期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 128, 期 9, 页码 3757-3768出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI120913
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资金
- Knut and Alice Wallenberg Foundation
- Swedish Medical Research Council
- Karolinska Institutet
- Novo Nordisk Foundation
- European Research Council (ERC Advanced Grants)
- Swedish Brain Foundation
- European Commission's 7th Framework Programme PAINCAGE integrated grant
Pain signals are transmitted by multisynaptic glutamatergic pathways. Their first synapse between primary nociceptors and excitatory spinal interneurons gates the sensory load. In this pathway, glutamate release is orchestrated by Ca2+-sensor proteins, with N-terminal EF-hand Ca2+- binding protein 2 (NECAB2) being particular abundant. However, neither the importance of NECAB2(+) neuronal contingents in dorsal root ganglia (DRGs) and spinal cord nor the function determination by NECAB2 has been defined. A combination of histochemical analyses and single-cell RNA-sequencing showed NECAB2 in small-and medium-sized C-and A delta D-hair low-threshold mechanoreceptors in DRGs, as well as in protein kinase C gamma excitatory spinal interneurons. NECAB2 was downregulated by peripheral nerve injury, leading to the hypothesis that NECAB2 loss of function could limit pain sensation. Indeed, Necab2(-/-) mice reached a pain-free state significantly faster after peripheral inflammation than did WT littermates. Genetic access to transiently activated neurons revealed that a mediodorsal cohort of NECAB2+ neurons mediates inflammatory pain in the mouse spinal dorsal horn. Here, besides dampening excitatory transmission in spinal interneurons, NECAB2 limited pronociceptive brain-derived neurotrophic factor (BDNF) release from sensory afferents. Hoxb8-dependent reinstatement of NECAB2 expression in Necab2-/- mice then demonstrated that spinal and DRG NECAB2 alone could control inflammation-induced sensory hypersensitivity. Overall, we identify NECAB2 as a critical component of pronociceptive pain signaling, whose inactivation offers substantial pain relief.
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