An afferent signal originating in the GI tract activates the nerve endings in the bowel wall and travels along the first-order spinal afferents, which synapse with the second-order neurons in the dorsal horn of the spinal cord. The second-order neurons project to the brain through the spinoreticular, spinomesencephalic, spinohypothalamic, and spinothalamic tracts. While the first three tracts mainly activate unconscious and autonomic responses to visceral sensory input including changes in emotion and behavior, the latter transmits conscious sensation by its projections to the somatosensory cortex, anterior cingulate cortex, and the insula. The spinothalamic pathway is mainly responsible for pain localization and assessment of pain intensity, and the other three pathways modulate affective pain behavior with stimulation of important autonomic and descending inhibitory pathways (Fig. 38.1). In animal models, the anterior cingulate cortex and its projections to the amygdala and periaqueductal gray matter of the midbrain and the rostral ventromedial medulla and the dorsolateral pontine tegmentum can selectively modulate nociceptive transmission. Stimulation of these sites inhibits responses of spinal neurons to noxious stimuli and can have an analgesic effect [16]. Therefore, second-order spinal neurons are activated by afferent input from the first-order neurons conveying messages from the bowel and inhibitory input from the brain. Traditional thinking assumes that disruption in this balance can result in hypersensitivity.

Peripheral sensitization represents a form of stimulus-evoked nociceptor plasticity in which more prolonged stimulation, especially in the context of inflammation or injury, leads to change in the chemical milieu that permits nociceptor firing at a lower level. The main sensitizers implicated in primary sensitization include bradykinin, histamine, serotonin, proteases, and cytokines [17]. Persistent abdominal pain following a gastrointestinal infection, surgery during infancy [18], or an inflammatory disorder such as gastroenteritis, Henoch–Schonlein purpura, and cow’s milk intolerance can alter pain perception, and visceral hypersensitivity is thought to be one of the mechanisms responsible for this change [19–21].

Under physiological states, spinal afferents respond only to noxious stimuli, but under conditions of injury and inflammation of peripheral nerve endings or repetitive noxious stimulation, they can respond to lower intensity afferent signal, a phenomenon called central sensitization [15]. Central sensitization can also affect adjacent neurons , leading to the recruitment of previously “silent” nociceptors and hyperalgesia in regions (somatic and visceral) remote to the site of peripheral sensitization. This is also termed secondary hyperalgesia. In animal models, this facilitation is triggered by presynaptic release of neurotransmitters and increased intracellular calcium, which lead to phosphorylation of N-methyl-d-aspartate (NMDA) receptors and resultant changes in receptor kinetics. Substance P and other tachykinins play a crucial role in central sensitization [17, 22]. Descending projections from the brain stem nuclei to the spinal cord enhance or reduce the excitability of dorsal horn neurons, which receive afferent input from the viscera, in part through the opioidergic and adrenergic descending pain inhibitory pathways. Using the water-drinking test and barostat studies, altered sensory gastric perception and visceral hypersensitivity have been reported in children with FAP [23–25].

This traditional view that chronic pain disorders are either driven by primary afferent input (e.g., post-infectious irritable bowel syndrome) or sustained by the local reverberating circuitry within the spinal cord and facilitated by descending pain modulation has been challenged. In the last decade advances in functional brain imaging has helped in identifying key neural structures involved in processing experimental gut stimulation [26, 27] The human brain is intrinsically organized into distinct functional networks supporting various sensory, motor, and cognitive functions [28]. Of particular relevance to the understanding of visceral hypersensitivity and altered brain–gut interaction in IBS is an intrinsic brain network, the salience network (SN), with two key anchor nodes in the anterior insula (AI) and anterior cingulate cortex (ACC ) [29]. The SN has extensive connections with cortical and subcortical brain structures, such as the medial prefrontal cortex, thalamus, amygdala, cerebellum, and midbrain structures. Pain produced in the absence of tissue injury (e.g., FGIDs) and pain relief in the absence of drugs (e.g., placebo analgesia) provide compelling evidence that salience—how we interpret the importance of a given physiological state—is able to reproduce experiences to those produced by overt tissue injury or potent analgesic medications. A number of studies using controlled rectal distension as the stimulus have shown greater engagement of regions of the salience network in IBS patients [27]. Our group evaluated changes in the brain networks in a small cohort of pediatric patients with chronic visceral pain and emphasized the crucial role of the SN in modulating the engagement of the executive control network and disengagement of the default mode network (brain activity during mental rest) when attending to a salience event (e.g., rectal distension) [30].

