal of which men voluntarily pursue to reach harmony with their souls, while pain is an involuntary disruption to the souls’

harmony⁴. Similarly, Antiphon stated that for humans to achieve great pleasure, pain should be eliminated. Following his realization, Antiphon developed a method to treat pain through conversation, which later considered to be the first precursor of modern psychotherapy⁵.

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Years later, Hippocrates (460-370 BC), a philosopher and the first doctor who separated religion from sickness (by searching for the physical causes of diseases)³, suggested a more mechanistic view.

According to which, pain reflects an imbalance in the four vital fluids of the body (blood, phlegm, yellow and black bile)⁶. For the first time, pain was considered a symptom that can be treated by men (and not by Gods). This consideration paved the way for new therapies that were grounded on physical substances (herbal medicine, chemical mixtures, and special diets), rather than on religious elements (pray, rituals).

Remarkably, Hippocrates’ view did not prevail for long. The succeeding philosopher, Plato (428-348 BC), decided to follow the previous approach of Pythagoras and Antiphon, and so, he contrasted pain with pleasure in his book “Passions of the Soul”. Plato, however, did not consider pain and pleasure as motivational goals (as Pythagoras and Antiphon did), but as different emotions.

Consistent with Plato, Aristotle (384-322 BC) also claimed that pain is an emotion. Though, Aristotle added that pain enters the body via injury, which is caused by evil spirits and Gods. According to this Aristotelian perception, since pain upsets and destroys the nature of the person who feels it⁷, the heart is the central pain organ. Centuries later, Galen (AD 130–201), the leading physician of Alexandria, disagreed with Aristotle’s view. Through observations made in his clinical experience, Galen claimed that the brain should be the central organ for all feeling senses, including pain⁸. Another opposition to the Aristotelian perception came hundreds of years later. Avicenna (AD 980–1037), a renowned Muslim philosopher and physician, noted that pain could be dissociated from touch or temperature recognition, and proposed pain to be an independent sensation⁹.

Even though not all ancient philosophers accepted the Aristotelian perception, its influence on philosophical thought had an enduring impact that persisted throughout the Middle Ages. As a result, in the period between the Middle Ages and the scientific Renaissance in Europe, the prevailing view on pain was shaped by religious beliefs. Pain was considered as something that enters the body from the outside, serving either as a punishment from God or as a test to reaffirm the person’s faith¹. Clearly, the heart was still regarded as the central pain organ.

Finally, the Aristotelian perception has come to an end during the Scientific Renaissance in Europe (1500-1700), where pain has been transformed from a spiritual, mystical experience to a physical, mechanical sensation that could be investigated by research. In this period, much of the attention was focused on the anatomy of the nervous system. As a result, this period concluded with the consensus of the brain as the central organ for pain perception.

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One of the major landmarks of the Scientific Renaissance occurred in 1664 when Descartes’

formulated the first description of the pain system¹⁰. It was also one of the first detailed descriptions of the somatosensory pathway in humans. Descartes described pain as a perception that exists in the brain and further distinguished between the neural phenomenon of sensory transduction and the subjective experience of pain. In his description, (Figure 1), the nerves are regarded as hollow tubes (“fine thread”) that convey both sensory and motor information. Ultimately, this information leads to a perceptual experience (feeling pain), and to an appropriate, consequent behavior (e.g. to move away from a source of pain).

Even though Descartes provided a detailed mechanistic description of the pain system; he did not offer a solid dissociation between the spirit and the physical, as he also designated “animal spirits” to flow from the brain to the muscles to control behavior. Such dissociation had only occurred later when Newton and Hartley proposed neuronal messages to be vibrations of substance in nerves¹¹. In sum, these two landmarks have provided a crucial framework for modern theories of pain, leading to a new era of empirical investigation.

Figure 1 - Descartes' pain pathway.

"Particles of heat" activate a spot of skin attached by a fine thread to a valve in the brain where this activity opens the valve, allowing the animal spirits to flow from a cavity into the muscles causing them to move away from the stimulus.

Taken from¹².

Following the Scientific Renaissance, in the early modern period, pain researchers have conducted experiments to investigate how pain is transmitted from the periphery to the spinal cord and brain.

