Cortical mechanism of emotional pain

Introduction

Chronic pain is a major medical problem that lacks effective medicine. For many years, people failed to distinguish acute or physiological pain from chronic or pathological pain. Drugs developed to stop or reduce pain also affect physiological sensory and cognitive processes and thus produce many CNS side effects.^1–3 For example, for inhibiting synaptic transmission, drugs that inhibit voltage-gated calcium or sodium channels also reduce many other central synapses as well as peripheral organs such as heart, lung, liver that are important for vital physiological functions. For drugs that inhibit excitability-related ion channels, these ions channels are widely distributed in neurons that are key for basic brain functions. One novel way to reduce or control chronic pain is to inhibit injury-related central plasticity by inhibiting plasticity-related signaling proteins. Genetic and pharmacological evidence have consistently suggested that neuronal-selective adenylyl cyclase subtype 1 (AC1) serves as one of such targets with few side effects.^4–6

Recently, there is increasing evidence that some of central pain may be different from physical pain, or I would call it emotional pain including social pain. Most emotional pain is specific to humans; it is hard to study basic mechanisms of emotional pain in animal models, such as sadness, loss of loved ones, divorce etc. Human emotional pain can be categorized into two major types: internal emotional pain that is caused by events or environments and empathic emotional pain that is caused by human- or animal-related events, especially those that are closed to the person. For humans, emotional pain is often highly related to society, and social pain is one of major forms of emotional pain. ⁷ Most animal models that are used to investigate neurobiological mechanisms are limited to basic emotional functions such as anxiety and fear. Few animal models can study emotional pain related sadness and hopelessness. Empathic sensory responses (pain or itch) or fear, has been recently investigated using mouse models (see below). In this review, I would propose emotional pain as a new category of unpleasantness caused by visual or other sensory modularity (in comparison to somatosensory stimuli we commonly use).

Emotional pain

Most pain research, especially those for basic mechanisms of pain transmission, modulation, and plasticity, are focused on individual pain or physical pain that is triggered by injuries. According to their duration and different characteristics, it can be divided into acute and chronic pain.^4,8 For these forms of pain, both input sensory stimuli and output neuronal and motor responses are well defined. It is only focused on the individuals who suffer these injuries.

Emotional pain, or psychological pain or mental pain is an unpleasant feeling (a suffering) of a psychological, non-physical origin. It can be a result of the actions of others, and mediated through visual, auditory, or other non-physical signaling. In the modern society, news media, internet, and cell phones are the great source and media of such unpleasant stimuli or triggers. Empathy to others, including family and friends, often cause emotional pain and suffering. Many common daily events such as sorrow, sadness, or without hope, isolation, and loneliness often accompany emotional pain. In certain cases, emotional pain can cause physical responses in the body such as sleepless, diarrhea, dizziness, headaches, muscle pain particularly in the neck, nausea, pain in the arms and legs, stomach pain, or gastrointestinal upset. Unlike physical pain, emotional pain is less studied at cellular and molecular levels of basic mechanisms and since many of these events and responses are unique for humans, it is difficult to recreate emotional pain using animal models. Recently, empathic pain, a form of emotional pain, has been established using adult mice.^9–11 These studies provide unique opportunities to investigate possible synaptic and cellular mechanism for emotional pain, especially at the cortical levels.

Peripheral and central mechanisms for physical and emotional pain

At neuronal levels, physical pain clearly has peripheral and central mechanisms. From peripheral nociceptive, to spinal cord dorsal horn neurons, and ascending pain pathways, each connection play important roles in both acute and chronic physical pain.^8,12 For emotional pain, however, it is quite different. In case of emotional pain (animal models), it is clear that peripheral nociceptors and spinal cord ascending sensory pathways are not required. Animals may use visual and odor signals, as well as ultrasonic signaling to process the input information. ¹³ Figure 1 is a simplified model for possible central pathways to distinguish these two pathways. While physical pain and emotional pain are different, there is research that suggests that both types of pain may share some neurological similarities. Both emotional and physical pain are linked to changes in pain-related cortical areas, ACC and IC that are commonly activated by both physical and emotional pain.

