Redox-Dependent Modulation of T-Type Ca(2+) Channels in Sensory Neurons Contributes to Acute Anti-Nociceptive Effect of Substance P.
Neuropeptide substance P (SP) is produced and released by a subset of peripheral sensory neurons that respond to tissue damage (nociceptors). SP exerts excitatory effects in the central nervous system, but peripheral SP actions are still poorly understood; therefore, here, we aimed at investigating these peripheral mechanisms.



SP acutely inhibited T-type voltage-gated Ca(2+) channels in nociceptors. The effect was mediated by neurokinin 1 (NK1) receptor-induced stimulation of intracellular release of reactive oxygen species (ROS), as it can be prevented or reversed by the reducing agent dithiothreitol and mimicked by exogenous or endogenous ROS. This redox-mediated T-type Ca(2+) channel inhibition operated through the modulation of CaV3.2 channel sensitivity to ambient zinc, as it can be prevented or reversed by zinc chelation and mimicked by exogenous zinc. Elimination of the zinc-binding site in CaV3.2 rendered the channel insensitive to SP-mediated inhibition. Importantly, peripherally applied SP significantly reduced bradykinin-induced nociception in rats in vivo; knock-down of CaV3.2 significantly reduced this anti-nociceptive effect. This atypical signaling cascade shared the initial steps with the SP-mediated augmentation of M-type K(+) channels described earlier.



Our study established a mechanism underlying the peripheral anti-nociceptive effect of SP whereby this neuropeptide produces ROS-dependent inhibition of pro-algesic T-type Ca(2+) current and concurrent enhancement of anti-algesic M-type K(+) current. These findings will lead to a better understanding of mechanisms of endogenous analgesia.



SP modulates T-type channel activity in nociceptors by a redox-dependent tuning of channel sensitivity to zinc; this novel modulatory pathway contributes to the peripheral anti-nociceptive effect of SP. Antioxid. Redox Signal. 25, 233-251.
1 Department of Pharmacology, Hebei Medical University , Shijiazhuang, P.R. China .
Dongyang
D
Huang
1 Department of Pharmacology, Hebei Medical University , Shijiazhuang, P.R. China .
Sha
S
Huang
1 Department of Pharmacology, Hebei Medical University , Shijiazhuang, P.R. China .|2 School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds , Leeds, United Kingdom .
Haixia
H
Gao
1 Department of Pharmacology, Hebei Medical University , Shijiazhuang, P.R. China .
Yani
Y
Liu
1 Department of Pharmacology, Hebei Medical University , Shijiazhuang, P.R. China .
Jinlong
J
Qi
1 Department of Pharmacology, Hebei Medical University , Shijiazhuang, P.R. China .
Pingping
P
Chen
1 Department of Pharmacology, Hebei Medical University , Shijiazhuang, P.R. China .
Caixue
C
Wang
3 Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM), Faculty of Medicine and Health, University of Leeds , Leeds, United Kingdom .
Jason L
JL
Scragg
2 School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds , Leeds, United Kingdom .
Alexander
A
Vakurov
3 Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM), Faculty of Medicine and Health, University of Leeds , Leeds, United Kingdom .
Chris
C
Peers
1 Department of Pharmacology, Hebei Medical University , Shijiazhuang, P.R. China .
Xiaona
X
Du
1 Department of Pharmacology, Hebei Medical University , Shijiazhuang, P.R. China .
Hailin
H
Zhang
1 Department of Pharmacology, Hebei Medical University , Shijiazhuang, P.R. China .|2 School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds , Leeds, United Kingdom .
Nikita
N
Gamper
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D002460:Cell Line; D005110:Extracellular Space / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008958:Models, Molecular; D010084:Oxidation-Reduction; D011485:Protein Binding; D051381:Rats; D017382:Reactive Oxygen Species; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013373:Substance P / Q000378:metabolism* / Q000494:pharmacology; D015032:Zinc / Q000378:metabolism
D000700:Analgesics; C479952:CACNA1H protein, human; D020747:Calcium Channels, T-Type; D017382:Reactive Oxygen Species; D018040:Receptors, Neurokinin-1; D013373:Substance P; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D015032:Zinc