Mevalonate sensitizes the nociceptive transmission in the mouse spinal cord

Isoprenylation is crucial for the biological activation of small molecular G proteins. Activation of Rho/Rho kinase (ROCK) signaling has been reported to be involved in the initiation and maintenance of hyperalgesia caused by nerve injury and inflammation. The present study was then undertaken to examine whether the protein isoprenylation could affect thermal nociceptive threshold in the mouse spinal cord. Intrathecal administration of mevalonate (0.05-5.0 μmol) dose-dependently decreased the paw-withdrawal latencies for the thermal stimulation, indicating that mevalonate induces thermal hyperalgesia. Intrathecal pretreatment with a geranylgeranyl transferase I inhibitor GGTI-2133 (0.001-1.0 nmol) or a ROCK inhibitor Y27632 (0.001-1.0 nmol) completely blocked the mevalonate-induced thermal hyperalgesia. On the other hand, mevalonate-induced thermal hyperalgesia was only slightly attenuated by a farnesyl transferase inhibitor FTI-277 (0.01-1.0 nmol). Intrathecal injection of mevalonate increased the amount of geranylgeranylated RhoA in the spinal cord, which was completely blocked by intrathecal pretreatment with GGTI-2133. Intrathecal injection of mevalonate also produced RhoA translocation from cytosol to plasma membrane. This mevalonate-induced RhoA translocation was also blocked by intrathecal pretreatment with GGTI-2133, indicating that the RhoA translocation is triggered by RhoA geranylgeranylation. Moreover, inhibition of mevalonate synthesis by HMG-CoA reductase inhibition with simvastatin attenuated the second phase, but not the first phase, of nociceptive response to formalin. Our present results suggest that mevalonate sensitizes the spinal nociceptive transmission, which is mediated by the activation of ROCK following the RhoA geranylgeranylation.