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New Insights Into Functional Abdominal Pain and Irritable Bowel Syndrome in Children: A Multidisciplinary Approach

Early Life Events and the Development of Visceral Hyperalgesia

Miranda, Adrian

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Journal of Pediatric Gastroenterology and Nutrition: November 2008 - Volume 47 - Issue 5 - p 682-684
doi: 10.1097/01.mpg.0000338958.94313.99
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The pathophysiology of functional bowel disorders in children such as irritable bowel syndrome (IBS) and functional abdominal pain is poorly understood. Enhancement of visceral sensitivity to physiological and noxious stimuli seems to be the hallmark of functional pain. Nociceptive neuronal circuits, formed during the neonatal period, normally require use-dependent activity for appropriate development. Noxious stimuli or stress during this critical period may alter their development and subsequently result in decreased pain thresholds later in life. The question of whether adverse events experienced in early life can prime a child to develop chronic abdominal pain is one that has only recently received much attention. Animal and human data suggest that there are at least 4 putative mechanisms that may help explain the development of visceral hypersensitivity following early life pain or stress: sensitization of central (spinal) neurons, sensitization of primary sensory neurons, impaired stress response (hypothalamic-pituitary-adrenal axis), and/or altered descending inhibitory control.

SPINAL NEURONAL SENSITIZATION

Sensitization of spinal sensory neurons can result in enhanced neurotransmission, increased neuronal spontaneous activity, and decreased firing thresholds. Recent evidence suggests that neonatal rat exposure to either repetitive colorectal distension (CRD) or colonic irritation results in permanent alterations in spinal dorsal horn neurons and subsequent chronic visceral hyperalgesia in adulthood (1). Similar results are obtained if a noxious stimulus is given early in development in areas of viscero-somatic convergence. For example, we have previously shown that noxious somatic stimulation in the gastrocnemius muscle of neonatal rats results in sensitization of CRD-sensitive spinal neurons and chronic visceral hyperalgesia in adult rats (2). This is not surprising because most spinal neurons that receive input from the visceral afferents in the thoraco-lumbar and the lumbo-sacral spinal cord also receive convergent synaptic input from afferents of the deep somatic domain. Thus, somatic pain experienced during a time of great neuronal plasticity such as trauma or surgery may influence the response and behavior of spinal neurons, resulting in sensitization and a decreased threshold for pain. Infants with prior surgery have been shown to require higher fentanyl dosages intraoperatively, display greater postoperative distress, and require higher doses of morphine postoperatively (3). Similarly, infants with prenatally diagnosed hydronephrosis demonstrate increased abdominal sensitivity compared to controls, which is an example of convergent viscero-somatic inputs (4).

SENSITIZATION OF PRIMARY SENSORY NEURONS

Visceral sensation is a complex process that involves transmission of impulses that start in the gut and travel through the spinal cord via afferent nerves. The enteric nervous system, often termed the “little brain,” has as many neurons as the spinal cord. The lower sensory threshold in patients with functional pain or IBS may reflect increased signaling from the peripheral gut (ie, sensitization of intramural mechanoreceptors) that occurs following low-grade inflammation or immune activation early in development. Previous studies show that colonic irritation in neonatal rats sensitizes primary sensory neurons in the lumbosacral region and results in higher neuronal spontaneous firing and response to colorectal distension (5). This may occur though a variety of potential mechanisms including increased expression of receptor molecules involved in nociceptive pathways, alteration of ionic channel properties (ie, N-methyl-D-aspartate, 5-hydroxytryptamine, transient receptor potential vanilloid receptor 1, natural killer), or the presence of inflammatory mediators. The severity and frequency of abdominal pain in patients with IBS has been shown to correlate with the presence of activated mast cells in proximity of nerve endings in the gut wall (6). Furthermore, not all patients with IBS or functional abdominal pain have somatic complaints, which supports a peripheral mechanism involved in the enhanced pain transmission. It is important to realize that sensitization early in life may not result in the development of symptoms but may prime or predispose a child to the development of hyperalgesia later in life when re-exposed to injury or stress. The effect of a second attack has been shown in a neonatal rat model of bladder inflammation (7).

IMPAIRED HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

Stress and anxiety are known triggers for symptoms of functional pain and IBS. Children with early life stress are more likely to develop IBS (8). Thus, it seems likely that adverse early life events can alter the stress response and bowel sensitivity later in life. The central corticotropin releasing factor (CRF) system has been implicated in mediating the effects of early life stress and may contribute to the development of abnormal reactivity of the hypothalamic-pituitary-adrenal axis. Rats pups exposed to 180 min of maternal separation for the first 2 weeks of life develop acute and delayed stress-induced visceral hyperalgesia to CRD (9). The stress of maternal separation has also been shown to increase CRF-like immunoreactivity and mRNA levels in the periventricular nucleus, locus coeruleus, and amygdala of adult rats (10). We have recently shown that stress associated with orogastric suctioning in neonatal rat pups induces visceral and somatic hyperalgesia in adult rats and that the visceral hyperalgesia is prevented with preemptive administration of the CRF1 receptor antagonist, antalarmin (11). Furthermore, administration of antalarmin inhibits colonic hypersensitivity in rats known to have high anxiety (12). In humans the effects of peripheral CRF include decreased threshold to rectal distension and increased motility (13). Peripheral administration of a CRF-receptor antagonist to patients with IBS improves gastrointestinal motility, visceral perception, and negative mood in response to gut stimulation (14).

ALTERED DESCENDING INHIBITORY CONTROL

Processing of incoming pain signals in the spinal cord is subject to descending modulatory control from the brain, which can be inhibitory or facilitatory. The descending inhibitory control, or “pain gate,” occurs through endogenous opioids and is postulated to play a role in a variety of chronic pain syndromes. The descending inhibitory controls are known to be immature at birth. Thus, persistent noxious sensory inputs in the immature spinal cord may not be properly modulated, ultimately altering inhibitory processing in the adult spinal cord. Recent animal data support this concept. Nalaxone, an opioid receptor antagonist, has no effect on rats following maternal separation but significantly increases visceral hypersensitivity in nonhandled rats, suggesting a diminished pain inhibitory opioidergic tone in animals with early life stress (9). In addition, the efficacy of fentanyl in response to rectal distension is greater in patients with IBS as compared with normal controls (15). This points to a diminished release of endogenous opioids that may involve the descending inhibitory system.

Taken together, these data constitute a compelling case that adverse early life events such as pain or stress can induce long-term changes in the nociceptive circuitry. Significant work remains to be done to answer the precise mechanistic questions that underlie the behavioral outcome in humans.

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