Conjugation of a brain-penetrant peptide with neurotensin provides antinociceptive properties
Michel Demeule, … , Jean-Paul Castaigne, Philippe Sarret
Michel Demeule, … , Jean-Paul Castaigne, Philippe Sarret
Published February 17, 2014
Citation Information: J Clin Invest. 2014;124(3):1199-1213. https://doi.org/10.1172/JCI70647.
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Technical Advance Neuroscience

Conjugation of a brain-penetrant peptide with neurotensin provides antinociceptive properties

Abstract

Neurotensin (NT) has emerged as an important modulator of nociceptive transmission and exerts its biological effects through interactions with 2 distinct GPCRs, NTS1 and NTS2. NT provides strong analgesia when administered directly into the brain; however, the blood-brain barrier (BBB) is a major obstacle for effective delivery of potential analgesics to the brain. To overcome this challenge, we synthesized chemical conjugates that are transported across the BBB via receptor-mediated transcytosis using the brain-penetrant peptide Angiopep-2 (An2), which targets LDL receptor–related protein-1 (LRP1). Using in situ brain perfusion in mice, we found that the compound ANG2002, a conjugate of An2 and NT, was transported at least 10 times more efficiently across the BBB than native NT. In vitro, ANG2002 bound NTS1 and NTS2 receptors and maintained NT-associated biological activity. In rats, i.v. ANG2002 induced a dose-dependent analgesia in the formalin model of persistent pain. At a dose of 0.05 mg/kg, ANG2002 effectively reversed pain behaviors induced by the development of neuropathic and bone cancer pain in animal models. The analgesic properties of ANG2002 demonstrated in this study suggest that this compound is effective for clinical management of persistent and chronic pain and establish the benefits of this technology for the development of neurotherapeutics.

Authors

Michel Demeule, Nicolas Beaudet, Anthony Régina, Élie Besserer-Offroy, Alexandre Murza, Pascal Tétreault, Karine Belleville, Christian Ché, Alain Larocque, Carine Thiot, Richard Béliveau, Jean-Michel Longpré, Éric Marsault, Richard Leduc, Jean E. Lachowicz, Steven L. Gonias, Jean-Paul Castaigne, Philippe Sarret

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Figure 5

Effect of NT receptor inactivation on ANG2002-induced analgesia.

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Effect of NT receptor inactivation on ANG2002-induced analgesia. (A) Inf...
(A) Influence of the NT receptor antagonist SR142948A on NT- and ANG2002-induced antinociceptive responses. MPE was calculated 60 minutes after i.t. injection. In the presence of 10 μg/kg SR142948A, antinociceptive responses to NT (20 μg/kg) and ANG2002 (50 μg/kg) were significantly reduced. No change in tail-flick latencies was seen after administration of SR142948A alone. ***P < 0.001 versus saline vehicle; ###P < 0.01 versus no SR142948A; 1-way ANOVA followed by Bonferroni post-test. (B and C) WT, NTS1-deficient (B), and NTS2-deficient (C) C57BL/6 mice submitted to the tail-immersion test after i.v injection of ANG2002 (5 mg/kg). In both NTS1-deficient and NTS2-deficient mice, ANG2002 conserved its analgesic properties. *P < 0.05, **P < 0.01, ***P < 0.001 versus vehicle-treated WT, 2-way ANOVA followed by Bonferroni post-test.