The present study was intended to examine the physiological relevance of peptidergic afferent vasodilative fibers in the regulation of blood flow in the vasa nervorum, with special reference to the axon reflex. The response of nerve blood flow (NBF) in the sciatic nerve to electrical stimulation of saphenous nerve afferents was examined using laser Doppler flowmetry in anesthetized rats whose lumbosacral afferents and efferents had been disconnected from the spinal cord. Repetitive electrical stimulation of unmyelinated fibers in the central cut end of the saphenous nerve produced an increase in NBF in the sciatic nerve ipsilateral to the stimulation, independent of changes in mean arterial blood pressure. This increase was abolished by topical application of a calcitonin gene-related peptide (CGRP) receptor antagonist, hCGRP (8-37). In conclusion, NBF in the sciatic nerve is regulated via an axon reflex-like mechanism by unmyelinated afferent CGRP containing vasodilators with collaterals in the saphenous nerve.