TRPC3/6 Channels Mediate Mechanical Pain Hypersensitivity via Enhancement of Nociceptor Excitability and of Spinal Synaptic Transmission.
TRPC3
TRPC6
mechanical pain hypersensitivity
nociceptor
synaptic potentiation
Journal
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
ISSN: 2198-3844
Titre abrégé: Adv Sci (Weinh)
Pays: Germany
ID NLM: 101664569
Informations de publication
Date de publication:
28 Sep 2024
28 Sep 2024
Historique:
revised:
11
09
2024
received:
23
04
2024
medline:
28
9
2024
pubmed:
28
9
2024
entrez:
28
9
2024
Statut:
aheadofprint
Résumé
Patients with tissue inflammation or injury often experience aberrant mechanical pain hypersensitivity, one of leading symptoms in clinic. Despite this, the molecular mechanisms underlying mechanical distortion are poorly understood. Canonical transient receptor potential (TRPC) channels confer sensitivity to mechanical stimulation. TRPC3 and TRPC6 proteins, coassembling as heterotetrameric channels, are highly expressed in sensory neurons. However, how these channels mediate mechanical pain hypersensitivity has remained elusive. It is shown that in mice and human, TRPC3 and TRPC6 are upregulated in DRG and spinal dorsal horn under pathological states. Double knockout of TRPC3/6 blunts mechanical pain hypersensitivity, largely by decreasing nociceptor hyperexcitability and spinal synaptic potentiation via presynaptic mechanism. In corroboration with this, nociceptor-specific ablation of TRPC3/6 produces comparable pain relief. Mechanistic analysis reveals that upon peripheral inflammation, TRPC3/6 in primary sensory neurons get recruited via released bradykinin acting on B1/B2 receptors, facilitating BDNF secretion from spinal nociceptor terminals, which in turn potentiates synaptic transmission through TRPC3/6 and eventually results in mechanical pain hypersensitivity. Antagonizing TRPC3/6 in DRG relieves mechanical pain hypersensitivity in mice and nociceptor hyperexcitability in human. Thus, TRPC3/6 in nociceptors is crucially involved in pain plasticity and constitutes a promising therapeutic target against mechanical pain hypersensitivity with minor side effects.
Identifiants
pubmed: 39340833
doi: 10.1002/advs.202404342
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2404342Subventions
Organisme : STI2030-Major Projects
ID : 2021ZD0203100(2021ZD0203104)
Organisme : STI2030-Major Projects
ID : 2021ZD0203200(2021ZD0203205)
Organisme : Natural Science Foundation of China
ID : 82330036
Organisme : Natural Science Foundation of China
ID : 32071002
Organisme : Natural Science Foundation of China
ID : 82171212
Organisme : Natural Science Foundation of China
ID : 82371225
Organisme : Natural Science Foundation of China
ID : 82221001
Organisme : Natural Science Foundation of China
ID : 82101293
Organisme : Natural Science Foundation of China
ID : 82201368
Organisme : Natural Science Foundation of China
ID : 82201370
Organisme : Innovation Team Accredited by Shaanxi Science and Technology
ID : 2022TD-49
Organisme : Intramural Research Program of the NIH
ID : Z01-ES-101684
Organisme : Joint Founding Project of Innovation Research Institute, Xijing Hospital
ID : (LHJJ24JH08)
Informations de copyright
© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.
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