Differential Sensitization of Afferent Neuronal Pathways During Postoperative Ileus in the Mouse Jejunum

Abstract

This study provides direct evidence from afferent nerve recordings that sensitivity to bradykinin, which stimulates predominantly spinal afferents, is augmented during postoperative ileus involving a COX-2 pathway. Vagal afferents were also sensitized because low-threshold mechanosensitivity and neuronal activation in the nTS were increased.

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

“…The activation of cardiac "sympathetic" and vagal afferents by epicardial or intra-arterial administration of bradykinin in anesthetized dogs was enhanced in heart failure, and these facilitated responses, unlike those in normal dogs, were inhibited by indomethacin, demonstrating a potential role of secondary prostanoids in cardiac pain (646,(763)(764)(765). In contrast to the above whole animal models, a lack of involvement of prostanoids in the neuronal excitatory effect of bradykinin was revealed in several cellular and isolated organ models (186,207,209,329,373,483,514,546,576,653).…”

Intestinal Afferent Nerve Sensitivity is Increased During the Initial Development of Postoperative Ileus in Mice

“…There are several possible explanations for this observation, which was persistent during the entire observation period. First, neuronal reflex inhibition is followed by a local inflammatory response during the development of POI, 8,29 and considering that at 24 h the intestine was similiarly dilated in our previous study, 27 it appears possible that in the dilated parts a local inflammatory response already developed in the intestinal muscularis, while the contracted part did not yet show this pattern 9 h after surgery. Based on this assumption, the increased afferent nerve discharge in the dilated parts would then be secondary to inflammatory mediators such as prostanoids that have permissive effects on the afferent nerve response to bradykinin and high-threshold distension.…”

“…One of the most intriguing findings was that at the 9-h time point, segmental dilatation of the small intestine occurred that-to our knowledge-has not been described previously. POI is typically characterized by dilated and flaccid intestine, 8,11,27 but in these previous studies, the early phase of POI was not investigated. One possible explanation is that at the 9-h time point, a transition from an early neuronal period of POI with contracted intestine is Figure 3 a, b Representative afferent nerve and motility recordings in a segment of small intestine from a 3 h sham control animals (a) and from an animal 3 h after induction of postoperative ileus.…”

“…15 Furthermore, vagal nuclei in the brain stem are activated 24 h after surgery. 27 This vagal sensitization at 24 h is likely to be secondary to inflammatory mediators such as histamine and serotonin (5-HT) that have the potential to sensitize intestinal vagal afferents 31 and are probably released during the inflammatory response which occurs at that stage of POI. 8,11 In summary, the present study supports the concept that spinal afferents are involved during the initiation of POI (i.e., ≤9 h), while previous work provided evidence that vagal afferents come into play at a later stage when the immune response in the intestinal wall is established.…”

Role of the vagus nerve on the development of postoperative ileus

“…Postoperative ileus was induced by standardized bowel manipulation as described previously [10]. Animals were deeply anesthetized with enflurane inhalation and a midline laparotomy was performed under sterile conditions.…”