Variability In The Development Of Sensitized States

To determine whether peripheral sensitization and central sensitization can occur in healthy human viscera in response to injury/inflammation, a model was developed which has demonstrated that acid infusion localized to the distal esophagus can reduce subsequent pain thresholds to electrical stimulation at the site of the infusion compared to preacid baseline levels. After the acid infusion, a previously nonpainful stimulus is reported as painful demonstrating hypersensitivity at the site of infusion (93). This hypersensitivity is likely to be due to peripheral sensitization. Although continuous pH monitoring demonstrates no acid reflux into the proximal esophagus, a similar reduction in pain thresholds to electrical stimulation can be demonstrated at this site. This secondary hypersensitivity is believed to occur through the sensitization of spinal neurons (central sensitization), and indeed further work in our department has shown that this secondary esophageal hypersensitivity can be attenuated by both PGE2 receptor-1 (94) and NMDA receptor antagonists (Fig. 5) (26). These studies suggest that both peripheral and central sensitization can induce visceral hypersensitivity.

It has however been noted that around 20% of subjects fail to sensitize to esophageal acid infusion. Furthermore, there is a variation in the magnitude of response (reduction in pain threshold to acid infusion) between subjects to the order of 24%. Also, while most subjects will demonstrate reproducible sensitization to acid in repeated studies, around 14% will habituate to acid with diminishing sensitization to repeated acid infusions (95). Recent work in healthy subjects has shown that visceral pain thresholds inversely correlate with baseline anxiety scores (96). Whether the effect of anxiety in these subjects is to amplify pain responses through the effect of attention toward the visceral stimulation is unknown.

Figure 5 (See color insert) The effect of an N-methyl-D-aspartate receptor antagonist, ketamine, on proximal esophageal pain thresholds when given following a distal esophageal acid infusion. The acid causes a reduction in pain thresholds in the nonacid exposed proximal esophagus, demonstrating the development of visceral hypersensitivity, and this is reversed by ketamine. The hypersensitivity is not reversed by saline infusion. Source: Adapted from Ref. 26.

Figure 5 (See color insert) The effect of an N-methyl-D-aspartate receptor antagonist, ketamine, on proximal esophageal pain thresholds when given following a distal esophageal acid infusion. The acid causes a reduction in pain thresholds in the nonacid exposed proximal esophagus, demonstrating the development of visceral hypersensitivity, and this is reversed by ketamine. The hypersensitivity is not reversed by saline infusion. Source: Adapted from Ref. 26.

There may be phenotypic differences between subjects that determine their magnitude of sensitization and pain responsiveness after visceral injury. The biological factors involved in mediating visceral sensitization, particularly after injurious/inflammatory events, are incompletely understood, but may involve the systems previously discussed. It seems plausible that the complex interactions of these factors result in phenotypic traits that may determine patterns of postinjury gut sensitization. Identifying phenotypes may provide clues as to the mechanism of prolonged sensitization to inflammation/injury seen in FGD patients, and may lead to the identification of genotypic correlations. Evidence for the involvement of these factors in FGD will now be presented.

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