The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent pain

The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase known for its oncogenic potential that is involved in the development of the peripheral and central nervous system. ALK receptor ligands ALKAL1 and ALKAL2 were recently found to promote neuronal differentiation and survival. Here, we...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of clinical investigation 2022-06, Vol.132 (12), p.1-16
Main Authors: Defaye, Manon, Iftinca, Mircea C, Gadotti, Vinicius M, Basso, Lilian, Abdullah, Nasser S, Cuménal, Mélissa, Agosti, Francina, Hassan, Ahmed, Flynn, Robyn, Martin, Jérémy, Soubeyre, Vanessa, Poulen, Gaetan, Lonjon, Nicolas, Vachiery-Lahaye, Florence, Bauchet, Luc, Mery, Pierre Francois, Bourinet, Emmanuel, Zamponi, Gerald W, Altier, Christophe
Format: Article
Language:English
Subjects:
Axonogenesis
Biomedical research
Blood-brain barrier
Capsaicin receptors
Central nervous system
Dorsal horn
Dorsal root ganglia
Excitability
Genes
Hyperalgesia
Inflammation
Kinases
Ligands
Lymphoma
Nervous system
Nociceptors
Non-small cell lung carcinoma
Pain
Pain perception
Phosphorylation
Protein-tyrosine kinase receptors
Proteins
Sensory neurons
Small cell lung carcinoma
Spinal cord
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase known for its oncogenic potential that is involved in the development of the peripheral and central nervous system. ALK receptor ligands ALKAL1 and ALKAL2 were recently found to promote neuronal differentiation and survival. Here, we show that inflammation or injury enhanced ALKAL2 expression in a subset of TRPV1+ sensory neurons. Notably, ALKAL2 was particularly enriched in both mouse and human peptidergic nociceptors, yet weakly expressed in nonpeptidergic, large-diameter myelinated neurons or in the brain. Using a coculture expression system, we found that nociceptors exposed to ALKAL2 exhibited heightened excitability and neurite outgrowth. Intraplantar CFA or intrathecal infusion of recombinant ALKAL2 led to ALK phosphorylation in the lumbar dorsal horn of the spinal cord. Finally, depletion of ALKAL2 in dorsal root ganglia or blocking ALK with clinically available compounds crizotinib or lorlatinib reversed thermal hyperalgesia and mechanical allodynia induced by inflammation or nerve injury, respectively. Overall, our work uncovers the ALKAL2/ALK signaling axis as a central regulator of nociceptor-induced sensitization. We propose that clinically approved ALK inhibitors used for non-small cell lung cancer and neuroblastomas could be repurposed to treat persistent pain conditions.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI54317