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Sci Adv. 2019 Jun 19;5(6):eaav9946. doi: 10.1126/sciadv.aav9946. eCollection 2019 Jun.

Sortilin gates neurotensin and BDNF signaling to control peripheral neuropathic pain.

Author information

1
The Lundbeck Foundation Research Center MIND, Department of Biomedicine, Aarhus University, Denmark.
2
Danish Research Institute of Translational Neuroscience (DANDRITE)-Nordic EMBL Partnership for Molecular Medicine, Department of Biomedicine, Aarhus University, Denmark.
3
Department of Molecular Biology and Genetics, Aarhus University, Denmark.
4
CERVO Brain Research Centre, Québec Mental Health Institute, Québec, QC, Canada.
5
Department of Psychiatry and Neuroscience, Université Laval, Québec, QC, Canada.
6
Neurodegeneration Disease Biology Unit, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark.
7
Department of Drug Design and Pharmacology, University of Copenhagen, Denmark.
8
The Danish National Research Foundation Center, PROMEMO, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
9
Department of Neurosurgery, Aarhus University Hospital, Aarhus, Denmark.

Abstract

Neuropathic pain is a major incurable clinical problem resulting from peripheral nerve trauma or disease. A central mechanism is the reduced expression of the potassium chloride cotransporter 2 (KCC2) in dorsal horn neurons induced by brain-derived neurotrophic factor (BDNF), causing neuronal disinhibition within spinal nociceptive pathways. Here, we demonstrate how neurotensin receptor 2 (NTSR2) signaling impairs BDNF-induced spinal KCC2 down-regulation, showing how these two pathways converge to control the abnormal sensory response following peripheral nerve injury. We establish how sortilin regulates this convergence by scavenging neurotensin from binding to NTSR2, thus modulating its inhibitory effect on BDNF-mediated mechanical allodynia. Using sortilin-deficient mice or receptor inhibition by antibodies or a small-molecule antagonist, we lastly demonstrate that we are able to fully block BDNF-induced pain and alleviate injury-induced neuropathic pain, validating sortilin as a clinically relevant target.

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