Impaired cutaneous wound healing after sensory denervation in developing rats: effects on cell proliferation and apoptosis

The role of sensory nociceptor nerves in cutaneous wound healing was investigated following full-thickness 4-mm diameter dorsal cutaneous excision wounding of rats on postnatal day 12. In rats with intact innervation, wounds at 3 days contained large numbers of TUNEL- and BRDU-labeled nuclei, consistent with inflammatory cell death and granulation cell proliferation. Wound area and volume decreased through 11 days in concert with a transient appearance of alpha-smooth muscle actin-immunoreactive myofibroblasts, declining rates of cell division, and increased occurrence of apoptotic cells. Sensory denervation by capsaicin injections on postnatal days 2 and 9 reduced calcitonin gene-related peptide-immunoreactive wound innervation persistently by up to 43%. This was associated with increased wound surface area and volume, and delays in scab loss and re-epithelialization. Relative to control wounds, granulation tissue showed increased myofibroblast content at 5-7 days. Capsaicin-treated rats had more BRDU-labeled cells, including myofibroblasts, through day 7. Numbers of TUNEL apoptotic cells per unit area of tissue section were reduced by denervation in both early and late stages of healing. We conclude that partial loss of sensory innervation impairs cutaneous wound healing in developing rats, as manifested by delayed re-epithelialization and failure of the wound area to decrease normally through at least 21 days. This is associated with an abnormally enlarged wound tissue volume resulting from increased granulation cell proliferation without proportionate increases in apoptosis. These findings suggest that nociceptor innervation plays a critical role in wound healing by regulating wound cellularity.