Altered colorectal afferent function associated with TNBS-induced visceral hypersensitivity in mice

Abstract

Feng B, La JH, Tanaka T, Schwartz ES, McMurray TP, Gebhart GF. Altered colorectal afferent function associated with TNBS-induced visceral hypersensitivity in mice. Am J Physiol Gastrointest Liver Physiol 303: G817-G824, 2012. First published August 1, 2012; doi:10.1152/ajpgi.00257.2012.-Inflammation of the distal bowel is often associated with abdominal pain and hypersensitivity, but whether and which colorectal afferents contribute to the hypersensitivity is unknown. Using a mouse model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, we investigated colorectal hypersensitivity following intracolonic TNBS and associated changes in colorectum and afferent functions. C57BL/6 mice were treated intracolonically with TNBS or saline. Visceromotor responses to colorectal distension (15-60 mmHg) were recorded over 8 wk in TNBS-and saline-treated (control) mice. In other mice treated with TNBS or saline, colorectal inflammation was assessed by myeloperoxidase assay and immunohistological staining. In vitro single-fiber recordings were conducted on both TNBS and saline-treated mice to assess colorectal afferent function. Mice exhibited significant colorectal hypersensitivity through day 14 after TNBS treatment that resolved by day 28 with no resensitization through day 56. TNBS induced a neutrophil-and macrophage-based colorectal inflammation as well as loss of nerve fibers, all of which resolved by days 14 -28. Single-fiber recordings revealed a net increase in afferent drive from stretch-sensitive colorectal afferents at day 14 post-TNBS and reduced proportions of mechanically insensitive afferents (MIAs) at days 14 -28. Intracolonic TNBS-induced colorectal inflammation was associated with the development and recovery of hypersensitivity in mice, which correlated with a transient increase and recovery of sensitization of stretch-sensitive colorectal afferents and MIAs. These results indicate that the development and maintenance of colorectal hypersensitivity following inflammation are mediated by peripheral drive from stretch-sensitive colorectal afferents and a potential contribution from MIAs. electrophysiology; IBS; PI-IBS; single-fiber; visceral pain IRRITABLE BOWEL SYNDROME (IBS) is a functional gastrointestinal disorder characterized by persistent pain and organ hypersensitivity in the absence of demonstrable gross structural or biochemical abnormalities. Although the cause(s) of IBS is unclear, postinfectious IBS (PI-IBS) seems to have a defined etiology because in those patients, an infectious gastroenteritis precedes the development of IBS symptoms (22).Intracolonic 2,4,6-trinitrobenzene sulfonic acid (TNBS) in rodents has been widely used as a model of colitis (23), and recently TNBS has been advanced as a model of postinflammatory colorectal hypersensitivity and thus a model of . Hughes et al. (14) reported, for example, an inflammation-associated increase in colorectal afferent sensitization and a long-lasting sensitization of serosal and mesenteric class afferents after resolution of TNBS-in...

Plasticity of dorsal root ganglion neurons in a rat model of post-infectious gut dysfunction: potential implication of nerve growth factor

“…Persistent inflammatory states of the gut have been associated with the remodeling of sensory neurons innervating the affected region [16,17]. In the present report, a chronic inflammatory-like response of the intestine (up to day 30 PI) was observed, as determined by an up-regulation of inflammatory cytokines (primarily IL-6) and RMCPII (a MMC marker).…”

Optogenetic activation of mechanically insensitive afferents in mouse colorectum reveals chemosensitivity

“…As previously described (14), mice (Cre ϩ/Ϫ ChR2 ϩ/Ϫ ) were killed via CO2 inhalation. The distal colon and L6 dorsal root ganglion (DRG) were harvested and fixed with 4% paraformaldehyde in 0.16 M phosphate buffer containing 14% picric acid (Sigma-Aldrich).…”

“…The functional role of colorectal MIAs in pain and hypersensitivity was studied previously in the context of long-term models of visceral hypersensitivity induced by intracolonic instillation of trinitrobenzene sulfonic acid (TNBS) (14) or zymosan (13). In both studies, the proportions of MIAs in mice that developed prolonged behavioral colorectal hypersensitivity were reduced by ϳ50%.…”

“…channelrhodopsin2; single fiber; silent afferents; irritable bowel syndrome; afferent sensitization; inflammatory soup SENSORY AFFERENTS INNERVATING the viscera have drawn significant research interest as clinical and preclinical evidence indicates that persistent afferent drive (e.g., afferent sensitization) contributes to long-lasting organ hypersensitivity, discomfort, and pain, hallmark complaints of patients with visceral pain disorders such as irritable bowel syndrome (IBS) (29,39,40) and bladder pain syndrome (27) for which a pathobiology is not apparent. Using an ex vivo colorectumnerve preparation together with different animal models of persistent colorectal hypersensitivity, we and others have documented long-term sensitization of mechanosensitive colorectal afferents that contribute to prolonged colorectal hypersensitivity (1,13,14).…”

“…Unlike most other studies in which MIAs were often recorded fortuitously after organ inflammation, ischemia, or injury (5,18,25), we systemically characterized the colorectal innervation using an unbiased electrical stimulation search strategy and discovered that MIAs comprise 25-30% of colorectal afferents in the lumbar splanchnic (LSN) and pelvic nerve (PN) pathways (8). We subsequently found an ϳ50% reduction in the proportion of MIAs in the PN pathway in mice with behavioral colorectal hypersensitivity, suggesting a phenotypical switch of those MIAs, which acquire mechanosensitivity and generate de novo sensory input to the central nervous system (CNS) (13,14,21). Further understanding of the role of MIAs in visceral sensation and nociception is hindered by the limited knowledge of sensory encoding and processing at the micrometer-thick afferent nerve terminals embedded in the colorectum, prohibiting direct studies by intracellular recordings (for discussion, see Ref.…”