Highlights
- •Experimental thalamic hemorrhage induced bilateral mechanical allodynia in rats.
- •Central poststroke pain (CPSP) rats exhibited reduced epoxyeicosatrienoic acid (EET), steroidogenic acute regulatory (StAR) protein, allopregnanolone (AP), and δ-subunit-containing gamma-aminobutyric acid A receptor (δGABAAR) levels along the lesion site.
- •14,15-EET attenuated mechanical allodynia by enhancing StAR-AP-δGABAAR signaling.
- •14,15-EET showed greater efficacy in the secondary prevention for CPSP than gabapentin.
- •Epoxyeicosatrienoic acids attenuated CPSP by reserving thalamic inhibition through AP-δGABAAR signaling.
Abstract
Central poststroke pain (CPSP) is a neuropathic pain syndrome arising after a lesion
of the central nervous system owing to cerebrovascular insult. Impaired daily activities
and reduced quality of life in people suffering from CPSP justify the need for improved
treatment. The detailed mechanism of CPSP is not well understood, but central disinhibition
has been suggested. Recent reports indicated that epoxyeicosatrienoic acids (EETs),
the cytochrome P450 metabolites of arachidonic acid, promoted neuronal survival after
stroke, displayed antinociception in peripheral inflammatory pain, and reduced neuronal
excitability in seizure model. Here, we tested the hypothesis that 14,15-EET may attenuate
CPSP by suppressing thalamic disinhibition through neurosteroids−δ-subunit-containing
gamma-aminobutyric acid A receptors (δGABAAR) signaling. In this study, we used a rat model of thalamic hemorrhagic stroke to
induce CPSP. Pain behavioral tests revealed that CPSP rats exhibited mechanical allodynia,
starting at day 7 postlesion and lasting at least 4 weeks. Analysis of the perithalamic
lesion tissue from the brain of CPSP rats demonstrated a decrease of 14,15-EET content,
steroidogenic acute regulatory protein expression, and allopregnanolone (AP) production.
This was accompanied by reduced δGABAAR expression in the medial thalamus at 4 weeks postlesion. Intrathalamic injection
of exogenous 14,15-EET into the ventral posterior lateral nucleus attenuated mechanical
allodynia, induced a marked increase in the abundance of the steroidogenic acute regulatory
protein and AP along the lesion site and a concomitant increase in δGABAAR expression in the medial thalamus under CPSP condition. However, this antinociceptive
effect could be eliminated by the 5α-reductase inhibitor finasteride or dutasteride
or GABAAR antagonist bicuculline. Moreover, compared with the current first-line drug gabapentin
for central neuropathic pain, an early treatment of EET showed greater efficacy in
the secondary prevention of CPSP. Taken together, this study provided a proof of concept
that EETs may have anti-CPSP effect by reserving normal thalamic inhibition through
AP-δGABAAR signaling.
Perspective
Agents targeting EETs may serve as potential therapeutic options for stroke, the use
of which at the initial period could not only block further nerve damage but also
prevent the occurrence of CPSP.
Key words
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Article info
Publication history
Published online: November 27, 2018
Accepted:
November 13,
2018
Received in revised form:
November 5,
2018
Received:
June 4,
2018
Footnotes
Supported by grants from the National Natural Science Foundation of China (Grant No. 81600965).
The authors have no conflicts of interest to declare.
Identification
Copyright
© 2018 by the American Pain Society