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Figure 1.

“Diego and I” by Freda Hahlo (1949).

Roles of ACC/IC in physical pain: Acute and chronic

Recent evidence consistently suggest that ACC and IC are two key cortical regions for pain perception as well as pain-related emotional responses.^1–4,8 Cumulative evidence is collected by using integrative neuroscience approaches in animal models of acute and chronic pain, human brain imaging in healthy subjects and patients with different types of chronic pain. For example, it has been consistently reported that the ACC is activated by different painful stimuli. ⁸ Similarly, the IC has been also reported in pain perception. ¹ In addition to somatosensory pain, it has also reported that ACC and IC are responsive for visceral pain.^4,14 There are also reports of ACC and IC involvement in different forms of chronic pain, such as neuropathic pain, irritable bowel syndrome, phantom pain.^1,8

Animal models of chronic and acute pain provide basic mechanisms that may explain what underlies pain processing in human patients. In both acute and chronic pain animal models, ACC and IC are found to be critical for pain processing. Peripheral noxious stimuli or injuries activate neurons in the ACC and IC, activate immediate early genes in neurons, enhances excitatory synaptic transmission in these regions. ⁸ Neuronal responses to subsequent sensory stimuli are significantly enhanced or sensitized. Inhibition by microinjection of different drugs and optogenetic inhibition of neurons in the ACC and IC produce analgesic effects in different animal models of chronic pain, including hyperalgesia and allodynia. Recent studies using virus and optogenetic approaches further identify selective projections from and into the ACC and IC.^9,15,16 It has been found that activation of selective projection related to ACC and IC may facilitate acute nociceptive responses, and inhibition of certain pathways produce analgesic effects in animal models of chronic pain.^16–18

ACC and IC in human emotional pain

With the development of language, music, and art, humans demonstrate advanced expression of emotion including emotional pain in the animal world. Human emotional pain can be expressed as sadness, loneliness, social rejection, hopeless, unhappiness,^19,20 fear, and anxiety. Due to the use of human brain imaging techniques, we have a good understanding of the involvement of brain regions in human emotional pain, and such unpleasantness can be triggered by a painful image or movie (visual), unpleasant sound (auditory), vocal language (music), and social rejection.^21–24 Among several key cortical areas, ACC and/or IC are commonly found to be activated or altered by emotional pain such as sadness, loneliness, rejection, hopelessness, and fear.^20,23–26

Empathy is generally regarded as an ability to perceive, and be sensitive to others’ situations, allowing individuals to feel or understand the emotions and experiences of others. ²⁷ Among its different forms, empathy for others’ pain (empathic pain) is particularly important for inspiring prosocial behaviors, inhibiting aggressive behaviors, and providing the basis for social moral development. Similar to emotional pain itself, empathic pain in humans can be conveyed through visual and auditory signaling, such as music, conversation, and bullying. Unlike rodents, olfaction plays a lesser role in humans for most emotional and empathic pain. It has been reported that ACC and/IC are activated by listening to sad music and looking at images of broken body parts.^28–31

Furthermore, it has been found that both ACC and IC are triggered by emotional pain in the patients without physical pain (CIP). In the case of emotional pain, recent studies using brain imaging combined with healthy and CIP patients revealed new information on how physical (sensory) pain and emotional pain are processed in the brain.^32,33 In patients with CIP, they showed normal brain responses to observed pain in the ACC and IC ³² ; clearly suggesting that ACC and IC are critical for emotional (empathic pain). Their findings also suggest that previous physical pain experience is not necessarily required for emotional pain, although it remains to be investigated if previous pain experience may affect more or less emotional pain in certain populations. ³⁴

ACC and IC in animal emotional pain (empathic pain)

While emotional pain is common in humans, it is difficult to study it in animal models ¹¹ reported that mice injected with acetic acid show increased pain responses when exposed to their cage-mates, ¹¹ suggesting seeing cage-mates suffering induces behavioral sensitization. Furthermore, it is likely that such sensitization may locate centrally. Several studies have indicated that ACC and its related networks play important roles in observational social learning.^35,36 Carrillo et al. ³⁵ indeed reported that ACC neurons fire more action potentials when they are witnessing another’s pain-like response. Subsequent studies have conformed empathic pain using different animal models.^10,37,38 In addition, empathic itch, another form unpleasant sensory responses, has also been reported.^37,39,40 One curious finding is that mice also showed empathic pain when they see their own pain-like images in the mirror, ³⁷ suggesting that such empathic pain behaviors may be induced without the concept of self.

