We examined the distribution of nerve fibers containing neurofilament protein (NFP), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP) and neuropeptide Y (NPY) in the periodontal ligament (PDL) of the rat first molar. In addition, we observed changes in the distribution of these nerve fibers in the PDL during experimental tooth movement induced by insertion of a separating elastic. In normal animals, both NFP- and CGRP-containing nerve fibers were observed in the apical part of the PDL, smaller numbers being found in the cervical part in normal rats. They terminated as free nerve endings in the apical part; no specialized endings were observed. VIP- and NPY-containing nerve fibers were associated with blood vessels near the alveolar bone in the apical part of the PDL of normal animals. Three days after tooth movement, the number of NFP- and CGRP-containing nerve fibers increased in both stretched and compressed parts of the PDL, and returned to normal levels after 14 days. Immediately after tooth movement, VIP-containing nerve fibers disappeared in the stretched part, and returned to the normal level after 14 days. VIP-containing nerve fibers were always observed during tooth movement in the compressed part of the PDL. NPY-containing nerve fibers disappeared immediately after tooth movement in the stretched part and returned to the normal level after 3 days. NPY-containing nerve fibers were not observed 1 day after insertion of the elastic in the compressed part and were the same as in the normal controls after 14 days. These results suggest that NFP-, CGRP-, VIP- and NPY-containing nerve fibers in the PDL play important roles in the modulation of pain, tissue remodeling and blood flow regulation during tooth movement.