TRPC3/6 Channels Mediate Mechanical Pain Hypersensitivity via Enhancement of Nociceptor Excitability and of Spinal Synaptic Transmission.

Autor: Sun ZC; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.; Department of Neurosurgery, Xi'an Daxing Hospital, Xi'an, 710016, China., Han WJ; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China., Dou ZW; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China., Lu N; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.; The Assisted Reproduction Center, Northwest Women and Children's Hospital, Xi'an, 710000, China., Wang X; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China., Wang FD; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China., Ma SB; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China., Tian ZC; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China., Xian H; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.; Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China., Liu WN; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China., Liu YY; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China., Wu WB; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China., Chu WG; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China., Guo H; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China., Wang F; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China., Ding H; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China., Liu YY; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China., Tao HR; Department of Orthopedic Surgery, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, 518053, China., Freichel M; Institute of Pharmacology, Heidelberg University, 69120, Heidelberg, Germany., Birnbaumer L; Institute of Biomedical Research (BIOMED), Catholic University of Argentina, Buenos Aires, C1107AVV, Argentina.; Signal Transduction Laboratory, National institute of Environmental Health Sciences, Research Triangle Park, NC, 27709, United States., Li ZZ; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China., Xie RG; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China., Wu SX; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China., Luo C; Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.; Innovation Research Institute, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
Jazyk: angličtina
Zdroj: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2024 Nov; Vol. 11 (44), pp. e2404342. Date of Electronic Publication: 2024 Sep 28.
DOI: 10.1002/advs.202404342
Abstrakt: 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.
(© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)
Databáze: MEDLINE
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