Zaniboni et al. ³⁸ reported that insular inactivation reverses hyperalgesia induced by empathic chronic pain. Recently, Smith et al. show that the ACC-nucleus accumbens (NAc) pathway is activated after rapid empathic pain training. Optogenetic inhibition of the ACC-NAc pathway alleviates the behavioral empathic pain in mice. ¹⁰ These findings suggest that ACC-NAC projection is critical for empathic pain. Zhang et al. ⁹ demonstrate that glutamatergic projection from the IC to basolateral amygdala is important for empathic pain triggered in chronic nerve ligation (CPN). It becomes clear that animals are capable to sense others’ emotion and pain; and this form of emotion will affect their own behavioral responses to subsequent noxious stimuli. It is still hard to discern whether sense of “self” and/or the emotion of empathy are distinct per se. However, the cortical circuits that involved in emotional pain and physical pain may overlap in pathways including neurons in the ACC and IC.

Cortical links supporting emotional pain (empathic pain)

Previous studies using different anatomical methods have found that ACC neurons receive different projections in adult monkeys, rabbits, and rats.^3,8 Recent progress from several studies made by the virus tracing technology and optogenetic approaches have confirmed that ACC neurons receive projections from cortical areas. These areas include visual and auditory cortices which are two major sensory cortical areas that convey visual and auditory signaling to the ACC in addition to classic inputs from somatosensory cortices.^41–43 Furthermore, a recent study by Wu et al. ⁴⁴ reported that neurons in the ACC are able to encode safety status by selectively responding to different auditory signaling. Kim et al. ⁴⁵ functionally demonstrated that optogenetic activation of visual inputs to the ACC induced task-relevant responses in adult mice; suggesting that visual inputs to the ACC play an important role in the generation of physiological related actions. In addition, the cortical areas, Xue et al. ⁴² reported that in adult mice neurons in the ACC received direct projections from different sub-nuclei in the thalamus, including the anterior, ventral, medial, lateral, midline, and intralaminar thalamic nuclei. These findings provide key anatomical evidence for the connection between the thalamus and ACC. This finding is particularly relevant, since most of behavioral and functional studies of empathic pain and fear were collected from adult mice. Figure 2 is a simplified diagram to show how ACC neurons may be activated by different non-physical (somatosensory) stimuli.

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Figure 2.

Sensory pathways for (a) emotional and (b) physical pain.

Similar to the ACC, IC is another cortical area that is indicated in different forms of pain including emotional pain. ¹ Recent anatomical studies in mice reveal that neurons in IC receive innervation from olfactory, auditory and visual cortices.^1,2,46,47 The connection between ACC and IC has also been found in a recent study in adult mice (Xue et al., ⁴² ).

Emotional pain versus physical pain: Different paths

Based on these observations from animal models and human studies, it is likely that physical pain and emotional pain share much of the same cortical mechanisms. In particular, it is quite likely that basic synaptic mechanisms at cellular and molecular levels may be shared by these two types of pain. As glutamate is the major and only key fast excitatory transmitter in the ACC and IC,^1–3,8 synaptic signaling process and plasticity is mostly mediated by excitatory synapses. Cumulative evidence has strongly suggested that adult glutamatergic synapses in the cortex are highly plastic, including the ACC and IC. Different forms of LTPs have also been reported in the ACC and IC.^1,4,8,12 Furthermore, synaptic tagging of LTP, another form of heterosynaptic LTP, has been reported in the ACC and IC ⁴⁸ (Book chapter). Tagging provides a unique form of plasticity to link different sensory modulation of stimuli with painful experiences or memories, that is unique feature of emotional pain in most cases.

