Calcitonin gene-related peptide (CGRP) is a potent vasodilator and widely distributed neuropeptide that may participate in the injury response of peripheral nerve. We examined evidence for the presence of CGRP immunoreactivity (IR) and its activity in experimental neuromas of Sprague-Dawley rats created by sectioning the midsciatic nerve with resection of 2-3 cm of its distal portion and branches. CGRP activity was evaluated by measuring local blood flow in neuromas using hydrogen polarography and laser-Doppler flowmetry. At all time points studied after nerve section (24 h, 48 h, 7 days, 14 days) there was a rise in local blood flow in the neuroma stumps. At 48 h the hyperemia was maximum but was reversed by topical application of human CGRP(8--37), a specific CGRP-receptor antagonist. CGRP presence was evaluated by immunohistochemistry and radioimmunoassay (RIA). At 24 and 48 h, CGRP IR was intense and distributed in a globular and diffuse pattern apparently not confined to discrete axonlike profiles. At 7 and 14 days, CGRP IR remained prominent and was associated with disorganized axonlike profiles, sometimes directed in a circumferential pattern around the outside of the neuroma. RIA confirmed rises in CGRP content at 24 and 48 h that accompanied the changes in local blood flow and altered distribution of CGRP IR. CGRP accumulates in a time-related fashion within experimental neuromas, where it induces among other possible actions prominent local vasodilatation. CGRP may be important in the regenerative milieu of injured nerves.