For instance, in 1858, Schiff demonstrated that particular lesions of the spinal cord resulted in the separate and independent loss of tactile and pain-related reactions¹³. Schiff reached the same conclusion that was offered a millennium earlier by Avicenna in which pain is an independent sensation. While Schiff’s view was popular at that time, it was not accepted by all. Based on

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experiments performed by Naunyn in 1859¹⁴, and on observations in which intense sensations are usually disagreeable and involve strong stimuli, Erb proposed in 1874 an alternative to Schiff’s conclusion - the Intensity Theory¹⁵, which is also considered to be the first explicit theory of pain.

According to the Intensity Theory, pain is not a unique sensory experience but rather a non-specific sensation that occurs when a stimulus is stronger (more intense) than usual¹⁵. Therefore, the theory suggests that there are no distinct pathways for non-noxious and noxious stimuli. Instead, a stimulus generates a certain number of impulses in neurons, which will determine its intensity. Furthermore, the Intensity Theory also portraited a signal-processing pathway; where the primary afferent neurons synapse onto second-order neurons (in the dorsal horn of the spinal cord), which encode low levels of activity as innocuous stimuli, and higher levels of activity as noxious stimuli.

Then, in 1884, two separate studies^16,17 indicated how separate skin spots, when stimulated mechanically with small probes, could produce different sensory experiences (e.g. pressure, cold, warmth, pain). This finding was also supported by a series of histological experiments, conducted by von Frey between 1894 and 1897. From these experiments, Von Frey deduced a relationship between the stimulated skin spots and the structurally defined neural endings^18–21, which eventually led to the formation of the Specificity Theory. In complete contrast to the Intensity Theory, the Specificity Theory²² suggests the presence of dedicated components for each somatosensory modality. These components consist of a receptor, a sensory fiber (primary afferent), and a pathway, all of which are sensitive and dedicated to conveying one specific stimulus²³. The theory defines pain as a unique sensation, which has specific peripheral sensory receptors that react to damage and send signals through pain-specific pathways to the brain; then, dedicated pain centers in the brain process those signals to produce the painful experience.

Evidence supporting the Specificity Theory came only later. Following a series of neurophysiological experiments, Sherrington concluded in 1906 that the main function of a receptor is to lower the excitability threshold for one kind of stimulus and to heighten it for all others^24–26. This conclusion for a “selection” approach provided the biological framework (i.e., the existence of pain-specific receptors) for the Specificity Theory. Remarkably, Sherrington’s explanation has also accounted those findings supporting the Intensity Theory, as it recognized the existence of an excitability threshold.

Moreover, during his studies Sherrington suggested to label a stimulus capable of tissue damage as

‘noxious’²⁶, and also to describe the specificity of the cutaneous end-organ (i.e. receptor) for noxious stimuli as “nociceptor”²⁷ (which is used until today). Furthermore, in 1926, Adrian and Zotterman showed that peripheral tissue stimulation, with different natural triggers (e.g. brushing/stroking, temperature changes, muscle stretch), can evoke a series of neuronal discharges from individual nerve

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fibers²⁸. These results were interpreted as stimulus-selective responses of nerve fibers, which were consistent with the Specificity Theory.

However, Adrian and Zotterman’s interpretation was not accepted by all, and so in 1929, Nafe offered an alternative explanation, which was later known as the Pattern Theory²⁹. Nafe claimed that all peripheral sensations are produced by spatial and temporal patterns of neural firing, and not by separate modality-specific afferents²⁹ (as suggested by Adrian and Zotterman²⁸). According to Nafe’s Pattern Theory²⁹, there is no separate system for perceiving pain, and the receptors for pain are shared with other senses, such as those of touch. Although the theory ignored previous observations supporting the Intensity or the Specificity Theories (threshold-dependent afferents, specialized nerve endings), it was reinforced by several stimulation studies. These studies demonstrated that nerve-fiber stimulation could trigger a wide range of sensory experiences (e.g. touch, cold, warm, prick, itch, and sharp pain), depending on the pattern of stimulation (and not on modality-specific nerve endings).^30,31.

By 1930, there were three main theories of pain: Intensity Theory, Specificity Theory, and Pattern Theory, each with its supporting evidence. Notably, all these theories have tried to explain pain as a peripheral sensory experience. Yet, in 1943 Livingston³¹ (and later Hebb in 1949³²) decided to revive an old concept (taken from Plato), and proposed a theory (here labeled Motivational-Affective Theory) in which pain (and pleasure) is considered as a subjective motivational state (termed “appetites”) of behavior. Moreover, the theory also posited that pain is arises from activation of aversive networks in the brain. Livingston’s theory brought back the concept of early philosophers into the modern scientific discussion, which eventually caused a dramatic shift in thought about pain, as can be seen in later theories.

