Activation of mTOR in the spinal cord is required for pain hypersensitivity induced by chronic constriction injury in mice.
BACKGROUND
The mammalian target of rapamycin (mTOR) is known to regulate cell growth, and it also participates in pain transmission as has been recently verified in inflammatory and neuropathic pain models. The targeting of mTOR represents a new strategy for the control of chronic pain. In the present study, we investigated the effect of mTOR in the expression of PSD95 and NR2B-PSD95 or GluA2-PSD95 interaction ratio in a chronic constriction injury (CCI) mice model.


METHODS
Paw mechanical withdrawal threshold (PMWT) and paw withdrawal thermal latency (PWTL) were respectively used to assess mechanical allodynia and thermal hyperalgesia after CCI operation and intrathecal injection of rapamycin. Western blot and co-immunoprecipitation were used to investigate the effects of rapamycin on the expression of PSD95 and interaction ratio of NR2B-PSD95 or GluA2-PSD95 in the spinal dorsal horn of mice.


RESULTS
Our study demonstrated that the inhibition of spinal mTOR with intrathecal injections of rapamycin (1 μg/5 μL) for days 1-6 after CCI surgery led to an obvious decrease in CCI-induced neuropathic pain. Rapamycin significantly reduced the PMWT of CCI mice, whereas there was no significant effect on PWTL. The active form of the mTOR signaling pathway (p-mTOR, p-4EBP1 and p-p70S6k) at the spinal level remarkably increased in CCI mice, and rapamycin could inhibit this up-regulation. The increased expression of PSD95 and the interaction ratio of GluA2-PSD95 or NR2B-PSD95 could also be inhibited by intrathecal injection of rapamycin.


CONCLUSIONS
These data suggest that the mTOR pathway is activated in the spinal dorsal horn in CCI-induced neuropathic pain, and the intrathecal injection of rapamycin can reduce mechanical allodynia. Our findings indicate that spinal mTOR is an important component of CCI-induced neuropathic pain, and mTOR may be a potential target for chronic pain therapy.
Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical Department of Nanjing University, Nanjing 210008, Jiangsu, People's Republic of China. Electronic address: genine@126.com.
Wei
W
Zhang
Xiao-Feng
XF
Sun
Jin-Hua
JH
Bo
Juan
J
Zhang
Xiao-Jie
XJ
Liu
Liu-Ping
LP
Wu
Zheng-Liang
ZL
Ma
Xiao-Ping
XP
Gu
D000818:Animals; D001522:Behavior, Animal; D002908:Chronic Disease; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017288:Pain Threshold / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D013117:Spinal Cord Compression / Q000378:metabolism / Q000503:physiopathology*; D013119:Spinal Cord Injuries / Q000378:metabolism / Q000503:physiopathology*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
Neuropathic pain; Rapamycin; mTOR