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      A new painkiller nanomedicine to bypass the blood-brain barrier and the use of morphine

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          A novel painkiller nanomedicine triggers the specific delivery of enkephalin neuropeptide into inflamed tissues.


          The clinical use of endogenous neuropeptides has historically been limited due to pharmacokinetic issues, including plasma stability and blood-brain barrier permeability. In this study, we show that the rapidly metabolized Leu-enkephalin (LENK) neuropeptide may become pharmacologically efficient owing to a simple conjugation with the lipid squalene (SQ). The corresponding LENK-SQ bioconjugates were synthesized using different chemical linkers in order to modulate the LENK release after their formulation into nanoparticles. This new SQ-based nanoformulation prevented rapid plasma degradation of LENK and conferred on the released neuropeptide a notable antihyperalgesic effect that lasted longer than after treatment with morphine in a rat model of inflammation (Hargreaves test). The biodistribution study as well as the use of brain-permeant and -impermeant opioid receptor antagonists indicated that LENK-SQ NPs act through peripherally located opioid receptors. This study represents a novel nanomedicine approach, allowing the specific delivery of LENK neuropeptide into inflamed tissues for pain control.

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          Most cited references 40

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          Ethical guidelines for investigations of experimental pain in conscious animals.

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            A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia.

            A method to measure cutaneous hyperalgesia to thermal stimulation in unrestrained animals is described. The testing paradigm uses an automated detection of the behavioral end-point; repeated testing does not contribute to the development of the observed hyperalgesia. Carrageenan-induced inflammation resulted in significantly shorter paw withdrawal latencies as compared to saline-treated paws and these latency changes corresponded to a decreased thermal nociceptive threshold. Both the thermal method and the Randall-Selitto mechanical method detected dose-related hyperalgesia and its blockade by either morphine or indomethacin. However, the thermal method showed greater bioassay sensitivity and allowed for the measurement of other behavioral parameters in addition to the nociceptive threshold.
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              Ethical guidelines for investigations of experimental pain in conscious animals


                Author and article information

                Sci Adv
                Sci Adv
                Science Advances
                American Association for the Advancement of Science
                February 2019
                13 February 2019
                : 5
                : 2
                [1 ]Institut Galien Paris-Sud, UMR8612, Univ. Paris-Sud, Université Paris-Saclay, Châtenay-Malabry 92290, France.
                [2 ]Centre de Psychiatrie et Neurosciences, INSERM UMR 894, Université Paris Descartes, 75014 Paris, France.
                [3 ]Laboratoire de Neuropharmacologie, INSERM UMRS 1178, Univ. Paris-Sud, Université Paris-Saclay, Châtenay-Malabry 92290, France.
                Author notes
                [* ]Corresponding author. Email: patrick.couvreur@
                Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                Funded by: doi, European Research Council;
                Award ID: 249835
                Funded by: RBUCE-UP;
                Award ID: 00001002483/78
                Research Article
                Research Articles
                SciAdv r-articles
                Health and Medicine
                Applied Sciences and Engineering
                Health and Medicine
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                Eunice Ann Alesin


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