Anti-hyperalgesic effect of CaMKII inhibitor is associated with downregulation of phosphorylated CREB in rat spinal cord

Purpose Calcium/calmodulin-dependent protein kinase (CaMK) II and its downstream effector cyclic adenosine monophosphate (cAMP) responsive element binding protein (CREB) may be involved in the development of neuropathic pain. The aim of this study was to examine the effect of the CaMKII inhibitor AIP on the association of CaMKII and CREB in a partial sciatic nerve ligation neuropathic pain model in rats. Methods Male Sprague-Dawley rats were randomly divided into six groups: Sham operation; partial sciatic nerve ligation (SNL); AIP administration prior to or after SNL; and normal saline (NS) administration prior to or after SNL. NS or 10 mu mol/L AIP (10 mu l) were injected intrathecally in the NS group and AIP group, respectively, 20 min before or 4 days after nerve injury. The mechanical withdrawal threshold of the hindpaw was measured before and after SNL. In another cohort treated as above, the lumbar spinal cord was removed on post-surgery days 1, 3, and 7 to detect the expression of phosphorylated CaMKII (pCaMKII) and phosphorylated CREB (pCREB), by in situ immunostaining and western blot, respectively. Results AIP significantly suppressed tactile allodynia in the SNL rats, and its effects lasted for 3 days when given prior to nerve injury. In contrast, it had a transitory effect when given after nerve injury. AIP decreased the expression of pCaMKII and pCREB and its effect was sustained for up to 3 days after the experiments. Conclusion Intrathecal injection of a CaMKII inhibitor attenuated neuropathic pain. This benefit may have been due to the downmodulation of its downstream effector pCREB.