Short-Term Sensitization of Colon Mechanoreceptors Is Associated With Long-Term Hypersensitivity to Colon Distention in the Mouse

Jones, Rhys Bevan; Otsuka, Eiji; Wagstrom, Emily; Jensen, Chris S.; Price, Margaret P.; Gebhart, G. F.

doi:10.1053/j.gastro.2007.04.042

Cited by 123 publications

(92 citation statements)

References 29 publications

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“…Muscular-mucosal afferents exhibited significantly greater responses to stretch in colorectums taken from hypersensitive mice 24 days after zymosan (but not saline) treatment; responses from muscular afferents were unchanged. This is consistent with a previous in vitro study (12) in which muscular-mucosal but not Fig. 4.…”

Section: Discussionsupporting

confidence: 93%

“…Visceromotor responses to colorectal distension, normalized to the percentage of the baseline response at 60 mmHg ( Previous reports (12,29) have shown that intracolonic zymosan does not increase myeloperoxidase activity at any time after intracolonic treatment, and so we assessed whether zymosan produced macrophage-based inflammation. Figure 2 shows the accumulation of F4/80-positive macrophages at the bottom of crypts and in the submucosa 4 and 24 h after the third daily zymosan treatment, which resolved by day 6.…”

Section: Colorectal Hypersensitivity and Inflammationmentioning

confidence: 99%

“…In support, there are increasing numbers of reports establishing that potential mediators of afferent sensitization, such as intestinal mucosal proinflammatory and lipotoxic lipids (14), mast cell products (1, 14, 21), and enteroendocrine cell products (20), are significantly increased in IBS (19). Furthermore, supernatants of colon biopsies and activated mucosal mast cells from patients with IBS directly excite rodent gastrointestinal afferent fibers (2, 10).We and others have previously characterized the mechanosensitive properties of colorectal afferents in rodents (3,7,12,13,29), including their ability to sensitize (i.e., increase excitability) after exposure to inflammatory mediators (7,12,13). In addition to mechanosensitive afferent endings, so-called silent (or sleeping) nociceptors are present in the visceral innervation.…”

mentioning

confidence: 99%

“…We and others have previously characterized the mechanosensitive properties of colorectal afferents in rodents (3,7,12,13,29), including their ability to sensitize (i.e., increase excitability) after exposure to inflammatory mediators (7,12,13). In addition to mechanosensitive afferent endings, so-called silent (or sleeping) nociceptors are present in the visceral innervation.…”

mentioning

confidence: 99%

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Long-term sensitization of mechanosensitive and -insensitive afferents in mice with persistent colorectal hypersensitivity

Feng

Schwartz

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Feng B, La J, Schwartz ES, Tanaka T, McMurray TP, Gebhart GF. Long-term sensitization of mechanosensitive and -insensitive afferents in mice with persistent colorectal hypersensitivity. Am J Physiol Gastrointest Liver Physiol 302: G676 -G683, 2012. First published January 19, 2012 doi:10.1152/ajpgi.00490.2011.-Afferent input contributes significantly to the pain and colorectal hypersensitivity that characterize irritable bowel syndrome. In the present study, we investigated the contributions of mechanically sensitive and mechanically insensitive afferents (MIAs; or silent afferents) to colorectal hypersensitivity. The visceromotor response to colorectal distension (CRD; 15-60 mmHg) was recorded in mice before and for weeks after intracolonic treatment with zymosan or saline. After CRD tests, the distal colorectum with the pelvic nerve attached was removed for single-fiber electrophysiological recordings. Colorectal afferent endings were located by electrical stimulation and characterized as mechanosensitive or not by blunt probing, mucosal stroking, and circumferential stretch. Intracolonic zymosan produced persistent colorectal hypersensitivity (Ͼ24 days) associated with brief colorectal inflammation. Pelvic nerve muscular-mucosal but not muscular mechanosensitive afferents recorded from mice with colorectal hypersensitivity exhibited persistent sensitization. In addition, the proportion of MIAs (relative to control) was significantly reduced from 27% to 13%, whereas the proportion of serosal afferents was significantly increased from 34% to 53%, suggesting that MIAs acquired mechanosensitivity. PGP9.5 immunostaining revealed no significant loss of colorectal nerve fiber density, suggesting that the reduction in MIAs is not due to peripheral fiber loss after intracolonic zymosan. These results indicate that colorectal MIAs and sensitized muscularmucosal afferents that respond to stretch contribute significantly to the afferent input that sustains hypersensitivity to CRD, suggesting that targeted management of colorectal afferent input could significantly reduce patients' complaints of pain and hypersensitivity. irritable bowel syndrome; pelvic pain; visceral afferent sensitization; colorectal distension; single-fiber recording INTRARECTAL INSTILLATION of local anesthetic rapidly relieves discomfort and pain in patients with irritable bowel syndrome (IBS) (22,23,32), revealing that persistent afferent drive plays an important role in IBS. Significantly, referred abdominal (somatic) hypersensitivity is simultaneously relieved, confirming that afferent drive onto spinal dorsal horn neurons receiving convergent visceral and somatic input is necessary for the development of central sensitization. In support, there are increasing numbers of reports establishing that potential mediators of afferent sensitization, such as intestinal mucosal proinflammatory and lipotoxic lipids (14), mast cell products (1, 14, 21), and enteroendocrine cell products (20), are significantly increased in IBS (19). Furthermore, supernatant...

