The Role of Visceral Afferents in Disease

Visceral pain is the number one reason for patient visits in the United States. In many cases, visceral pain is not associated with obvious pathology. For example, irritable bowel syndrome (IBS), which can occur following inflammation (Gwee et al. 1996; Collins et al. 1999; Bercik et al. 2005), is a diagnosis of exclusion because its hallmarks include abdominal pain accompanied by diarrhea or constipation in the absence of any obvious pathophysiology. It has been proposed that one of the contributing factors to these persistent pain states is chronic hypersensitivity of visceral sensory neurons (Wood 2002; Cenac et al. 2007). Afferents innervating somatic tissue, such as skin, muscle, or bone, can be categorized based on their response properties to stimulation. Large, myelinated afferents generally mediate information related to proprioception and light touch or vibration, whereas small, thinly myelinated or unmyelinated afferents, commonly termed nociceptors, detect noxious or potentially damaging stimuli, including thermal, high-threshold mechanical and chemical stimuli. This is in contrast to the sensory innervation of the viscera, which is mostly made up of small, thinly myelinated or unmyelinated afferents that display low mechanical thresholds, enabling them to code normal physiological stimuli (i.e., non-noxious), as well as an ability to code stimuli in the noxious range (Sengupta and Gebhart 1994a, 1994b; Wood 2002; Cenac et al. 2007). Thus, if one uses a functional definition for nociceptors (i.e., the ability to code noxious stimuli), most visceral afferents would be classified as nociceptors. To further separate themselves from somatic afferents, which receive sensory innervation only from neurons located in the dorsal root ganglia (DRG), visceral structures from the esophagus to the transverse colon are innervated not only by DRG located in the cervical, thoracic, and upper lumbar regions, but also by sensory neurons arising from the superior and inferior vagal ganglia (jugular and nodose ganglia, respectively; Figure 3.1) (Ricco et al. 1996; Undem et al. 2004; Yu et al. 2005; Zhong et al. 2008). Visceral structures located distal to the transverse colon, particularly the distal colon, rectum and bladder are also innervated by two populations of afferents; however, these are both of spinal origin arising from two different levels of the spinal cord (thoracolumbar and lumbosacral; Figure 3.1) (de Groat 1987; Keast and de Groat 1992; Wang et al. 1998; Traub et al. 1999; Christianson et al. 2006a, 2007). Sensory neurons arising from these two spinal locations appear to convey different aspects of the complex sensation that humans identify as visceral pain. The functional difference between these populations is not as obvious as that between vagal and spinal afferents, but evidence suggests that they may differentially respond to injury and disease (Traub 2000; Traub and Murphy 2002; Lin and Al-Chaer 2003). In this chapter, we will discuss recent findings regarding the anatomy and physiology of visceral afferents and how these discoveries may lead to new treatments for visceral pain. In addition, we will discuss exciting new studies that suggest hyperactive visceral nociceptors might not only mediate persistent visceral pain, but that they may actually drive the initial visceral disease processes.