LTPs and synaptic tagging: Synaptic mechanisms for emotional pain

AMPA receptors mediated most fast synaptic responses in cortical synapses.^3,8 This transmission is dynamic, and some of these synapses are even silent or inactive in physiological conditions. The existence of silent synapses or inactive synapses provide a human reservoir of memory or capacity for brain functions. ¹² Different experimental protocols have been reported to induce LTP of synaptic responses. ⁸ One major form of LTP in the ACC and IC are a postsynaptic form of LTP (post-LTP), a form of LTP that is mediated by modification of postsynaptic AMPA receptors or recruitment of silent synapses. ¹² Post-LTP can be induced through various experimental protocols, including theta-burst stimulation by using field recordings,^49,50 stimulus-depolarization pairing and spike-EPSP pairing, ⁵¹ and as detected by whole-cell patch-clamp recordings in slices from adult mice. For field recordings using the MED technology, this form of LTP can be recorded up to 3–6 h in slice conditions. It has been found that some of silent responses can be re-activated after the induction of LTP. ¹² For the active synapses, the phosphorylation of AMPA receptor GluA1 receptors by PKA is critical. ⁵² The same mechanism may also contribute to the recruitment of silent responses. Among upstream signaling proteins, AC1 is critical in both ACC and IC synapses. Genetic deletion of AC1 or pharmacological inhibition of AC1 blocked post-LTP in the ACC and IC (see Figure 2). Long-lasting LTP or L-LTP also requires this protein synthesis and possible diffusible messenger BDNF. ⁵³

In addition to post-LTP, a presynaptic form of LTP (pre-LTP) has also been reported. ⁵⁴ Using whole-cell patch recordings or chemical application in MED recording system, this NMDA receptor independent pre-LTP can be recorded up to 3 h after the induction. Unlike post-LTP which is NMDA receptor dependent, pre-LTP requires activation of presynaptic kainate receptors. ⁵⁴ Interestingly, pre- and post-LTP have been observed in the same neurons, presumably at the same excitatory synapses. Behavioral studies indicate that pre-LTP is related to anxiety induced by chronic pain. For emotional pain which is often related to anxiety and fear, it is very likely that pre-LTP may play more important roles at synaptic levels among cortical network.

Most of LTP studies are homosynaptic. Heterosynaptic forms of LTP has also recently reported in adult ACC and IC (Figure 3). Depending on induction protocols, ACC LTP has at least two distinct temporal phases: protein synthesis-independent early-phase LTP (E-LTP), and protein synthesis-dependent late-phase LTP (L-LTP). Recently, we have reported that E-LTP and L-LTP can interact with each other in a “synaptic tagging-like manner.” ⁵⁵ While weak tetanus-inducing E-LTP sets a “tag,” which can capture the plasticity-related proteins (PRPs) synthesized following the strong tetanus-inducing L-LTP. A weak stimulus can induce L-LTP if it is preceded or followed by strong tetanus given to a separate, independent pathway that converges into the same neuronal population. For memory mechanism, synaptic tagging is believed to play important roles in long-term memory storage/allocation.^56,57 In the pain-related cortical areas, synaptic tagging may provide a unique mechanism for emotional pain. Human emotional pain is often related to some subtle sensory stimuli that alone may not be unpleasant at all. However, if these visual or auditory stimuli occurred at the same time of strong events, these stimuli may become a tagged trigger for emotional pain.

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Figure 3.

Different forms of synaptic plasticity in the pain-related cortex.

Synaptic enhancement during empathic pain

Recent electrophysiological studies have revealed that IC-amygdala excitatory transmission is enhanced after observing other mice suffering pain. ¹⁶ As compared with those recorded from injured animals, both the frequency and amplitude of mEPSCs were increased in IC-BLA-projecting neurons in siblings. These findings suggest both increased presynaptic release of glutamate and enhanced postsynaptic AMPA receptor-mediated responses in siblings. The increased presynaptic glutamate release was confirmed by the decreased paired-pulse ratio (PPR) of evoked excitatory postsynaptic currents (EPSCs). These results are similar to those reported excitatory transmission changes in the IC as well as ACC after peripheral nerve injury and/or other injuries.^8,58 Future studies are clearly needed to determine which of these mechanisms are unique for empathic pain and which are selective in chronic pain.

