Retention of supraspinal delta-like analgesia and loss of morphine tolerance in δ opioid receptor knockout mice

Gene targeting was used to delete exon 2 of mouse DOR-1, which encodes the delta opioid receptor. Essentially all 3H-[D-Pen(2),D-Pen(5)]enkephalin (H-3-DPDPE) and 3H-[D-Ala(2),D-Glu(4)]deltorphin (H-3-deltorphin-2) binding is absent from mutant mice, demonstrating that DOR-1 encodes both delta(1) and delta(2) receptor subtypes. Homozygous mutant mice display markedly reduced spinal 6 analgesia, but peptide 6 agonists retain supraspinal analgesic potency that is only partially antagonized by naltrindole. Retained DPDPE analgesia is also demonstrated upon formalin testing, while the nonpeptide 6 agonist BW373U69 exhibits enhanced activity in DOR-l mutant mice. Together, these findings suggest the existence of a second delta-like analgesic system. Finally, DOR-1 mutant mice do not develop analgesic tolerance to morphine, genetically demonstrating a central role for DOR-1 in this process.