The mu opioid receptor MOR-1 is internalized by many mu agonists, but not morphine. To see whether differences in the intracellular carboxy terminus influences internalization, we examined internalization of a splice variant of the mu opioid receptor, MOR-1C, in the lateral septum of the mouse in vivo. Following intracerebroventricular (i.c.v.) saline treatment, MOR-1C-like immunoreactivity (LI) within neurons in naive mice was found predominantly in clusters close to the plasma membrane. Following either intracerebroventricular [d-Ala2, MePhe4,Gly(ol)5]enkephalin (DAMGO) or morphine, MOR-1C-LI clustered into endosomes in the cytoplasm. This effect was suppressed by prior administration of the opioid antagonist naloxone. In contrast, only DAMGO, and not morphine, internalized MOR-1-LI. These results illustrate differences in internalization between two MOR-1 variants that have alternative splicing at the COOH terminus.