SNC80 specific down-regulation of the human δ-opioid receptor (hDOR) truncated at Gly338

δ-opioid receptor down-regulation, reduced receptor level on the cell surface, is thought to contribute to loss of opioid receptor activation after chronic agonist treatment. It has been shown that δ-opioid receptor down-regulation mediated by a limited number of agonists is dependent on the carboxyl terminal tail. However, it is uncertain whether the mechanism mediating down-regulation of δ-opioid receptor is identical for all agonists. We examined down-regulation of full length and truncated hDOR after chronic treatment with structurally distinct δ-opioid agonists. CHO cells expressing epitope tagged hDOR were incubated with SNC80, DPDPE, (-)TAN67 or deltorphin II(100 nM, 24 hr) and cell membrane receptor levels were determined by saturation binding with [^^3 H]naltrindole. All δ-agonists mediated down-regulation of full length hDOR. Truncation of carboxyl terminal tail of hDOR abolished down-regulation mediated by DPDPE, (-)TAN67 and deltorphin II. However, SNC80 still mediated significant down-regulation of the truncated hDOR. These findings suggest that SNC80-mediated down-regulation involves receptor domains in addition to the carboxyl terminal tail whereas DPDPE-, (-)TAN67- and deltorphin II-mediated down-regulation is solely dependent on the carboxyl terminal tail. (Supported by NIDA and ADCRC grants.)