Three Classes Of Sensory Neurontargeting Drugs

Sensory neuron-specific targets can be grouped into three categories: (i) receptors and sensors at the peripheral terminals of afferent neurons that are relevant to stimulus transduction, (ii) ion channels that govern the excitability and conduction properties of afferent neurons, and (iii) transmitters and transmitter receptors that mediate communication between primary afferents and second-order neurons in the spinal cord and brain stem. There is a large number of receptors and sensors on afferent nerve terminals as listed in Table 3, although, importantly, not all of them are selectively expressed by sensory neurons. Among the ion channels relevant to nerve excitability and conduction, much attention is put on sensory neuron-specific ion channels such as the tetrodotoxin-resistant Nav1.8 sodium channel. Primary sensory neurons can be differentiated by their chemical coding in terms of transmitter expression, with glutamate, calcitonin gene-related peptide (CGRP), and the tachykinins substance P and neurokinin A being the prevalent messenger molecules (2,3). In assessing the significance of targets on sensory neurons in visceral hyperalgesia, it is important to explore whether number, subunit composition, and biophysical properties of sensory neuron-specific ion channels and receptors are persistently altered in GI disease (1,4). Appropriate experimental models of GI disease (5) and clinical proof-of-concept studies are needed to evaluvate critically which quantitative contribution various sensory neuron-specific targets make to the induction and/or maintenance of visceral hyperalgesia and whether modulation of a single target is therapeutically sufficient.

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