Sortilin gates neurotensin and BDNF signaling to control peripheral neuropathic pain

Mette Richner; Lone T Pallesen; Maj Ulrichsen; Ebbe T Poulsen; Thomas H Holm; Hande Login; Annie Castonguay; Louis-Etienne Lorenzo; Nádia P Gonçalves; Olav M Andersen; Karin Lykke-Hartmann; Jan J Enghild; Lars C B Rønn; Ibrahim J Malik; Yves De Koninck; Ole J Bjerrum; Christian B Vægter; Anders Nykjær

doi:10.1126/sciadv.aav9946

Sortilin gates neurotensin and BDNF signaling to control peripheral neuropathic pain

Mette Richner, Lone T Pallesen, Maj Ulrichsen, Ebbe T Poulsen, Thomas H Holm, Hande Login, Annie Castonguay, Louis-Etienne Lorenzo, Nádia P Gonçalves, Olav M Andersen, Karin Lykke-Hartmann, Jan J Enghild, Lars C B Rønn, Ibrahim J Malik, Yves De Koninck, Ole J Bjerrum, Christian B Vægter, Anders Nykjær

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

41 Citations (Scopus)

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.

Original language	English
Article number	eaav9946
Journal	Science Advances
Volume	5
Issue	6
Number of pages	13
ISSN	2375-2548
DOIs	https://doi.org/10.1126/sciadv.aav9946
Publication status	Published - 19 Jun 2019

Keywords

ANION GRADIENT
BRAIN
IDENTIFICATION
INTERNALIZATION
MAINTENANCE
MESSENGER-RNA
NERVE INJURY
PROTEIN
RECEPTOR
SPINAL-CORD

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Richner, M., Pallesen, L. T., Ulrichsen, M., Poulsen, E. T., Holm, T. H., Login, H., Castonguay, A., Lorenzo, L.-E., Gonçalves, N. P., Andersen, O. M., Lykke-Hartmann, K., Enghild, J. J., Rønn, L. C. B., Malik, I. J., De Koninck, Y., Bjerrum, O. J., Vægter, C. B., & Nykjær, A. (2019). Sortilin gates neurotensin and BDNF signaling to control peripheral neuropathic pain. Science Advances, 5(6), Article eaav9946. https://doi.org/10.1126/sciadv.aav9946

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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{\c c}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 = jun,

day = "19",

doi = "10.1126/sciadv.aav9946",

language = "English",

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Richner, M , Pallesen, LT, Ulrichsen, M, Poulsen, ET, Holm, TH, Login, H, Castonguay, A, Lorenzo, L-E, Gonçalves, NP, Andersen, OM , Lykke-Hartmann, K , Enghild, JJ, Rønn, LCB, Malik, IJ, De Koninck, Y, Bjerrum, OJ, Vægter, CB & Nykjær, A 2019, 'Sortilin gates neurotensin and BDNF signaling to control peripheral neuropathic pain', Science Advances, vol. 5, no. 6, eaav9946. https://doi.org/10.1126/sciadv.aav9946

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

C2 - 31223654

SN - 2375-2548

VL - 5

JO - Science Advances

JF - Science Advances

IS - 6

M1 - eaav9946

ER -

Sortilin gates neurotensin and BDNF signaling to control peripheral neuropathic pain

Abstract

Keywords

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