Emotional pain related physiological and pathological changes

It has been reported that emotional pain is also accompanied with anxiety, fear, sad, hopelessness, and depression. In some cases, it has been reported that emotional pain may trigger headache. Several cortical areas, including the ACC and IC are known to contribute to emotional functions and disorders such as anxiety, fear, and depression. Some emotional responses related to emotional pain may be mediated by the same ACC and IC neurons that are active during pain or ACC-projection to other cortical and subcortical regions. Recent studies reported that ACC-amygdala, and ACC-striatum may contribute to fear and depression. ¹⁸ Both ACC and IC have been indicated to be involved in loneliness. ⁵⁹ Altered connection between ACC to the lateral basal amygdala has been reported to contribute to loneliness. ²²

ACC/IC linked networks including top-down modulation of pain may explain some of the symptoms related to emotional pain. In addition to emotional anxiety and fear, it has also been reported that emotional pain may cause abnormal or sensitive physical sensations. Recent animal studies have revealed that a deep layer of ACC neurons sends its projection to the dorsal horn of the spinal cord and facilitates pain transmission. ¹⁶ Enhanced sensory information is conveyed to the thalamus and cortex, triggering abnormal sensation of the body including somatosensory information from internal organs. In some cases, ACC may also affect transmission of somatosensory cortex by direct projections,^16,60 and thus produce abnormal sensation during emotional pain.

Some of these activities may further enhance top-down modulation by positive feedback activity (see Figure 4). Thus, this direct cortico-spinal pathway may provide a novel means to link mood changes with the bodily sensation. Since abnormal ACC activity has been linked to different functions, where is the selectivity of functions and neurons? Recent evidence suggests that distinct projection connections with the ACC is at least contributing the selectivity of different functions. Li et al. ¹⁷ recently reported that the connection between ACC and striatum play an important role in sleep disorders related to chronic pain.^15,61 Previously, Chen et al. ¹⁶ reveal a top-down projection from the ACC directly to spinal cord dorsal horn neurons. Activation of this projection significantly facilitates spinal sensory synaptic transmission, including evoked responses to peripheral sensory stimulation. This unique pathway may allow abnormal neuronal activity within the ACC to affect physiological synaptic transmission at spinal cord level, including sensory transmission from body surface as well as visceral organs. It may provide an anatomic link for explaining several body responses during emotional pain.^1,2

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Figure 4.

Enhancement of persistent inflammatory pain by mirror exposure in adult mice. Behavioral nociceptive responses were examined under mirror and non-mirror conditions in adult mice. (a) Experimental setup showing the open-field apparatus equipped with a bottom-mounted camera for behavioral recording. (b) Representative images of a mouse in the open field following formalin injection. The left chamber represents the standard open field (control), while the right chamber includes mirrored walls. (c) In the presence of mirrors, acute flinching responses (Phase I) were not significantly altered. (d) However, during Phase II, which reflects persistent inflammatory pain, a significant enhancement of nociceptive behavior was observed under the mirror condition.

In addition to receive different inputs from cortical and subcortical areas, neurons in the ACC also receive direct innervation from the other side of ACC. ¹⁷ This connection is monosynaptic and excitatory. Activation of this connection can facilitate behavioral responses to nociceptive stimuli, suggesting that ACCs located at two hemispheres work together. Future studies should always keep the fact in mind that ACC network is likely bilateral in nature.

