Involvement of inhibition of RhoA/Rho kinase signaling in simvastatin-induced amelioration of neuropathic pain.
Small molecular G-protein plays a key role in several diseases. This study was designed to reveal the role of RhoA signaling in the pathophysiology of neuropathic pain in mice. Partial sciatic nerve injury caused thermal hyperalgesia, mechanical allodynia, and increased plasma membrane translocation of RhoA in the lumber spinal cord. GFAP-immunoreactivity (ir), Iba-1-ir, and Rho kinase 2 (ROCK2-ir) was also increased in the ipsilateral spinal dorsal horn of nerve-ligated mice. Moreover, partial nerve ligation increased the expression of phosphorylated myristoylated alanine-rich protein kinase C substrate (MARCKS)-ir in the ipsilateral spinal dorsal horn. Daily intrathecal administration of simvastatin, beginning 3days before nerve injury, completely blocked all these changes in nerve-ligated mice. Pharmacological inhibition of ROCK also attenuated the increased expression of GFAP-ir and phosphorylated MARCKS-ir. Together, it is suggested that astrogliosis initiated by the activation of RhoA/ROCK signaling results in MARCKS phosphorylation in nerve terminals, which leads to hyperalgesia in neuropathic pain. Furthermore, simvastatin exerts antihyperalgesic and antiallodynic effects through the inhibition of spinal RhoA activation.
['Ohsawa|Masahiro|M|', 'Ishikura|Kei-Ichiro|K|', 'Mutoh|Junpei|J|', 'Hisa|Hiroaki|H|']
D000700:Analgesics D000818:Animals D001253:Astrocytes D002135:Calcium-Binding Proteins D004195:Disease Models, Animal D005904:Glial Fibrillary Acidic Protein D005911:Gliosis D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors D006930:Hyperalgesia D047908:Intracellular Signaling Peptides and Proteins D008159:Lumbar Vertebrae D008297:Male D008565:Membrane Proteins D008813:Mice, Inbred ICR D008840:Microfilament Proteins D017628:Microglia D000076250:Myristoylated Alanine-Rich C Kinase Substrate D009437:Neuralgia D047428:Protein Kinase Inhibitors D012584:Sciatic Nerve D019821:Simvastatin D013116:Spinal Cord D020741:rho GTP-Binding Proteins D054460:rho-Associated Kinases D020742:rhoA GTP-Binding Protein
RhoA neuropathic pain simvastatin Rho kinase (ROCK) astrocyte myristoylated alanine-rich protein kinase C substrate (MARCKS)