Acid solution is a suitable medium for introducing QX-314 into nociceptors through TRPV1 channels to produce sensory-specific analgesic effects.
BACKGROUND
Previous studies have demonstrated that QX-314, an intracellular sodium channel blocker, can enter into nociceptors through capsaicin-activated TRPV1 or permeation of the membrane by chemical enhancers to produce a sensory-selective blockade. However, the obvious side effects of these combinations limit the application of QX-314. A new strategy for targeting delivery of QX-314 into nociceptors needs further investigation. The aim of this study is to test whether acidic QX-314, when dissolves in acidic solution directly, can enter into nociceptors through acid-activated TRPV1 and block sodium channels from the intracellular side to produce a sensory-specific analgesic effect.


RESULTS
Acidic solution or noradrenaline was injected intraplantarly to induce acute pain behavior in mice. A chronic constrictive injury model was performed to induce chronic neuropathic pain. A sciatic nerve blockade model was used to evaluate the sensory-specific analgesic effects of acidic QX-314. Thermal and mechanical hyperalgesia were measured by using radiant heat and electronic von Frey filaments test. Spinal Fos protein expression was determined by immunohistochemistry. The expression of p-ERK was detected by western blot assay. Whole cell clamp recording was performed to measure action potentials and total sodium current in rats DRG neurons. We found that pH 5.0 PBS solution induced behavioral hyperalgesia accompanied with the increased expression of spinal Fos protein and p-ERK. Pretreatment with pH 5.0 QX-314, and not pH 7.4 QX-314, alleviated pain behavior, inhibited the increased spinal Fos protein and p-ERK expression induced by pH 5.0 PBS or norepinephrine, blocked sodium currents and abolished the production of action potentials evoked by current injection. The above effects were prevented by TRPV1 channel inhibitor SB366791, but not by ASIC channel inhibitor amiloride. Furthermore, acidic QX-314 employed adjacent to the sciatic nerve selectively blocked the sensory but not the motor functions in naïve and CCI mice.


CONCLUSIONS
Acid solution is a suitable medium for introducing QX-314 into nociceptors through TRPV1 channels to produce a sensory-specific analgesic effect.
Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China.
He
H
Liu
Hong-Xing
HX
Zhang
Hui-Yan
HY
Hou
Xian-Fu
XF
Lu
Jing-Qiu
JQ
Wei
Chun-Guang
CG
Wang
Li-Cai
LC
Zhang
Yin-Ming
YM
Zeng
Yong-Ping
YP
Wu
Jun-Li
JL
Cao
D000143:Acids / Q000737:chemistry*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051379:Mice; D009619:Nociceptors / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D012996:Solutions; D050916:TRPV Cation Channels / Q000378:metabolism*
D000143:Acids; D000700:Analgesics; D026941:Sodium Channel Blockers; D012996:Solutions; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C493922:Trpv1 protein, rat; C012647:QX-314; D008012:Lidocaine