We examined the contribution of the human delta-opioid receptor carboxyl terminal tail to (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80)- and cyclic[D-Pen(2),D-Pen(5)]enkephalin (DPDPE)-mediated receptor down-regulation. Both SNC80 and DPDPE mediated down-regulation of an epitope tagged human delta-opioid receptor. Truncation of the human delta-opioid receptor after Gly(338) blocked DPDPE-mediated down-regulation. However, SNC80 mediated significant down-regulation of the truncated receptor. These findings suggest that SNC80-mediated down-regulation involves receptor domains in addition to the carboxyl terminal tail.