Analytical characterization and comparison of the blood–brain barrier permeability of eight opioid peptides

Opioid drugs, including the newly developed peptides, should penetrate the blood–brain barrier (BBB) for pain management activity. Although BBB transport is fragmentarily described for some μ-opioid peptides, a complete and comparative overview is currently lacking. In this study, the BBB transport of eight opioid peptides (EM-1, EM-2, CTAP, CTOP, DAMGO, dermorphin, TAPP and TAPS) is described and compared. In addition, the metabolic stability in plasma and brain was evaluated. The highest influx rate was obtained for dermorphin (Kin = 2.18 μl/(g × min)), followed by smaller rates for EM-1, EM-2 and TAPP (Kin = 1.06–1.14 μl/(g × min)). Negligible influx was observed for DAMGO, CTOP and TAPS (Kin = 0.18–0.40 μl/(g × min)) and no influx for CTAP. Capillary depletion revealed that all peptides reached brain parenchyma for over 75%. Efflux was shown for TAPP (t1/2 = 2.82 min) and to a lesser extent for EM-1, EM-2 and DAMGO (t1/2 = 10.66–21.98 min), while no significant efflux was observed for the other peptides. All peptides were stable in mouse plasma and brain, with generally higher stability in brain, except for EM-1 and EM-2 which showed plasma half-life stabilities of a few minutes only.