The first step in understanding the nociceptive experience as an affective response is by appreciating the origins and purposes of emotion. Many physicians regard emotions as epiphenomenal feeling states associated with mental activity, subjective in character, and largely irrelevant to the state of a patient’s physical health. In fact, emotions are primarily physiologic and only secondarily subjective. Because they can strongly affect cardiovascular function, visceral motility, genitourinary function, and immune competence, patient emotions can have an important role in health overall and especially in pain management. Simple negative emotional arousal can exacerbate certain pain states such as sympathetically maintained pain, angina, headache, neuropathic pain, and fibromyalgia. It contributes significantly to musculoskeletal pain, pelvic pain, and other pain problems in some patients.

Emotions are complex states of physiologic arousal and awareness that impute positive or negative hedonic qualities to a stimulus (event) in the internal or external environment. The objective aspect of emotion is autonomically and hormonally mediated physiologic arousal. The subjective aspects of emotion, feelings, are phenomena of consciousness. Emotion represents in consciousness the biologic importance or meaning of an event to the perceiver.

Emotion as a whole has two defining features: valence and arousal. Valence refers to the hedonic quality associated with an emotion—the positive or negative feeling attached to perception. Arousal refers to the degree of heightened activity in the central nervous system and autonomic nervous system (ANS) associated with perception.

Although emotions as a whole can be either positive or negative in valence, pain research addresses only negative emotion. Viewed as an emotion, pain represents a threat to the biologic, psychological, or social integrity of the person. In this respect, the emotional aspect of pain is a protective response that normally contributes to adaptation and survival. If uncontrolled or poorly managed in patients with severe or prolonged pain, it produces suffering.

Psychologists have many frameworks for studying emotion. Nature has equipped us with the capability of negative emotion for a purpose; bad feelings are not simply accidents of human consciousness. They are protective mechanisms that normally serve us well, but like uncontrolled pain, sustained and uncontrolled negative emotions can become pathologic states that can produce both maladaptive behavior and physiologic pathology.

By exploring the emotional dimension of pain from the sociobiologic perspective, the reader may gain some insight about how to prevent or control the negative affective aspect of pain, which fosters suffering. Unfortunately, implementing this perspective requires that we change conventional language habits that involve describing pain as a transient sensory event. Pain is a compelling and emotionally negative state of the individual that has as its primary defining feature awareness of, and adaptive adjustment to, tissue trauma or disease.

Emotions, including the emotional dimension of pain, characterize mammals exclusively, and they foster mammalian adaptation by making possible complex behaviors and adaptations. Importantly, they play a strong role in consciousness, producing and summarizing information that is important for selection among alternative behaviors. According to MacLean,⁷ emotions “impart subjective information that is instrumental in guiding behavior required for self-preservation and preservation of the species. The subjective awareness that is an affect consists of a sense of bodily pervasiveness or by feelings localized to certain parts of the body [emphasis added].” Because negative emotions, such as fear, evolved to facilitate adaptation and survival, emotion plays an important defensive role. The ability to experience threat when encountering injurious events protects against life-threatening injury.

The strength of emotional arousal associated with an injury indicates and expresses the magnitude of perceived threat to the biologic integrity of the person. Within the contents of consciousness, threat is a strong negative feeling state and not a pure informational appraisal. In humans, threatening events, such as injury that are not immediately present, can exist as emotionally colored somatosensory images.

Phenomenal awareness consists largely of the production of images. Visual images are familiar to everyone: We can readily imagine seeing things. We can also produce auditory images by imaging a familiar tune, a bird song, or the sound of a friend’s voice. Similarly, we can generate somatosensory images. We can, for example, imagine the feeling of a full bladder, the sensation of a particular shoe on a foot, or a familiar muscle tension or ache. Cognition operates largely on images and plays a strong role in the experience of symptoms.

Patients can react emotionally to the mental image of a painful event before it happens (e.g., venipuncture), or for that matter, they can respond emotionally to the sight of another person’s injury. The emotional intensity of such a feeling marks the adaptive significance of the event that produced the experience for the perceiver. In general, the threat of a minor injury normally provokes less feeling than one that incurs a risk of death. The emotional magnitude of a pain is the internal representation of the threat associated with the event that produced the pain.

