Author(s): L Ashley Blackshaw [*] 5 2 3 , Stuart M Brierley 1 2 4
abdominal pain; constipation; cyclic GMP; guanylate cyclase C; irritable bowel syndrome; linaclotide
How is pain transmitted from the colon?
When we experience abdominal pain or discomfort, our ability to discriminate between the location and type of the stimulus causing the discomfort is poor. This is due to the low density of visceral innervation in the gut, and the polymodal nature of visceral afferent nerves, which can be activated by several different stimuli. The innervation of the GI tract is complex, with an intrinsic enteric neuronal pathway and dual innervation via the extrinsic vagal and spinal primary afferent pathways. Information is then transmitted via ascending neuronal pathways to two main cortical brain regions: the perigenual anterior cingulate cortex and the insula cortex  .
Spinal afferent nerves are generally polymodal, responding to both chemical and mechanical stimuli. However, these nerves can be subdivided into different classes, as they can be activated by either low- or high-intensity mechanical stimuli. Correspondingly, five different classes of colonic spinal afferent nerves have been classified, based on their differing responsiveness to mechanical stimuli and according to the location of their endings in the gut wall. In the colon, these classes include mucosal (class 1), muscular/mucosal (class 2), muscular (class 3), mesenteric (class 4) and serosal (class 5) afferent nerve endings (Figure 1)  . Classes 1-3 include tactile and/or low-threshold stretch-sensitive nerve endings. Only mesenteric and serosal afferent nerve endings respond at sufficiently high thresholds to warrant designation as specific nociceptors [1,2] . These high-threshold serosal and mesenteric afferent endings are located close to or on blood vessels or branching points of capillaries  . Stimuli that activate these nociceptors and elicit sensations of pain and/or discomfort include over-distension of the bowel (intraluminal pressure: >40 mm Hg), such as that caused by bloating or constipation. These nociceptors are also activated by high-amplitude contractions and the effects of twisting of the intestine on mesenteric attachments [4,5] .
How is abdominal pain increased in irritable bowel syndrome with constipation?
Visceral hypersensitivity is associated with symptoms of abdominal pain and discomfort and is considered to be one of the most important pathological factors in the development of irritable bowel syndrome (IBS) [6,7] . However, the mechanisms by which pain increases in patients with IBS have yet to be fully elucidated. Spinal afferent nerves from the colon enter the spinal cord via the splanchnic nerve and the thoracolumbar dorsal root ganglia, whereas spinal afferent nerves from the rectum and distal colon enter via the pelvic nerves and the lumbosacral dorsal root ganglia  . Tactile and low-threshold stretch receptors are predominantly located in the pelvic pathway, whereas high-threshold nociceptive afferents are predominantly found in the splanchnic pathway  . This division has enabled researchers to investigate both acute and chronic sensitization of peripheral nerve endings, which occur poststress or postinflammation in a rodent model of trinitrobenzene sulfonic acid (TNBS)-induced colitis  . Specifically, the contribution of each class of mechanosensitive colonic afferent nerve ending to postinflammatory visceral hypersensitivity...