The experimental investigations on the pathogenesis of
remifentanil-induced
hyperalgesia (RIH) have been primarily conducted, but the effective treatment of RIH remains unclear. Recent reports highlight the necessity of
ionotropic glutamate receptors in oxidative damage in spinal nociceptive transduction.
Artesunate, the 1st-line anti-
malaria drug, has been identified to be valid in removing
superoxide in several pathological conditions. This study evaluated whether
artesunate inhibits RIH via regulating
metabotropic glutamate receptor 5 (mGluR5) and mitochondrial
antioxidant enzyme peroxiredoxin-3 in rats.
Artesunate was injected intrathecally 10 min before
intravenous infusion of
remifentanil (1 μg·kg-1·min-1 for 60 min) in rats. The antinociception of
artesunate was verified by assessment of paw withdrawal mechanical threshold and paw withdrawal thermal latency. Spinal mGluR5 expression and peroxiredoxin-3 hyperacetylation were examined. Also, both the mGluR5 agonist
DHPG and antagonist MPEP were utilized to explore the involvement of mGluR5 in the anti-hyperalgesic property of
artesunate. Here, we found that
artesunate (10 μg and 100 μg but not 1 μg) prevented RIH in a dose-dependent manner.
Artesunate reduced
remifentanil-related spinal over-expression of mGluR5 gene and
protein, and hyperacetylation of peroxiredoxin-3. Intrathecal application of MPEP (10 nmol and 100 nmol but not 1 nmol) inhibited behavioral RIH and peroxiredoxin-3 acetylation. Moreover,
hyperalgesia and peroxiredoxin-3 hyperacetylation were attenuated after the combination of
artesunate (1 μg) and MPEP (1 nmol). Additionally,
artesunate treatment reversed
acute pain and peroxiredoxin-3 hyperacetylation following spinal exposure to
DHPG. In conclusion,
intrathecal injection of
artesunate impairs RIH by down-regulating spinal mGluR5 expression and peroxiredoxin-3 hyperacetylation-mediated oxidative stress in rats.