Negative emotions compel action, such as fight or flight, along with expression through vocalization, posture, variations in facial musculature patterns, and alterations of activity. This represents communication and often elicits social support, thus contributing to survival. Darwin,⁸ observing animals, noted that emotions enable communication through vocalization, startle, posture, facial expression, and specific behaviors. He held that emotions must be inborn rather than learned tendencies. Darwin⁸ pursued this issue by comparing the facial and other emotional expressions of children born blind with those of other children, reasoning that blind children would express emotion differently if emotion is primarily a learned behavior. As others have since confirmed,⁹ Darwin⁸ learned that the basic blueprints for human emotional expression are innate.

Contemporary investigators who study emotions and human or animal social behavior emphasize that communication is a fundamental adaptive function of emotional expression.^10,11 Social mammals, including humans, depend on one another or their social group as resources for adaptation and survival. The emotional expression of pain in the presence of supportive persons is socially powerful; it draws on a fundamental sociobiologic imperative: communicating threat and summoning assistance.

The limbic brain represents an anatomical common denominator across mammalian species,⁷ and emotion is a common feature of mammals. Consequently, investigators can learn much about human emotion by studying mammalian laboratory animals. Humans and animals differ in that the limbic brain is more developed in humans, the frontal lobes are unique to our species, and the interdependence of cognition and emotion is greatest in humans.

Early investigators focused on the role of olfaction in limbic function, and this led them to link the limbic brain to emotion. Emotion may have evolutionary roots in olfactory perception. MacLean¹² introduced the somewhat controversial term “limbic system” and characterized its functions. He identified three main subdivisions of the limbic brain: amygdala, septum, and thalamocingulate⁷ that represent sources of afferents to parts of the limbic cortex. He also postulated that the limbic brain responds to two basic types of input: interoceptive and exteroceptive. These refer to sensory information from internal and external environments, respectively. Figure 29.1 summarizes and extends this concept. Noxious signaling can arise from an injurious event in the external environment or from a pathologic condition in the internal environment.

Over the last decade, numerous studies have employed functional brain imaging to investigate how the human brain responds to painful laboratory stimulation as well as how it behaves in chronic pain conditions. These studies reveal unequivocally that limbic structures involved in emotion and cognition are active during pain. In addition, related studies show that cognitive processes such as threat appraisal and perceived control are related to pain modulation. Early brain imaging studies have shown that the following brain structures are consistently active during states of pain: thalamus, primary and secondary somatosensory cortices, insular cortex, anterior cingulate, and the prefrontal cortices (PFC) as well as deactivation of the posterior cingulate cortex and medial prefrontal cortex,^13,14,15 which compose of the default mode network involved in self-referential processing.¹⁶ Thalamus and the somatosensory cortices played a prominent role in early neurophysiologic models of pain and processing of ascending nociceptive information. Insular cortex may play a role in the somatosensory representation of the body, and it appears to integrate multimodal sensory information.¹⁷ PFC control the executive functions of the brain and the sense of self. They are involved in threat appraisal, meaning, and the integration of information from the internal and external environment.

The ANS plays a major role in regulating the constancy of the internal environment, and it does so in a feedback regulated fashion under the direction of the hypothalamus, the solitary nucleus (nucleus tractus solitarius) and ventral lateral medulla, the amygdala, and other brain structures.^18,19 In general, it regulates activities that are not normally under voluntary control. The hypothalamus is the principal integrator of autonomic activity. Stimulation of the hypothalamus elicits highly integrated patterns of response that involve the limbic system and other structures.²⁰

Many researchers hold that the ANS has three divisions: the sympathetic, the parasympathetic, and the enteric.^21,22 Others subsume the enteric under the other two divisions. Broadly, the sympathetic nervous system makes possible the arousal needed for fight and flight reactions, whereas the parasympathetic system governs basal heart rate, metabolism, and respiration. The enteric nervous system innervates the viscera via a complex network of interconnected plexuses.

The sympathetic and parasympathetic systems are largely mutual physiologic antagonists—if one system inhibits a function, the other typically augments it. There are, however, important exceptions to this rule that demonstrate complementary or integratory relationships. The mechanism most heavily involved in the affective response to tissue trauma is the sympathetic nervous system.

