| Abstract: |
The dermorphin-derived peptide (Dmt1)DALDA (H-Dmt-D-Arg-Phe-Lys-NH2), is a highly potent and selective mu-opioid agonist. It displays a pharmacological profile distinct from morphine, as evidenced by lack of cross tolerance to morphine and an insensitivity to MOR-1 antisense probes that reduce morphine analgesia. Moreover, the binding of (3H)(Dmt1)DALDA is insensitive to divalent cations, Na+, and GTP analogs. The following study was undertaken to determine the abilities of (Dmt1)DALDA and morphine to produce analgesia in genetically different strains of mice, including mice lacking exon1 of MOR-1. We show that in contrast to morphine, systemic (Dmt1)DALDA retains its sensitivity in mu-/-animals. In addition, systemic and supraspinally administered (Dmt1)DALDA produce analgesia in morphine-insensitive CXBK mice. In C57BL/6J mice, systemic (Dmt1)DALDA analgesia was 6-fold less potent than in CD-1 mice, whereas systemic morphine analgesia did not differ. In conclusion, (Dmt1)DALDA clearly produces analgesia via a unique mechanism of action and further illustrates the differing sensitivities of various mouse strains to opioid analgesia. |
