A role of tachykinin NK 2 receptor antagonists in the treatment of IBS?

Abstract

The localization of tachykinins in the PNS is generally restricted to a subset of afferent (i.e. capsaicin-sensitive) nerves, with the notable exception of the enteric nervous system: several populations of enteric neurons, including excitatory acetylcholine-containing motor neurons, express these peptides. The receptors for tachykinins, NK1, NK2 and NK3, are also present in the gastrointestinal tract; both NK1 and NK2 receptors are expressed in muscle layers and neurons, whereas NK3 receptors are selectively localized to neurons. Most enteric neurons express the preprotachykinin-I gene, which encodes both substance P and neurokinin A (NKA). These two transmitters act as preferential agonists for NK1 and NK2 receptors, respectively. However, the selectivity of natural tachykinins for receptors of their family is limited and there is evidence for an extensive crosstalk between natural tachykinins and their receptors. NKA is a particularly efficient NK1 receptor agonist and can act as a physiological agonist of NK1 receptors at some neuroeffector junctions/synapses. Some cell types (e.g. the gastrointestinal smooth muscle cells) express both NK1 and NK2 receptors, and these serve the same function (e.g. muscle contraction); therefore, questions arise about the relative role of these receptors, and whether a selective NK2 (or NK1) receptor antagonist can be fully effective in blocking tachykinin-mediated transmission. To further complicate the issue, NK1 or NK2 receptors are also expressed by inhibitory neurons in the gut, and species-related differences exist in receptor expression and distribution in various regions of the gut, and in relation to disease states.