Calcitonin gene-related peptide (CGRP) increases the production of insulin-like growth factor-I (IGF-I) in the mouse brain. IGF-I exerts beneficial effects on the cognitive function by increasing synaptic transmission and by inducing angiogenesis and neurogenesis in the hippocampus. In the current study, we examined whether stimulation of sensory neurons by capsaicin improved the cognitive function by increasing the production of IGF-I in the hippocampus using wild-type (WT) and CGRP-knockout (CGRP-/-) mice. Significant increases of the hippocampal tissue levels of CGRP, IGF-I, and IGF-I messenger RNA (mRNA) were observed after capsaicin administration in WT mice (P < 0.01) but not in CGRP-/- mice. Increase in the expression of c-fos was also observed in the spinal dorsal horn, the parabrachial nuclei, and the hippocampus after capsaicin administration in WT mice but not in CGRP-/- mice. Significant enhancement of angiogenesis and neurogenesis was observed in the dentate gyrus of the hippocampus after capsaicin administration in WT mice (P < 0.01) but not in CGRP-/- mice. Although capsaicin administration improved spatial learning in WT mice, no such effect was observed in CGRP-/- mice. Capsaicin-induced improvement of the spatial learning was reversed by administration of an anti-IGF-I antibody and by that of a CGRP receptor antagonist CGRP (8-37) in WT mice. The administration of IGF-I improved the spatial learning in both WT and CGRP-/- mice. These observations strongly suggest that the stimulation of sensory neurons by capsaicin might increase IGF-I production via increasing the hippocampal tissue CGRP levels, and it may thereby promote angiogenesis and neurogenesis to produce improvement of the cognitive function in mice.