Calcitonin gene-related peptide (CGRP) increases insulin-like growth factor-I (IGF-I) production in fetal rat osteoblasts in vitro, suggesting that stimulation of sensory neurons might increase IGF-I production, thereby preventing apoptosis. We examined whether stimulation of sensory neurons by capsaicin might reduce reperfusion-induced hepatic apoptosis by increasing IGF-I production. Administration of capsaicin increased tissue levels of IGF-I and IGF-I mRNA in various organs in wild-type (WT) mice, but not in CGRP-knock-out (CGRP-/-) mice. Administration of CGRP increased tissue levels of IGF-I and IGF-I mRNA in both WT and CGRP-/- mice. Increases in hepatic tissue levels of TNF, serum levels of transaminases, hepatic apoptosis and hepatic tissue levels of caspase-3 after hepatic ischemia/reperfusion (I/R) were more marked in CGRP-/- mice than in WT mice. Hepatic IGF-I levels were increased in WT mice after reperfusion, while they were not changed in CGRP-/- mice. Although administration of capsaicin enhanced increases in IGF-I levels and reduced reperfusion-induced events in WT mice, it had no effect in CGRP-/- mice. Administration of CGRP and IGF-I reduced reperfusion-induced effects in both strains of mice. These observations suggested that capsaicin-induced sensory neuron activation, which leads to release of CGRP, might increase IGF-I production, thereby reducing reperfusion-induced liver injury by reducing apoptosis.