During emergency or injury to the body, the hypothalamus uses the sympathetic nervous system to increase cardiac output, respiration rate, and blood glucose. It also regulates body temperature, causes piloerection, alters muscle tone, provides compensatory responses to hemorrhage, and dilates pupils. These responses are part of a coordinated, well-orchestrated response pattern called the defense response.^23,24,25 It resembles the better known orienting response in some respects, but it can only occur following a strong stimulus that is noxious or frankly painful. It sets the stage for escape or confrontation, thus serving to protect the organism from danger. In an awake cat, both electrical stimulation of the hypothalamus and infusion of norepinephrine into the hypothalamus elicit a rage reaction with hissing, snarling, and attack posture with claw exposure, and a pattern of sympathetic nervous system arousal accompanies this.^26,27,28 Circulating epinephrine and norepinephrine produced by the adrenal medulla during activation of the sympathoadrenomedullary (SAM) axis accentuate the defense response, fear responses, and aversive emotional arousal in general.

Central sensory and affective pain processes share common sensory mechanisms in the periphery. As other chapters in this book describe, Aδ and C fibers serve as tissue trauma transducers (nociceptors) for both, the chemical products of inflammation sensitize these nociceptors, and peripheral neuropathic mechanisms such as ectopic firing excite both processes. In some cases, neuropathic mechanisms may substitute for transduction as we classically define it, producing afferent signal volleys that appear, to the central nervous system, like signals originating in nociceptors. Differentiation of sensory and affective processing begins at the dorsal horn of the spinal cord. Sensory transmission follows spinothalamic pathways and transmission destined for affective processing takes place in spinoreticular pathways.

Noxious centripetal transmission engages multiple pathways: spinoreticular, spinomesencephalic, spinolimbic, spinocervical, and spinothalamic tracts,^31,32 as Figure 29.3 indicates. The spinoreticular tract contains somatosensory and viscerosensory afferent pathways that arrive at different levels of the brain stem. Spinoreticular axons possess receptive fields that resemble those of spinothalamic tract neurons projecting to medial thalamus, and, like their spinothalamic counterparts, they transmit tissue injury information.^33,34 Most spinoreticular neurons carry noxious signals, and many of them respond preferentially to noxious activity.^35,36 The spinomesencephalic tract comprises several projections that terminate in multiple midbrain nuclei, including the periaqueductal gray (PAG), the red nucleus, nucleus cuneiformis, and the Edinger-Westphal nucleus.³² Spinolimbic tracts include the spinohypothalamic tract, which reaches both lateral and medial hypothalamus^37,38 and the spinoamygdalar tract that extends to the central nucleus of the amygdala.³⁹ The spinocervical tract, like the spinothalamic tract, conveys signals to the thalamus. All of these tracts transmit tissue trauma signals rostrally.

Substantial evidence supports the hypothesis that noradrenergic brain pathways are major mechanisms of anxiety and stress.⁴¹ The majority of noradrenergic neurons originate in the LC. This pontine nucleus resides bilaterally near the wall of the fourth ventricle. The locus has three major projections: ascending, descending, and cerebellar. The ascending projection, the DNB, is the most extensive and important pathway for our purposes.⁴⁷ Projecting from the LC throughout limbic brain and to all of neocortex, the DNB accounts for about 70% of all brain norepinephrine.⁴⁸ The LC gives rise to most central noradrenergic fibers in spinal cord, hypothalamus, thalamus, and hippocampus,⁴⁹ and in addition, it projects to limbic cortex and neocortex. Consequently, the LC exerts a powerful influence on higher level brain activity.

The noradrenergic stress response hypothesis holds that any stimulus that threatens the biologic, psychological, or psychosocial integrity of the individual increases the firing rate of the LC, and this in turn results in increased release and turnover of norepinephrine in the brain areas involved in noradrenergic innervation. Studies show that the LC reacts to signaling from sensory stimuli that potentially threaten the biologic integrity of the individual or signal damage to that integrity.⁴⁸ Spinal cord lamina I cells terminate in the LC.³³ The major sources of LC afferent input are the paragigantocellularis and prepositus hypoglossi nuclei in the medulla, but destruction of these nuclei does not block LC response to somatosensory stimuli.^50,51 Other sources of afferent input to the locus include the lateral hypothalamus, the amygdala, and the solitary nucleus. Whether noxious signaling stimulates the LC directly or indirectly is still uncertain.

