Sortilin gates neurotensin and BDNF signaling to control peripheral neuropathic pain

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Sortilin gates neurotensin and BDNF signaling to control peripheral neuropathic pain. / Richner, Mette; Pallesen, Lone T; Ulrichsen, Maj; Poulsen, Ebbe T; Holm, Thomas H; Login, Hande; Castonguay, Annie; Lorenzo, Louis-Etienne; Gonçalves, Nádia P; Andersen, Olav M; Lykke-Hartmann, Karin; Enghild, Jan J; Rønn, Lars C B; Malik, Ibrahim J; De Koninck, Yves; Bjerrum, Ole J; Vægter, Christian B; Nykjær, Anders.

In: Science Advances, Vol. 5, No. 6, eaav9946, 19.06.2019.

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@article{81baa09b5c544b8291e26a5fde210696,
title = "Sortilin gates neurotensin and BDNF signaling to control peripheral neuropathic pain",
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.",
keywords = "ANION GRADIENT, BRAIN, IDENTIFICATION, INTERNALIZATION, MAINTENANCE, MESSENGER-RNA, NERVE INJURY, PROTEIN, RECEPTOR, SPINAL-CORD",
author = "Mette Richner and Pallesen, {Lone T} and Maj Ulrichsen and Poulsen, {Ebbe T} and Holm, {Thomas H} and Hande Login and Annie Castonguay and Louis-Etienne Lorenzo and Gon{\cc}alves, {N{\'a}dia P} and Andersen, {Olav M} and Karin Lykke-Hartmann and Enghild, {Jan J} and R{\o}nn, {Lars C B} and Malik, {Ibrahim J} and {De Koninck}, Yves and Bjerrum, {Ole J} and V{\ae}gter, {Christian B} and Anders Nykj{\ae}r",
year = "2019",
month = "6",
day = "19",
doi = "10.1126/sciadv.aav9946",
language = "English",
volume = "5",
journal = "Science Advances",
issn = "2375-2548",
publisher = "AMER ASSOC ADVANCEMENT SCIENCE",
number = "6",

}

RIS

TY - JOUR

T1 - Sortilin gates neurotensin and BDNF signaling to control peripheral neuropathic pain

AU - Richner, Mette

AU - Pallesen, Lone T

AU - Ulrichsen, Maj

AU - Poulsen, Ebbe T

AU - Holm, Thomas H

AU - Login, Hande

AU - Castonguay, Annie

AU - Lorenzo, Louis-Etienne

AU - Gonçalves, Nádia P

AU - Andersen, Olav M

AU - Lykke-Hartmann, Karin

AU - Enghild, Jan J

AU - Rønn, Lars C B

AU - Malik, Ibrahim J

AU - De Koninck, Yves

AU - Bjerrum, Ole J

AU - Vægter, Christian B

AU - Nykjær, Anders

PY - 2019/6/19

Y1 - 2019/6/19

N2 - 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.

AB - 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.

KW - ANION GRADIENT

KW - BRAIN

KW - IDENTIFICATION

KW - INTERNALIZATION

KW - MAINTENANCE

KW - MESSENGER-RNA

KW - NERVE INJURY

KW - PROTEIN

KW - RECEPTOR

KW - SPINAL-CORD

U2 - 10.1126/sciadv.aav9946

DO - 10.1126/sciadv.aav9946

M3 - Journal article

VL - 5

JO - Science Advances

JF - Science Advances

SN - 2375-2548

IS - 6

M1 - eaav9946

ER -