It has also become clear that some of the brain circuitry involved in processing pain-related information can be engaged by social and emotional experiences such as viewing another individual in pain, and these experiences appear to selectively involve neuro-circuitry related to emotional rather than sensory aspects of pain. Viewed in the context of a more comprehensive conceptual framework, rather than the narrow viewpoint of nociceptive processing, IBS symptoms can be defined by dysfunctions in a generalized model of visceral homeostatic regulation network within the brain–gut axis, regulating not only physiological conditions of viscera, but also the associated emotional and motivational contents [31]. Children with FAP appear to be temperamentally anxious and suffer from emotional difficulties. Such temperamental traits have been associated with pessimistic worry, fear of uncertainty, harm avoidance, and a lowered response threshold to environmental challenges [32–36]. Children with a high pain dysfunctional profile have been characterized by poor coping skills, negative affect, pain catastrophizing, higher disability, and enhanced pain sensitization several years later [37].

Early life stress can also influence illness behavior and emotional response to pain [38]. Work in animal models suggests that severe, prolonged, or repetitive pain can trigger neurobiological changes that can permanently modify pain pathways [39]. These changes are likely to be mediated through the hypothalamic–pituitary–adrenal axis [40–42]. A higher incidence of FGIDs and psychiatric comorbidities has been reported in adults who were abused as children [43–45]. A recent meta-analysis reported a 2.7 higher risk of functional somatic syndromes in individuals exposed to trauma as young [46]. What constitutes a painful or a potential sensitizing event is not clear. Painful experiences in neonatal life have been related to altered pain processing and hypersensitivity in later life [47, 48]. A stressful life event such as marital turmoil in the family, school bullying, and being involved in an accident can predate the onset of FAP. Therefore, stressful life events both early and later on in life seem to be a common in children with FAP. Corticotropin-releasing factor is an important hormone involved in stress response and can alter GI motility and visceral sensitivity [49].

Parenting style can influence a child’s ability to cope with pain. Children of parents who have IBS report more bothersome gastrointestinal symptoms compared to control children [50]. They also have more school absences and physician visits for gastrointestinal symptoms [51]. Twin studies have shown that the presence of IBS in the respondent’s parents made a larger contribution to the risk of having IBS than did the presence of IBS in one’s twin, suggesting social learning is more important than the environmental factors in determining illness behavior [52]. Further support for social learning in determining illness behavior comes from research showing a relationship between parental responses and children’s behavior [9]. Higher levels of parental solicitousness in response to their child illness behaviors are related to higher levels of children’s symptoms and disability as measured by school absences. Factors associated with solicitous behavior include non-Caucasian race, lower educational status, single mother or no partner, and parental perception of severity of their child’s condition [9, 11].

Cognitive behavioral therapy (CBT) is based on the belief that our thoughts, behaviors, and feelings interact and aims to reduce or eliminate physical symptoms through cognitive and behavioral changes. Cognitive behavioral therapy guides patients to modify or change cognitive distortions or irrational, negative thinking to improve mood and functioning. Parental response to pain reports and beliefs about the significance of pain and levels of psychological distress in the child can affect the severity of GI symptoms and disability. Cognitive behavioral therapy would guide a patient who believes that his or her pain is a symptom of undiagnosed terminal illness to challenge this belief and consider substituting a more realistic thought, such as that the pain is likely to subside and does not represent a terminal illness. Several randomized controlled trials to test the effectiveness of pain interventions in children, using a self-management approach that includes components of CBT and involvement of parents in treatment, yielded encouraging results (Table 38.3) [67–71]. However, methodological limitations in some of these studies have made interpretation of results difficult. A recent Cochrane review thought CBT is worth considering for some children with functional abdominal pain, but better quality studies to show the efficacy of CBT are needed [72]. The American Academy of Pediatrics also rates CBT as efficacious in the treatment of FAP [73]. Recent guidelines for addressing anxiety in children with FAP have been suggested by Cunningham et al. [74].