Dental innervation and CGRP in adult p75-deficient mice

Adult dental tissues have unusual neurotrophin biology. Pulpal fibroblasts express nerve growth factor (NGF) and the low-affinity p75 neurotrophin receptor, their sensory nerve fibers express p75 and trk A, and pulpal sympathetic fibers lack p75. Following tooth injury, there is increased pulpal NGF, sprouting of sensory nerve endings, and increased immunoreactivity for the sensory neuropeptide calcitonin gene-related peptide (CGRP). In the present study, we have analyzed tooth structure and innervation of pulp and periodontal ligament in young (6-8 weeks, 3 months) and older (5-12 months) adult mice carrying a null mutation in the p75 gene and compared the results with those of age-matched wild-type controls. Our hypotheses were that tooth structure would be abnormal and that pulpal innervation would be greatly reduced because it consists primarily of nociceptive fibers that have been found to be severely depleted in skin of p75(-/-) mice. Tissues were fixed, X-rayed for gross dental morphology, decalcified, and analyzed for immunoreactivity for CGRP and for a general nerve marker, protein gene product 9.5. Radiographs showed worn-down molar crowns in p75-deficient mice. Light microscopy confirmed the accelerated molar wear and showed intense CGRP immunoreactivity in pulp nerve endings of mutant mice, compared with a gradual decrease in CGRP intensity in controls during normal aging. The CGRP intensity in 5-12-month-old pairs of mice was threefold greater in the mutants (P < 0.03), and in younger mice the mutant always had more CGRP than its matched control. The innervation of molar ligament in all p75-deficient mice was similar to that of controls except there was nerve sprouting near bone loss in mutants. The incisors of mutant mice did not have unusual wear and their pulpal CGRP immunoreactivity remained normal, but their periodontal ligament had fewer thin branched nerve endings at all ages. Thus, most innervation of teeth and their supporting tissues developed normally, and the only neural changes in p75(-/-) mutant mice were the reduction of incisor ligament sensory receptors and increased molar CGRP. Sensory nerves in teeth gradually lose neuropeptide intensity during aging, but that did not happen in the mutant mice, suggesting that the accelerated molar wear stimulated persistent high levels of CGRP.