There is now good reason to assume that visceral pain involves persistent sensitization of GI afferent neurons. Although central sensitization processes and a distorted processing and representation of the incoming information in the brain are also involved, the contribution made by sensory neurons should not be underestimated. It is via these afferents that the discomfort and pain localized to abdominal viscera is signaled to the brain. Furthermore, visceral sensory neurons are usually polymodal and all of them seem to have the capacity to sensitize (4). In view of these properties, it can be predicted that sensitization of visceral afferents by inflammatory events may tremendously increase the afferent input to the brain (4). If this state of exaggerated responses to peripheral stimuli persists after inflammation has

Table 5 Unsolved Issues In Visceral Pain Research

There is no animal model equivalent of painful functional bowel disorders, although it is possible to model individual symptoms.

The available animal models of visceral hyperalgesia do not assess the perception of pain but record pseudoaffective responses that are interpreted as being indicative of pain.

Reliable quantitation and analysis of pain perception and emotional-affective alterations in animals will require real-time functional brain imaging.

Most animal models of visceral pain (as well as clinical studies) are modality biased inasmuch as they assess only reactions to mechanical, but not chemical, stimuli.

The study of visceral pain has been focused on the spinal afferent innervation of the gut, while the emerging implication of vagal afferent pathways in foregut nociception has been neglected.

Nausea may be seen as a particular form of gastrointestinal discomfort and pain that is mediated by vagal afferents.

Sensory neuron-directed drugs will be efficacious in visceral pain only if visceral hyperalgesia is to a significant extent due to peripheral sensitization.

It is at present difficult to predict whether or not targeting a single receptor or ion channel on visceral afferents will be sufficient to manage visceral hyperalgesia.

subsided, physiologic processes in the alimentary canal may be interpreted by the brain as inappropriately painful (4). For all these reasons, afferent neurons represent an intriguing target at which to aim novel therapies for visceral discomfort and pain (1,10,304).

Efforts to identify molecular traits that are specific for sensory neurons and therefore hold potential for therapeutic exploitation have been remarkably successful (Table 3). These targets include, among others, TRPV1, ASICs (ASIC2b/3), tetrodotoxin-resistant Na+ channels (Nav1.8), and ionotropic purinoceptors (P2X2/3 and P2X3). Since many of these sensors and ion channels are selectively expressed by subpopulations of afferent neurons thought to subserve a nociceptive function, drugs directed at those targets may be antinociceptive without necessarily interfering with physiologic functions of afferent neurons. Changes in the expression and functional properties of sensory neuron-specific molecules in visceral hyperalgesia may add to the selectivity of drugs directed at these molecules. This concept is borne out by observations that blockade of certain sensory neuron-specific targets reverses experimentally induced visceral hyperalgesia but does not influence acute nociception. In addition, selectivity for targets on nociceptive afferent neurons, and preferentially to visceral but not somatic afferents, will be a considerable asset for drug safety. However, despite the identification of sensory neuron-specific drug targets, there is a number of issues that need to be resolved before these advances in basic research can be translated to the development of efficacious and safe drugs for visceral pain (Table 5).

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