So far, the early modern theories of pain (i.e. Intensity Theory, Specificity Theory, Pattern Theory, and Motivational-Affective Theory) were considerably limited. These theories could not explain a broad range of experimental and clinical observations at that time (e.g. variable relationship between injury and reported pain, non-noxious stimuli leading to pain, persisting of pain after tissue healing, temporal changes in the nature and the location of pain, etc.)³³. Most importantly, these early models were unable to provide efficient model-based treatments for patients in pain. The failure of these sensory and affective models to explain much of what was observed experimentally and clinically, have boosted the motivation to search for a more integrative model.

And so, in 1965, Melzack and Wall proposed the Gate Control Theory³⁴, an idea that would become one of the most influential theories of pain research. The theory postulates nociception to be "gated"

by non-nociceptive signals through interneurons within the spinal cord. According to the theory,

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specialized nociceptors and dedicated central pathways do not exist, instead the spectrum of primary afferent neurons has a range of thresholds in which the interplay between small nerve-fibers (Aδ and C) and large nerve-fibers (Aβ) determines the transmission of pain signals to the brain. Specifically, large-fiber activity inhibits (or closes) the gate, whereas small-fiber activity facilitates (or opens) the gate (Figure 2). When nociceptive information reaches a threshold that exceeds the inhibition elicited, it opens the gate, allowing the projection neurons to send the information through the dorsal column to the brain, resulting in the experience of pain (Figure 2). For instance, the theory could explain why rubbing a bumped knee could alleviate the resulting pain. Furthermore, the theory also proposed that the brain could modulate the gate via descending fibers (“top-down” modulation). Therefore, the theory also set an initial framework for psychological modulations on pain. Therefore, it suggested the existence of a descending modulatory system, which provided a physiological solution to those cases that could not be explained by previous pain theories (particularly because it offered possible explanations for aberrant pain after lesions of the nervous system). Although the Gate Control Theory was received with excitement and broadly accepted by the scientific community, it couldn’t provide a differentiation between distinct types of pain (cold, hot, visceral, dental), including those without an apparent sensory input (e.g. spinal cord injuries).

Figure 2 - Melzack and Wall’s Gate Control Theory of Pain (1965).

Reproduced from³⁵.

Several seminal discoveries made in following years have shown in fact, that the mechanisms of pain transduction and perception are much more complex than described in the Gate Control Theory.

During this period (late 20^th century), scientists have focused their investigation on the cellular arrangement of the central nervous system (CNS) and on the molecular mechanisms involved in nociception^36–40. Few of those landmark discoveries were: the finding of various types of presynaptic inhibitors that can gate pain^41–43, linking between evoked activity (impulses) in nociceptive afferent fibers and behavioral measures (at first in animals^44,45, but later also in humans^46–48), and the identification of pain-specific ascending pathways such as the Spinothalamic tract^49–51. Critically, nociceptors were demonstrated to differ from low-threshold afferent fibers not only by having elevated thresholds for all stimuli ordinarily affecting a tissue, but also in their cellular properties^52–56. On the cortical level, at first, pain was suggested to be a product of thalamic mechanisms, discounting a contribution by the cerebral cortex. This was based on studies showing absence of change in pain

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perception following lesions or electrical stimulation^57–60. Later, there was evidence in which cortical injuries resulted in a persisting loss of capacity to recognize painful stimulation in restricted body regions^61–64. Taken together, at the beginning of the twenty-first century two things accepted by all pain researchers: (i) nociceptors are a separate class of primary sensory neurons that can discriminate reliably between noxious and innocuous stimulation, and (ii) nociceptive signals are processed in subcortical and cortical regions of the brain, leading to the perception of pain.