Empathic fear and anxiety

In additional to pain, empathic fear and itch has been reported using animal models. For example, Jeon et al. ⁶² reported that mice developed freezing behavior by observing other mice receiving repetitive foot shocks. Interestingly, observers showed higher fear responses when demonstrators were socially related to themselves such as siblings or mating partners. They are the first to demonstrate that activity of ACC is required for this observational fear. ⁶² Subsequent studies confirmed the existence of empathic fear in mice using similar tests, and the important role of ACC or ACC-related subcortical regions are found to be required for empathic fear.^27,63–66 Previous studies using behavioral, gene mapping, and electrophysiological approaches reveal that ACC plays important roles in the induction and expression of fear memory.^13,67 Fear conditioning activates pyramidal neurons located in the ACC and direct stimulation of the ACC generates fear memory in freely moving mice. ¹³ Neuronal activities of ACC are affected by freezing behaviors. ⁶⁸ Biochemical studies revealed that fear training induced postsynaptic expression of AMPA GluA1 receptors in ACC pyramidal cells. ⁶⁷ Genetic studies using an ACC-limited deletion of Ca(v)1.2 Ca²⁺ channels in mice impaired observational fear. Interestingly, physical pain responses were also affected, ⁶² suggesting that some ACC neurons are involved in both emotional and physical pain.

Recent studies using optogenetic approaches reveal more evidence for the involvement of selective projection pathways from ACC in empathy of fear versus pain. Smith et al. ¹⁰ reported that the ACC to the nucleus accumbens (NAc) was selectively involved in the social transfer of both pain and analgesia. By contrast, the ACC→NAc circuit was not necessary for the social transfer of fear. Kim et al. ⁶⁹ reported that rhythmic oscillation in the ACC-amygdala circuits (both directions) drive empathic fear in mice; further supporting the roles of ACC-amygdala connections in empathic fear.

A recent study using human brain imaging demonstrated that ACC and IC are activated during learning as well as the expression of empathic fear in human subjects ⁷⁰ ; confirming the key discovery of empathic pain using animal models.

Future translational neuroscience for emotional pain

While integrative researches using different animal models provide key basic mechanisms for different types of pain including emotional pain, it is important to point out that animal behavioral responses may not mimic human emotion such as sadness, empathy, and psychological pain. Future studies in human subjects including patients with emotional disorders are clearly needed to test these hypotheses generated from animal studies. The combination of animal and human studies are clearly needed for the research of emotional pain.

Considering the important role of ACC and IC in both emotional pain and chronic pain, it is likely that some signaling mechanisms may be shared between these two different forms of pain. For example, it has been shown that excitatory synaptic transmission in the IC was enhanced after peripheral injuries or exposure to emotional pain.^9,71 Similarly, excitatory transmission in the ACC is also significantly enhanced, including both presynaptic release of glutamate as well as postsynaptic responses of AMPA and NMDA receptors. By studying different forms of LTPs in the ACC/IC, it is conceivable that some key molecular targets may play important roles in emotional pain. ⁸ For example, Li et al. ⁷² reported that ACC microinjection of oxytocin reduced injury-related anxiety by erasing anxiety-related pre-LTP. In a human study, Zunhammer et al. ⁷³ reported that intranasal oxytocin pretreatment increases the effects of emotional context (such as negative valence) on the subjective unpleasantness of experimental heat pain. Xie et al. ⁷⁴ reported that pain contagion occurred in stranger female rats and blocking oxytocin receptors in the ACC inhibited pain contagion. Furthermore, they found that such effect is sex-dependent, and can be found in stranger male rats. ⁷⁴ In animal models of chronic pain, KA receptors, HCN channels, NMDA receptors, AMPA receptors, AC1, and PKA have been indicated in the ACC/IC LTPs. A selective inhibitor for AC1, NB001, has been found to be able to pass through the the blood brain barrier and produces its effect in the ACC. Preclinical and clinical Phase I studies have found that NB001 is safe in both rodents and healthy human subjects.^6,75 Future studies will be needed to termine if NB001 may help to reduce emotional pain in patients. From basic research point of view, it is important for future studies to investigate basic synaptic mechanisms for emotional pain in the ACC and IC.

In conclusion, emotional pain is likely to be increased in modern society with increased negative information flooding in the internet and media. By investigating emotional pain using different animal models as well as human studies, it is possible that we will understand basic mechanism for emotional pain including those long-lasting, and develop new treatment for those patients.