Overexpression of neurotrophin‐3 enhances the mechanical response properties of slowly adapting type 1 afferents and myelinated nociceptors

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Abstract
Constitutive overexpression of neurotrophin-3 (NT3) in murine skin results in an increased number of sensory neurons within the dorsal root ganglia, an increase of myelinated axons in cutaneous nerves, hyperinnervation of the skin, and an increased number of Merkel cells found in flank skin. Here we used a saphenous skin/nerve preparation to determine if these anatomical changes affect the functional response characteristics of cutaneous sensory neurons. Overexpression of NT3 significantly increased the responses of slowly adapting type 1 (SA1) low-threshold mechanoreceptors and Adelta high-threshold mechanoreceptors to suprathreshold mechanical stimulation. It also resulted in significantly faster conduction velocities of SA1 fibers. In contrast to earlier findings in flank skin, no differences were noted in the numbers of Merkel cells in the touch domes in hindlimb skin of NT3-overexpressing mice. In addition, the number of dermal Merkel cells, located around hair follicles on the dorsum of the foot, was reduced by 55%. The increase in mechanical sensitivity was found to correlate with significant increases in the expression of acid-sensing ion channels (ASIC) 1 and 3. Additional experiments using intracellular recordings and staining procedures confirmed that at least some cutaneous myelinated nociceptors and SA1 mechanoreceptors stained positively for both trkC and ASIC3. These results indicate that cutaneous NT3 overexpression alters the response properties of specific cutaneous sensory neurons, and that these changes may be due to the modulation of putative mechanosensitive ion channels.