It is well known that genotypic differences can account for the subject-specific responses to opiate administration. In this regard, the basal activity of the endogenous system (either at the receptor or ligand level) can modulate the effects of exogenous agonists as morphine and vice versa. The μ opioid receptor from zebrafish, dre-oprm1, binds endogenous peptides and morphine with similar affinities. Morphine administration during development altered the expression of the endogenous opioid propeptides proenkephalins and proopiomelanocortin. Treatment with opioid peptides (Met-enkephalin [Met-ENK], Met-enkephalin-Gly-Tyr [MEGY] and β-endorphin [β-END]) modulated dre-oprm1 expression during development. Knocking down the dre-oprm1 gene significantly modified the mRNA expression of the penk and pomc genes, thus indicating that oprm1 is involved in shaping penk and pomc expression. In addition, the absence of a functional oprm1 clearly disrupted the embryonic development, since proliferation was disorganized in the central nervous system of oprm1-morphant embryos: mitotic cells were found widespread through the optic tectum and were not restricted to the proliferative areas of the mid- and hindbrain. Transferase-mediated dUTP nick-end labeling (TUNEL) staining revealed that the number of apoptotic cells in the central nervous system (CNS) of morphants was clearly increased at 24-h postfertilization. These findings clarify the role of the endogenous opioid system in CNS development. Our results will also help unravel the complex feedback loops that modulate opioid activity and that may be involved in establishing a coordinated expression of both receptors and endogenous ligands. Further knowledge of the complex interactions between the opioid system and analgesic drugs will provide insights that may be relevant for analgesic therapy.