It is quite clear that noxious signaling inevitably and reliably increases activity in neurons of the LC, and LC excitation appears to be a consistent response to noxious signaling.^48,52,53,54 Notably, this does not require cognitively mediated attentional control because it occurs in anesthetized animals. Foote et al.⁵⁵ reported that slow, tonic spontaneous activity at the locus in rats changed under anesthesia in response to noxious stimulation. Experimentally induced phasic LC activation produces alarm and apparent fear in primates,^56,57 and lesions of the LC eliminate normal heart rate increases to threatening stimuli.⁵⁸ In a resting animal, LC neurons discharge in a slow, phasic manner.⁵⁹

The LC reacts consistently, but not exclusively, to noxious signaling. LC firing rates increase following nonnoxious but threatening events, such as strong cardiovascular stimulation,^53,60 and certain visceral events, such as distention of the bladder, stomach, colon, or rectum.^48,61 Highly novel and sudden stimuli that could represent potential threat, such as loud clicks or light flashes, can also excite the LC in experimental animals.⁵⁹ Thus, the LC responds to biologically threatening or potentially threatening events, of which tissue injury is a significant subset. Amaral and Sinnamon⁶² described the LC as a central analog of the sympathetic ganglia. Viewed in this way, it is an extension of the autonomic protective mechanism described earlier.

Invasive studies confirm the linkage between LC activity and threat. Direct activation of the DNB and associated limbic structures in laboratory animals produces sympathetic nervous system response and elicits emotional behaviors such as defensive threat, fright, enhanced startle, freezing, and vocalization.⁶³ This indicates that enhanced activity in these pathways corresponds to negative emotional arousal and behaviors appropriate to perceived threat. LC firing rates increase two- to threefold during the defense response elicited in a cat that has perceived a dog.²⁶ Moreover, infusion of norepinephrine into the hypothalamus of an awake cat elicits a defensive rage reaction that includes activation of the LC noradrenergic system. In general, the mammalian defense response involves increased regional turnover and release of norepinephrine in the brain regions that the LC innervates. The LC response to threat, therefore, may be a component of the partly “prewired” patterns associated with the defense response.

Increased alertness is a key element in early stages of the defense response. Normally, activity in the LC increases alertness. Tonically enhanced LC and DNB discharge corresponds to hypervigilance and emotionality.^41,55,64 The DNB is the mechanism for vigilance and defensive orientation to affectively relevant and novel stimuli. It also regulates attentional processes and facilitates motor responses.^40,43,48,65 In this sense, the LC influences the stream of consciousness on an ongoing basis and readies the individual to respond quickly and effectively to threat when it occurs.

LC and DNB support biologic survival by making possible global vigilance for threatening and harmful stimuli. Siegel and Rogawski⁶⁶ hypothesized a link between the LC noradrenergic system and vigilance, focusing on rapid eye movement (REM) sleep. They noted that LC noradrenergic neurons maintain continuous activity in both normal waking state and non-REM sleep, but during REM sleep, these neurons virtually cease discharge activity. Moreover, an increase in REM sleep ensues after either lesion of the DNB or following administration of clonidine, an α₂ adrenoceptor agonist. Because LC inactivation during REM sleep permits rebuilding of noradrenergic stores, REM sleep may be necessary preparation for sustained periods of high alertness during subsequent waking. Siegel and Rogawski^66(p226) contended that “a principal function of NE in the CNS is to facilitate the excitability of target neurons to specific high priority signals.” Conversely, reduced LC activity periods (REM sleep) allow time for a suppression of sympathetic tone.

Both adaptation and sensitization can alter the LC response to threat. Abercrombie and Jacobs^67,68 demonstrated a noradrenergically mediated increase in heart rate in cats exposed to white noise. Elevated heart rate decreased with repeated exposure as did LC activation and circulating levels of norepinephrine. Libet and Gleason⁶⁹ found that stimulation via permanently implanted LC electrodes did not elicit indefinite anxiety. This indicates that the brain either adapts to locus excitation or engages a compensatory response to excessive LC activation under some circumstances. In addition, central noradrenergic responsiveness changes as a function of learning. In the cat, pairing a stimulus with a noxious air puff results in increased LC firing with subsequent presentations of the stimulus, but previous pairing of that stimulus with a food reward produces no alteration in LC firing rates with repeated presentation.⁵⁹ These studies show that, despite its apparently “prewired” behavioral subroutines, the noradrenergic brain shows substantial neuroplasticity. The emotional response of animals and people to a painful stimulus can adapt, and it can change as a function of experience.