Simvastatin attenuates formalin-induced nociceptive behaviors by inhibiting microglial RhoA and p38 MAPK activation.
UNLABELLED
Several recent studies have revealed that statins exert anti-inflammatory effects in addition to their lipid-lowering property in vivo and in vitro. Recently, statins were shown to alleviate pain associated trauma in a neuropathic pain model. The aim of the present study was to investigate the underlying mechanisms of analgesia caused by the lipophilic statin simvastatin in an animal model of formalin-induced pain in the rat. Intrathecal pretreatment with simvastatin significantly attenuated the second phase of the acute nociceptive response to formalin injection, and daily administration of simvastatin for 7 days inhibited the long-term mechanical hyperalgesia caused by formalin injection. Spinal microglial activation (detected by Iba-1 and CD11 b immunohistochemistry and Western blot), and phosphorylated-p38 mitogen-activated protein kinase (detected by immunohistochemistry and Western blot) were significantly inhibited by simvastatin treatment at day 7 after formalin injection. In addition, peripheral formalin injection induced a significant increase in microglial RhoA activation (detected by membrane RhoA translocation ratio using Western blot) in the spinal cord. The spinal RhoA activation in microglia was reversed by simvastatin treatment. These findings suggest that simvastatin attenuates formalin-induced nociceptive behaviors, at least in part, by inhibiting microglial RhoA and p38 mitogen-activated protein kinase activation.


PERSPECTIVE
Our novel findings indicated that simvastatin attenuated formalin-induced nociceptive responses by inhibiting microglial RhoA and p38 mitogen-activated protein kinase activation. Inactivation of RhoA-p38 signaling pathway may be a pharmacologic target for treating microglia-directed central nervous system inflammation and chronic pain conditions.
['Chen|Xin-Yi|XY|', 'Li|Kai|K|', 'Light|Alan R|AR|', 'Fu|Kai-Yuan|KY|']
D000818:Animals D001522:Behavior, Animal D005557:Formaldehyde D006930:Hyperalgesia D008297:Male D017628:Microglia D059225:Nociception D010147:Pain Measurement D051381:Rats D017207:Rats, Sprague-Dawley D015398:Signal Transduction D019821:Simvastatin D013116:Spinal Cord D048051:p38 Mitogen-Activated Protein Kinases D020742:rhoA GTP-Binding Protein
RhoA statins microglia p38 mitogen-activated protein kinase Formalin pain model