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The skin is the largest sensory organ of the body. It is innervated by a diverse array of primary sensory neurons, including a heterogeneous subset of unmyelinated afferents called C fibers. C fibers, sometimes classified as nociceptors, can detect various painful stimuli, including temperature extremes. However, it is increasingly evident that these afferents respond to various pruritic stimuli and transmit information to the brain that is perceived as itch; this can subsequently drive scratching behavior. Although itch and pain are distinct sensations, they are closely related and can, under certain circumstances, antagonize each other. However, it is not clear precisely when, where, and how the processes generating these two sensations originate and how they are dissociated. Clues have come from the analysis of the activities of specific ligands and their receptors. New data indicate that specific pruritic ligands carrying both itch and pain information are selectively recognized by different G protein–coupled receptors (GPCRs), and this information may be transduced through different intracellular circuits in the same neuron. These findings raise questions about the intracellular mechanisms that preprocess and perhaps encode GPCR-mediated signals.