Calmodulin (CaM) is a principal multifunctional mediator of Ca2+ signaling in cells. It is reported that morphine increases CaM contents in mouse brain. However, the precise mechanism of CaM induction by morphine is unknown. We investigated the changes of CaM by opioid receptor stimulation in mRNA and protein levels. Expression of CaM was increased in dose- and time-dependent manners by morphine with RT-PCR assay in PC12 cells, and naloxone inhibited the effect of morphine. The expression was also increased with DAMGO (μ-opioid agonist), but not by DPDPE (δ) and U50488 (κ). Northern blot analysis revealed that the CaMIII gene was responsive to morphine or DAMGO. CaM protein increased by DAMGO were distributed in both soluble and membranous fractions in the cells. Taken together, the data suggest that morphine induces the expression of CaMIII gene through μ-opioid receptor stimulation.