Osthole, a herbal compound, alleviates nucleus pulposus-evoked nociceptive responses through the suppression of overexpression of acid-sensing ion channel 3 (ASIC3) in rat dorsal root ganglion.
BACKGROUND
Osthole (Ost), a natural coumarin derivative, has been shown to inhibit many pro-inflammatory mediators and block voltage-gated Na+ channels. During inflammation, acidosis is an important pain inducer which activates nociceptors by gating depolarizing cationic channels, such as acid-sensing ion channel 3 (ASIC3). The aim of this study was to examine the effects of Ost on nucleus pulposus-evoked nociceptive responses and ASIC3 over-expression in the rat dorsal root ganglion, and to investigate the possible mechanism.


METHODS
Radicular pain was generated with application of nucleus pulposus (NP) to nerve root. Mechanical allodynia was evaluated using von Frey filaments with logarithmically incremental rigidity to calculate the 50% probability thresholds for mechanical paw withdrawal. ASIC3 protein expression in dorsal root ganglions (DRGs) was assessed with Western blot and immunohistochemistry. Membrane potential (MP) shift of DRG neurons induced by ASIC3-sensitive acid (pH6.5) was determined by DiBAC(4) (3) fluorescence intensity (F.I.).


RESULTS
The NP-evoked mechanical hyperalgesia model showed allodynia for 3 weeks, and ASIC3 expression was up-regulated in DRG neurons, reaching peak on Day 7. Epidural administration of Ost induced a remarkable and prolonged antinociceptive effect, accompanied by an inhibition of over-expressed ASIC3 protein and of abnormal shift of MP. Amiloride (Ami), an antagonist of ASIC3, strengthened the antinociceptive effect of Ost.


CONCLUSIONS
Up-regulation of ASIC3 expression may be associated with NP-evoked mechanical hyperalgesia. A single epidural injection of Ost decreased ASIC3 expression in DGR neurons and the pain in the NP-evoked mechanical hyperalgesia model. Osthole may be of great benefit for preventing chronic pain status often seen in lumbar disc herniation (LDH).
Department of Anesthesiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Qiu-Lan
QL
He
Yuling
Y
Chen
Jian
J
Qin
Sui-Lin
SL
Mo
Ming
M
Wei
Jin-Jun
JJ
Zhang
Mei-Na
MN
Li
Xue-Nong
XN
Zou
Shu-Feng
SF
Zhou
Xiao-Wu
XW
Chen
Lai-Bao
LB
Sun
D062565:Acid Sensing Ion Channels; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005455:Fluorescent Antibody Technique; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D006930:Hyperalgesia / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D007403:Intervertebral Disc / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D059225:Nociception / Q000187:drug effects*; D010146:Pain / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D017288:Pain Threshold / Q000187:drug effects; D008517:Phytotherapy; D028321:Plant Preparations / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000378:metabolism*
C568269:ASIC3 protein, rat; D062565:Acid Sensing Ion Channels; D000700:Analgesics; D003374:Coumarins; D009419:Nerve Tissue Proteins; D028321:Plant Preparations; D015222:Sodium Channels; C046627:osthol