In response to all the new discoveries since his initial theory, Melzack proposed in 2001 a new theory – the Neuromatrix Model of pain^65,66. In this theory, pain is defined as a multifaceted experience that is produced by a characteristic neurosignature of a widely distributed brain neural network, called the body–self neuromatrix^65,66. The neuromatrix integrates cognitive–evaluative, sensory–discriminative, and motivational–affective aspects to engage perceptual, behavioral, and homeostatic systems in response pain. Since previous models (Specificity Theory, Pattern Theory, Gate Control Theory) mainly focused on peripheral mechanisms, they have difficulty in accounting observations of reported pain in patients with spinal cord injuries and in patients that experience phantom limb pain^67–70. The body–

self neuromatrix, on the other hand, admits the possibility that somatic experiences (including pain) might also stem in the absence of any sensory input.

However, only with the advance of neuroimaging techniques (e.g. positron emission tomography (PET), and functional magnetic resonance imaging (fMRI)), neuroscientists could finally look inside the brain to find that administration of noxious stimuli activates a widespread network of brain regions better known as “the pain matrix” (Figure 3)^71–80. Noxious stimulation evokes prominent signs of localized metabolic increases in several distinct cerebral cortical areas comprehending the comprehending primary (S1) and secondary (S2) somatosensory cortex, posterior (PI) and anteior (AI) insular cortex, the middle cingulate cortex (MCC), the thalamus, and the periaqueductal gray (PAG).

Figure 3 - NeuroSynth term-based meta-analyses of pain.

The likelihood of each coordinate belongs to studies investigating Pain [420 studies]. Neurosynth^81,82.

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At first, neuroimaging studies on pain have suggested that the pain matrix is a network unique to pain^71–78. Indeed, the recruitment of this network has been replicated in studies employing different modalities of painful stimulations including: thermal (heat/cold), electrical (electric shock), mechanical (esophagus/rectal distention, ischemia, cutaneous pinprick), and chemical (checapsaicin, ascorbic acid, irritant odors such as CO2)^83–86. Later neuroimaging studies, however, have started to speculate the precise role played by each region of the pain matrix, especially in light of studies which revealed how parts of pain matrix might be recruited in experimental manipulations involving pain, but in the absence of any noxious stimulation. These include, for instance, cases in which individuals were:

awaiting pain to occur (expectation paradigms)^73,87–94, observing others in pain (empathic pain)^95–100, reading texts describing painful situations^101–105, or “suffering” following a social mistreatment by peers (social pain)^106–109. Later neuroimaging studies suggested that due to the functional heterogeneity in the recruitment of the pain matrix, the pain matrix should be divided to parts involved in the processing of the sensory (e.g. intensity, noxiousness, location) or the affective (e.g.

unpleasantness, pain-related emotions, avoidance-goals) features of pain. For instance, the somatosensory cortex¹¹⁰ and the posterior portion of the insula were associated with the sensory processing of pain¹¹¹, whereas the anterior part of the insula, the amygdala, and the cingulate cortex might be associated with affective processing of pain^112–117.

However, the debate about the definition, the sources, and the signature of pain has not come into an end with the advances in neuroimaging. In respect to definitions, Craig (2003) considers pain as a homeostatic emotion that is both a specific interoceptive sensation and an integrated affective behavioral drive caused by a physiological imbalance¹¹⁸. Interestingly, the latter part can remind the physiological imbalance that was first mentioned by Hippocrates in Ancient Greece. On the other hand, Perl (2007) argues that the primary evidence for considering pain from noxious stimulation as a discriminative sense, rather than an emotion, is its dissociation from other body sensations in disorders of the nervous system⁸. Perl also criticizes Craig’s view by indicating that since homeostasis implies holding an organism and its systems to a stable state, it is a concept that poorly fit to pain, especially when a tissue is injured. In addition, there is also a current disagreement revolving around the sources of pain. For instance, events in which an individual is being excluded/rejected or mistreated by others, is advocated as a genuine form of pain (“social pain”)106,108,109,119. However, others have demonstrated a neural dissociation from physical pain, and suggest that these events should not be considered a form of pain^120,121. As for the pain-matrix, following neuroimaging studies have shown that part of the pain matrix is also active in many affairs that are not pain, including other aversive experiences such as disgust (see Figure 4a-b), affective states (e.g. arousal), or even in prediction error. This finding opened a huge debate as to whether (and to which extent) the pain

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matrix processes pain specifically^122–125. Most importantly, it led scientists to offer a complete alternative views about the processing and the meaning of pain. For example, according to one view,

matrix processes pain specifically^122–125. Most importantly, it led scientists to offer a complete alternative views about the processing and the meaning of pain. For example, according to one view,