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Section: Discussionsupporting

confidence: 93%

Section: Colorectal Hypersensitivity and Inflammationmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Long-term sensitization of mechanosensitive and -insensitive afferents in mice with persistent colorectal hypersensitivity

Feng

Schwartz

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…On the other hand, an earlier study by Sengupta et al [79] using an identical in vivo protocol, recording from the same population of afferents did not reveal any sensitization, so there is clearly controversy in this area. Similar to Sengupta's [79] findings in rat, Jones et al [80] in a mouse zymosan colonic inflammation model saw no change in mechanosensitivity of pelvic muscular or muscular-mucosal afferents. The behavioural response to colorectal distension was, however, increased after zymosan, and this persisted in TRPV1 knockouts, so the mechanism underlying pain hypersensitivity was not revealed.…”

Section: Changes In Sensory Signalling In Diseasesupporting

confidence: 56%

TRP Channels in Visceral Pain

Blackshaw¹,

Brierley²,

Harrington³

et al. 2013

TOPAINJ

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Visceral pain is both different and similar to somatic pain - different in being poorly localized and usually referred elsewhere to the body wall, but similar in many of the molecular mechanisms it employs (like TRP channels) and the specialization of afferent endings to detect painful stimuli. TRPV1 is sensitive to low pH. pH is lowest in gastric juice, which may cause severe pain when exposed to the oesophageal mucosa, and probably works via TRPV1. TRPV1 is found in afferent fibres throughout the viscera, and the TRPV1 agonist capsaicin can recapitulate symptoms experienced in disease. TRPV1 is also involved in normal mechanosensory function in the gut. Roles for TRPV4 and TRPA1 have also been described in visceral afferents, and TRPV4 is highly enriched in them, where it plays a major role in both mechanonociception and chemonociception. It may provide a visceral-specific nociceptor target for drug development. TRPA1 is also involved in mechano-and chemosensory function, but not as selectively as TRPV4. TRPA1 is colocalized with TRPV1 in visceral afferents, where they influence each other's function. Another modulator of TRPV1 is the cool/mint receptor TRPM8, which, when activated can abrogate responses mediated via TRPV1, suggesting that TRPM8 agonists may provide analgesia via this pathway. In all, the viscera are rich in TRP channel targets on nociceptive neurones which we hope will provide opportunities for therapeutic analgesia.

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TRPV1 in Visceral Pain and Other Visceral Disorders

Avelino

Cruz

2010

Vanilloid Receptor TRPV1 in Drug Discovery

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Short-Term Sensitization of Colon Mechanoreceptors Is Associated With Long-Term Hypersensitivity to Colon Distention in the Mouse

Cited by 123 publications

References 29 publications

Long-term sensitization of mechanosensitive and -insensitive afferents in mice with persistent colorectal hypersensitivity

Long-term sensitization of mechanosensitive and -insensitive afferents in mice with persistent colorectal hypersensitivity

TRP Channels in Visceral Pain

TRPV1 in Visceral Pain and Other Visceral Disorders

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