Hair-cycle-associated remodeling of the peptidergic innervation of murine skin, and hair growth modulation by neuropeptides

As the neuropeptide substance P can manipulate murine hair growth in vivo, we here further studied the role of sensory neuropeptides in hair follicle biology by determining the distribution and hair-cycle-dependent remodeling of the sensory innervation in C57BL/6 mouse back skin. Calcitonin-gene-related peptide, substance P, and peptide histidine methionine (employed as vasoactive intestinal peptide marker) were identified by immunohistochemistry, All of these markers immunolocalized to bundles of nerve fibers and to single nerve fibers, with distinct distribution patterns and major hair-cycle-associated changes. In the epidermis and around the distal hair follicle and the arrector pill muscle, only calcitonin-gene-related peptide immunoreactive nerve fibers were visualized, whereas substance P and peptide histidine methionine immunoreactive nerve fibers were largely restricted to the dermis and subcutis. Compared to telogen skin, the number of calcitonin-gene-related peptide, substance P, and peptide histidine methionine immunoreactive single nerve fibers increased significantly (p<0.01) during anagen, including around the bulge region (the seat of epithelial stem cells). Substance P significantly accelerated anagen progression in murine skin organ culture, whereas calcitonin-gene-related peptide and a substance-P-inhibitory peptide inhibited anagen (p<0.05). The inhibitory effect of calcitonin-gene-related peptide could be antagonized by coadministrating substance P. In contrast to substance P, calcitonin-gene-related peptide failed to induce anagen when released from subcutaneous implants. This might reflect a differential functional assignment of the neuropeptides calcitonin-gene-related peptide and substance P in hair growth control, and invites the use of neuropeptide receptor agonists and antagonists as novel pharmacologic tools for therapeutic hair growth manipulation.