Regulation of the KATP-JNK gap junction signaling pathway by immunomodulator astragaloside IV attenuates neuropathic pain.
BACKGROUND AND OBJECTIVES
Gap junctions play a pivotal role in contributing to the formation of astroglial networks and in chronic pain. However, the mechanisms underlying the dysfunction of astroglial gap junctions in chronic pain have not been fully elucidated.


METHODS
Chronic constriction injury (CCI) of the sciatic nerve was used to establish rat neuropathic pain model. C6 cells were used to perform experiments in vitro. Von Frey hairs and Hargreave's method were used to determine the withdrawal threshold of rats. Protein expression was detected by immunofluorescence and western blotting.


RESULTS
Astragaloside IV (AST IV) significantly attenuated neuropathic pain and suppressed the excitation of spinal astrocytes in rats with CCI. The antinociceptive effect of AST IV was reversed by the gap junction decoupler carbenoxolone (CBX). AST IV inhibited the high expression of phosphorylated connexin 43 (p-Cx43) and p-c-Jun N-terminal kinase (p-JNK) in spinal cord of rats with CCI. JNK inhibitor alleviated neuropathic pain, which was reversed by CBX. JNK inhibitor decreased the high expression of p-Cx43 in both rats with CCI and tumor necrosis factor-alpha (TNF-α)-treated C6 cells. Additionally, the analgesic effect of AST IV was reversed by the adenosine triphosphate-sensitive potassium (KATP) channel blocker, glibenclamide (Glib). Glib abolished the inhibitory effects of AST IV on p-JNK and p-Cx43 both in vivo and in vitro. KATP channel opener (KCO) mimicked the inhibitory effects of AST IV on p-JNK and p-Cx43 in TNF-α-treated C6 cells.


CONCLUSION
Our results indicate that the sciatic nerve CCI induces the dysfunction of gap junctions in the spinal cord by activating KATP/JNK signaling to contribute to neuropathic pain. AST IV attenuates neuropathic pain via regulating the KATP-JNK gap junction axis.
['Dai|Wen-Ling|WL|', 'Zhang|Li|L|', 'Han|Liu|L|', 'Yang|Xing|X|', 'Hu|Liang|L|', 'Miao|Chen|C|', 'Song|Ling|L|', 'Xiao|Hang|H|', 'Liu|Ji-Hua|JH|0000-0002-5769-9989', 'Liu|Wen-Tao|WT|']
D000255:Adenosine Triphosphate D000818:Animals D017629:Gap Junctions D006930:Hyperalgesia D007155:Immunologic Factors D009437:Neuralgia D051381:Rats D017207:Rats, Sprague-Dawley D012503:Saponins D015398:Signal Transduction D013116:Spinal Cord D014315:Triterpenes
Chronic pain: neuropathic pain basic science of pain pain medicine