Opioid peptide interactions with lipid bilayer membranes

The interaction of the δ-opioid receptor selective peptides, cyclic [d-Pen², d-Pen⁵]-enkephalin [DPDPE] and its acyclic analog, DPDPE(SH)₂, with neutral phospholipid bilayer membranes was examined by permeability and calorimetry measurements. The permeabilities were accomplished by entrapping either peptide inside of unilamellar liposomes (composed of a mixture of a molar ratio 65:25:10 phosphatidylcholine/prosphatidylethanolamine/cholesterol) then monitoring the peptide efflux through the bilayer. The initial permeability of DFDPE (first 12 h) averaged over four experiments was (0.91 ± 0.47) · 10^-12 cm s^-1. In contrast the average permeability of the acyclic DPDPE(SH)₂ was (4.26 ± 0.23) · 10^-12 cm s^-1. The effect of these peptides on the phase transition, T_m, of 1,2-dipalmitoylphosphatidylcholine (DPPC) bilayers was examined by high sensitivity differential scanning calorimetry. The T_m, the calorimetric enthalpy, and the van 't Hoff enthalpy of DPPC were not significantly altered by the presence of DPDPE, whereas the calorimetric data for DPPC with DPDPE(SH)₂ showed a small, yet significant, increase (0.2°C) in the T_m with a 30% decrease in the cooperative unit. Both the permeability and calorimetry data reveal a stronger peptide-membrane interaction in the case of the more flexible acyclic peptide.