Neuronal plasticity of the "brain-skin connection": stress-triggered up-regulation of neuropeptides in dorsal root ganglia and skin via nerve growth factor-dependent pathways

Emerging research indicates that central-nervous stress perception is translated to peripheral tissues such as the skin not only via classical stress hormones but also via neurotrophins and neuropeptides. This can result in neurogenic inflammation, which is likely to contribute to the triggering and/aggravation of immunodermatoses. Although the existence of such a "brain-skin connection" is supported by steadily increasing experimental evidence, it remains unclear to which extent perceived stress affects the sensory "hardwiring" between skin and its afferent neurons in the corresponding dorsal root ganglia (DRG). In this paper, we provide experimental evidence in a murine model of stress (exposure of C57BL/6 mice to sound stress) that stress exposure, or intracutaneous injection of recombinant nerve growth factor (NGF) to mimic the skin's response to stress, up-regulate the percentage of substance P (SP)(+) stop or calcitonin gene-related peptide (CGRP)(+) stop sensory neurons in skin-innervating DRG. Further, we show that the number of SP+ stop or CGRP(+) stop sensory nerve fibers in the dermis of stressed C57BL/6 mice is significantly increased. Finally, we document that neutralization of NGF activity abrogates stress-induced effects on the percentage of SP+ stop and CGRP(+) stop sensory neurons in skin-innervating DRG as well as on dermal sensory nerve fibers. These data suggest that high stress perception results in an intense cross talk between the skin and skin-innervating DRG, which increases the likelihood of NGF-dependent neurogenic skin inflammation by enhancing sensory skin innervation.